Elevated serum RAS p21 is an independent prognostic factor in metastatic breast cancer - Banys-Paluchowski, Malgorzata; Fehm, Tanja; Janni, Wolfgang; Aktas, Bahriye; Fasching, Peter; Kasimir-Bauer, Sabine; Milde-Langosch, Karin; Pantel, Klaus; Rack, Brigitte; Riethdorf, Sabine; Solomayer, Erich-Franz; Witzel, Isabell; et al. (BMC Cancer, 2018)
An important component of the RAS signalling pathway, the RAS p21 oncogene, is frequently hyperactivated in breast cancer. Its expression in tumor tissue has been linked to poor clinical outcome. This study was designed to evaluate the clinical relevance of RAS p21 levels in peripheral blood in a large cohort of metastatic breast cancer patients.Two hundred fifty-one patients with metastatic breast cancer were enrolled in this prospective, multicentre, open-label, non-randomized study. Blood samples were collected before start of first-line or later-line treatment. RAS p21 was determined using a sandwich-type ELISA immunoassay. For the determination of the cutoff, blood samples from age-matched healthy controls were analyzed. A value above 452 pg/ml was regarded as elevated (mean + 2 x SD). In the univariate survival analysis, two other cutoffs were considered as well (50th and 75th percentile of patients, i.e. 229 pg/ml and 320 pg/ml). Circulating tumor cells (CTCs) were detected using the CellSearch system.29 of 251 (12%) patients had RAS p21 levels above the cut-off level of 452 pg/ml. Clinical-pathological parameters, such as hormone receptor and HER2 status, line of therapy and CTC status, did not correlate with RAS p21 levels. Elevated RAS p21 was significantly associated with shorter progression-free and overall survival in the univariate analysis (median PFS: 3.9 months [95%-CI: 1.8-6.0] for patients with elevated RAS p21 levels versus 8.5 months [95%-CI: 7.4-9.5] with non-elevated levels [p = 0.01]; median OS: 7.1 months [95%-CI: 0.3-14.2] versus not reached [p = 0.002], respectively). When RAS p21 cutoffs other than 452 pg/ml were considered, elevated RAS p21 was significantly associated with OS but not with PFS. Classical clinical-pathological factors were included into a multivariate Cox regression analysis. In addition, factors previously shown to influence survival in a univariate analysis, such as serum HER2, CAIX and TIMP1, were included as well. In the multivariate analysis, RAS p21, presence of >=5 CTCs per 7.5 ml blood, higher grading and higher line of therapy remained independent predictors of shorter OS.Metastatic breast cancer patients with elevated levels of circulating RAS p21 have significantly worse clinical outcome. Hypothetically, these patients might benefit from therapeutic strategies targeting RAS pathway.Current Controlled Trials ISRCTN59722891 (DETECT); trial registration date: April, 17th 2010; the trial was registered retrospectively.
EVALuna2:56163

Endocrine treatment for breast cancer patients revisited—history, standard of care, and possibilities of improvement - Nabieva, Naiba; Fasching, Peter (Cancers, 2021)
Purpose of review: Due to the findings of current studies and the approval of novel substances for the therapy of hormone-receptor-positive breast cancer patients, the established standards of endocrine treatment are changing. The purpose of this review is to give an overview of the history of endocrine treatment, to clarify its role in the present standard of care, and to discuss the possibilities of improvement. Recent findings: Tamoxifen, aromatase inhibitors, and fulvestrant are the main drugs that have been used for decades in the therapy of hormone-receptor-positive breast cancer patients. However, since a relevant number of women suffer at some point from disease recurrence or progression, several novel substances are being investigated to overcome resistance mechanisms by interfering with certain signaling pathways, such as the PI3K/AKT/mTOR or the CDK4/6 pathways. mTOR and CDK4/6 inhibitors were the first drugs approved for this purpose and many more are in development. Summary: Endocrine treatment is one of the best tolerable cancer therapies available. Continuous investigation serves to improve patients’ outcomes and modernize the current standard of care. Considering the resistance mechanisms and substances analyzed against these, endocrine treatment of hormone-receptor-positive breast cancer is on the brink of a new era.
CRIS-Team Scopus Importer:2021-11-19
Keywords: Abemaciclib; Alpelisib; Aromatase inhibitor; Breast cancer; CDK 4/6 in-hibitor; Compliance; Endocrine treatment; Fulvestrant; MTOR inhibitor; Palbociclib; PI3K inhibitor; Ribociclib; SERD; Tamoxifen

Endocrine Treatment with 2 Years of Tamoxifen versus 2 Years of Exemestane in Postmenopausal Patients with High-Risk Early Breast Cancer and Persisting Circulating Tumor Cells - First Results of the SUCCESS C Endocrine Treatment Sub-Study - Schochter, Fabienne; Rack, Brigitte; Tzschaschel, Marie; Polasik, Arkadius; Andergassen, Ulrich; Trapp, Elisabeth; Alunni-Fabbroni, Marianna; Schneeweiss, Andreas; Muller, Volkmar; Pantel, Klaus; Gade, Joerg; Lorenz, Ralf; et al. (Oncology Research and Treatment, 2018)
Optimal choice and sequence of endocrine treatment following adjuvant chemotherapy in postmenopausal early breast cancer patients are still under discussion and treatment stratification factors are missing.Postmenopausal women with HER2-negative, hormone receptor-positive tumors and persisting circulating tumor cells (CTCs; assessed using the FDA-approved CellSearch® System, Janssen Diagnostics, LLC) after chemotherapy were randomized to 2 years of tamoxifen followed by 3 years of exemestane (tamoxifen-exemestane group, n = 54) or 5 years of exemestane (exemestane-only group, n = 54). CTCs were again assessed after the first 2 years of endocrine treatment. In addition, safety data were compared between the 2 groups.The 2 groups were well-balanced with regard to baseline characteristics. The CTC clearance rate after 2 years was 89% in the exemestane-only group and 97% in the tamoxifen-exemestane group (exact Fisher test, p = 0.36). The safety profile showed good tolerability with few grade 3 or 4 adverse events in both groups.The similar CTC clearance rate after 2 years of endocrine therapy with exemestane or tamoxifen, and the safety profiles obtained may indicate comparable efficacy and tolerability of both endocrine treatment regimens. However, these results have to be confirmed by final survival and safety analysis.
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Endogenous Retroviral-K Envelope Is a Novel Tumor Antigen and Prognostic Indicator of Renal Cell Carcinoma - Weyerer, Veronika; Strissel, Pamela; Stohr, Christine; Eckstein, Markus; Wach, Sven; Taubert, Helge; Brandl, Lisa; Geppert, Carol-Immanuel; Wullich, Bernd; Cynis, Holger; Beckmann, Matthias; Seliger, Barbara; et al. (Frontiers in Oncology, 2021)
Renal cell carcinoma (RCC) is one of the ten most common cancers for men and women with an approximate 75% overall 5-year survival. Sixteen histological tumor subtypes exist and the most common are papillary, chromophobe and clear cell renal cell carcinoma (ccRCC) representing 85% of all RCC. Although epigenetically silenced, endogenous retroviral (ERV) genes become activated in tumors and function to ignite immune responses. Research has intensified to understand ERV protein function and their role as tumor antigens and targets for cancer (immune) therapy. ERV-K env is overexpressed and implicated as a therapeutic target for breast cancer, however studies in RCC are limited. In this investigation a human RCC tissue microarray (TMA) (n=374) predominantly consisting of the most common histological tumor subtypes was hybridized with an ERV-K env antibody and correlated with patient clinical data. TMA results showed the highest amount of ERV-K env protein expression and the strongest significant membrane expression in ccRCC versus other RCC subtypes. High ERV-K env total protein expression of all tumor subtypes significantly correlated with low tumor grading and a longer disease specific survival using multivariable analyses. Cell proliferation and invasion were assayed using the kidney cell lines HEK293 with wild-type p53 and a ccRCC cell line MZ1257RC mutated for p53. Transfecting these cell lines with a codon optimized ERV-K113 env overexpressing CMV vector was performed with or without 5'-Aza-2'-deoxycytidine (Aza) treatment to sustain promoter de-methylation. MZ1257RC showed induction of ERV-K113 expression and significantly increased both proliferation and invasion in the presence or absence of Aza. HEK293 cells demonstrated a restriction of ERV-K113 env expression and invasion with no changes in proliferation in the absence of Aza. However, in the presence of Aza despite increased ERV-K113 env expression, an inhibition of HEK293 proliferation and a further restriction of invasion was found. This study supports ERV-K env as a single prognostic indicator for better survival of RCC, which we propose represents a new tumor antigen. In addition, ERV-K env significantly regulates proliferation and invasion depending on p53 status and Aza treatment.
CRIS-Team WoS Importer:2021-05-14
Keywords: tumor antigen; renal cell carcinoma; patient prognosis; p53; ERV-K; invasion; azacytidine; endogenous retrovirus

Endometrial Dating Method Detects Individual Maturation Sequences During the Secretory Phase - Alfer, Joachim; Fattahi, Amir; Bleisinger, Nathalie; Krieg, JÜrgen; Behrens, Rolf; Dittrich, Ralf; Beckmann, Matthias; Hartmann, Arndt; Classen-Linke, Irmgard; Popovici, Roxana M. (In Vivo, 2020)
BACKGROUND/AIM: This study assessed whether a new immunohistochemical dating method allows precise endometrial dating allowing optimal timing for embryo transfer. PATIENTS AND METHODS: A novel method was used for endometrial dating, with parameters including menstrual cycle days, Noyes histological criteria, along with immunohistochemical expression pattern of estrogen and progesterone receptors and proliferation marker Ki-67. Endometrial maturation was analyzed on days +5 to +10 after ovulation or progesterone administration in 217 biopsies from 151 subfertile patients during the secretory phase. RESULTS: Endometrial maturation varied individually, occurring 1.68±1.67 days late. Comparison of histological maturation with clinical days after ovulation showed a delay of about 2 days. CONCLUSION: Endometrial maturation requires 8 days, rather than the expected 6 days, to reach the histological mid-secretory phase. This is not a delay and is also seen in fertile patients. The new analysis method used is superior to that using Noyes criteria alone and provides a better basis for determining conditions for optimal timing of embryo transfers.
CRIS-Team Scopus Importer:2020-07-17
Keywords: Endometrial dating; endometrial receptivity; estrogen receptor; progesterone receptor; window of implantation

Endometrial delay is found to be part of a normal individual dynamic transformation process - Alfer, Joachim; Popovici, Roxana M.; Fattahi, Amir; Krieg, Juergen; Dittrich, Ralf; Beckmann, Matthias; Hartmann, Arndt; Bleisinger, Nathalie (Archives of Gynecology and Obstetrics, 2021)
Purpose: Limited information is clinically available concerning endometrial receptivity; assessing endometrial transformation status is therefore an urgent topic in assisted reproductive technology. This study aimed to investigate individual endometrial transformation rates during the secretory phase in subfertile patients using personal endometrial transformation analysis. Methods: Monitoring was carried out during the secretory phase to obtain endometrial receptivity profiles. For the investigation, two endometrial biopsies were taken within one menstrual cycle. The extended endometrial dating was based on the Noyes criteria, combined with immunohistochemical analyses of hormone receptors and proliferation marker Ki-67. Biopsies were taken mainly at days ovulation (OV, n = 76)/hormone replacement therapy (HRT, n = 58) + 5 and + 10. Results: The results of the two biopsies were correlated with the clinically expected day of the cycle and showed temporal delays or hypercompensations, diverging from the expected cycle days by 0.5–5 days. In comparison with the first biopsies, the transformation rate in the second biopsies showed compensation, augmented delay, or constant transformation in 48.69, 22.37, and 28.94% of cases for ovulation in natural cycles and 56.89, 25.85, and 17.26% for HRT cycles, respectively. Conclusion: The study revealed an individually dynamic transformation process of the endometrium, with the ability to compensate or enlarge an initial “delay”, which is now identified as a normal individual transformation process during the secretory phase. This information is of great importance for the scientific investigation of dynamic changes in endometrial tissue, as well as for the timing of embryo transfers.
CRIS-Team Scopus Importer:2021-07-02
Keywords: Delay; Endometrium; Maturation; Receptivity

Endometriose – gynäkologische Diagnostik und Therapie: Was sollten Schmerzmediziner*innen wissen? - Burghaus, Stefanie; Beckmann, Matthias (Schmerz, 2021)
Background: Endometriosis is one of the most common diseases in women of reproductive age. Despite characteristic symptoms such as dysmenorrhea, chronic abdominal pain, dysuria, dyschezia and dyspareunia, the average latency until diagnosis is around 10 years. In addition to the individual limitations, the disease also has economic and health policy relevance. The complaints are followed by reductions in working hours, cyclically recurring short-term sick leave or presenteeism with reduced performance. Objective: An overview of the main recommendations of the S2k guideline on the diagnosis and treatment of endometriosis. Material and methods: For the S2k guideline “Diagnostics and therapy of endometriosis”, a systematic literature search was conducted in PubMed and Cochrane according to a defined algorithm and over a period of more than 5 years, from 01.01.2014 to 31.12.2018. For the evaluation, 322 publications, including systematic reviews, meta-analyses and randomized controlled trials were considered and these were assessed by 41 mandate holders and representatives from 25 Association of the Scientific Medical Societies in Germany (AWMF) and non-AWMF professional societies, organizations, associations and working groups of the German Society for Gynecology and Obstetrics (DGGG), as well as two patient target groups. Results: In a structured consensus process, 48 recommendations and 27 statements were formulated, which are presented in extracts in this paper. Discussion: Interdisciplinary cooperation is essential in the treatment of patients with (suspected) endometriosis. This team should include all necessary disciplines in a cross-sectoral network. This is most likely to be achieved in a certified structure.
CRIS-Team Scopus Importer:2021-04-02
Keywords: Classification/endometriosis; Interdisciplinary care team; Laparoscopy; Progestins; Ultrasonography; transvaginal

Endometriosis as a risk factor for ovarian or endometrial cancer - results of a hospital-based case-control study - Burghaus, Stefanie; Haeberle, Lothar; Schrauder, Michael G.; Heusinger, Katharina; Thiel, Falk; Hein, Alexander; Wachter, David; Strehl, Johanna; Hartmann, Arndt; Ekici, Arif Bülent; Renner, Stefan; Beckmann, Matthias; et al. (BMC Cancer, 2015)
No screening programs are available for ovarian or endometrial cancer. One reason for this is the low incidence of the conditions, resulting in low positive predictive values for tests, which are not very specific. One way of addressing this problem might be to use risk factors to define subpopulations with a higher incidence. The aim of this study was to investigate the extent to which a medical history of endometriosis can serve as a risk factor for ovarian or endometrial cancer.In a hospital-based case-control analysis, the cases represented patients with endometrial or ovarian cancer who were participating in studies aimed at assessing the risk for these diseases. The controls were women between the age of 40 and 85 who were invited to take part via a newspaper advertisement. A total of 289 cases and 1016 controls were included. Using logistic regression models, it was tested whether self-reported endometriosis is a predictor of case-control status in addition to age, body mass index (BMI), number of pregnancies and previous oral contraceptive (OC) use.Endometriosis was reported in 2.1 % of the controls (n = 21) and 4.8 % of the cases (n = 14). Endometriosis was a relevant predictor for case-control status in addition to other predictive factors (OR 2.63; 95 % CI, 1.28 to 5.41).This case-control study found that self-reported endometriosis may be a risk factor for endometrial or ovarian cancer in women between 40 and 85 years. There have been very few studies addressing this issue, and incorporating it into a clinical prediction model would require a more precise characterization of the risk factor of endometriosis.
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Endometriosis in women undergoing ovarian tissue transplantation due to premature menopause after gonadotoxic treatment or spontaneous premature ovarian failure - Lotz, Laura; Dietl, Anna; Hoffmann, Inge; Mueller, Anrdreas; Burghaus, Stefanie; Beckmann, Matthias; Dittrich, Ralf (Acta Obstetricia Et Gynecologica Scandinavica, 2022)
Introduction: Cryopreservation of ovarian tissue with subsequent transplantation is an efficient option for restoring fertility in women at risk of premature ovarian failure. The association between infertility and endometriosis is well recognized. Although endometriosis usually ends with the onset of natural or iatrogen menopause due to declining estrogen levels, endometriosis can in rare cases occur after menopause. This study aims to investigate women with premature menopause who were diagnosed with endometriosis during laparoscopy for ovarian tissue transplantation, and to address the questions of how endometriotic lesions after cytotoxic treatment and premature menopause might be explained, whether endometriosis affects pregnancy rates, and whether there is an association between endometriosis and the original cancer. Material and Methods: Seventeen patients who had undergone ovarian tissue transplantation to restore their fertility and who were diagnosed with endometriosis during transplantation were included in this retrospective study. The endometriosis foci were completely removed and ovarian tissue was transplanted into the pelvic peritoneum. Preexisting conditions, use of hormonal preparations, endometriosis stage pain assessment, as well as pregnancy and live birth rate were evaluated. Results: The mean age of the patients was 29.5 ± 6.3 years (range 14–39) at the time of ovarian tissue harvest and 34.6 ± 4.3 years (range 28–40) at transplantation. Prior to transplantation, four patients had taken hormone replacement therapy, four women oral contraceptives and two patients’ tamoxifen. Twelve women had stage I endometriosis and five stage II endometrioses according to the rASRM classification. Four patients reported dysmenorrhea. None of the women complained of general pelvic pain or dyspareunia. The pregnancy rate in the study population was 41.2%, with a live birth rate of 35.3%. The pregnancies occurred in three cases after spontaneous conception, in four women after a natural cycle IVF/ICSI. Conclusions: This study highlights the under-researched association between endometriosis in women entering premature or early menopause either after gonadotoxic treatment or due to primary ovarian insufficiency. As more and more patients seek to have their cryopreserved ovarian tissue transplanted to fulfill their desire to have children, specialists will inevitably encounter women with this condition.
CRIS-Team Scopus Importer:2022-05-20
Keywords: cryopreservation; endometriosis; gonadotoxic; infertility; ovarian tissue; premature ovarian failure; transplantation

Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci - Kar, Siddhartha P.; Adler, Emily; Tyrer, Jonathan; Hazelett, Dennis; Anton-Culver, Hoda; Bandera, Elisa V.; Beckmann, Matthias; Berchuck, Andrew; Bogdanova, Natalia; Brinton, Louise; Butzow, Ralf; Campbell, Ian; et al. (British Journal of Cancer, 2017)
BACKGROUND: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. METHODS: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). RESULTS: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10-5 (including six with P<5 × 10-8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. CONCLUSIONS: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.
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Epigenetic regulation of the putative breast cancer metastasis suppressor gene SCN4B - Hilgers, L.; Hartmann, Arndt; Fasching, Peter; Villwock, S.; Moll, L.; Roger, S.; Knuechel-Clarke, R.; Steib, F.; Dahl, E. D. (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-28

EPIK-B3: A phase III, randomised, double-blind (DB), placebo (PBO)-controlled study of alpelisib (ALP) plus nab-paclitaxel (nabPTX) in advanced triple-negative breast cancer (TNBC) with either PIK3CA mutation or phosphatase and tensin homolog (PTEN) loss without PIK3CA mutation - Sharma, P.; Farooki, A.; Fasching, Peter; Loi, S.; Peterson, K.; Prat, A.; Tripathy, D.; Xu, B.; Yardley, D. A.; Mills, D.; Klauss, G.; Wong, C.; et al. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-10-30

Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk - Amankwah, Ernest K.; Lin, Hui-Yi; Tyrer, Jonathan P.; Lawrenson, Kate; Dennis, Joe; Chornokur, Ganna; Aben, Katja K. H.; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V.; Bean, Yukie T.; et al. (Genetic Epidemiology, 2015)
Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.
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Erlangen, 28th November 2016 241th Opinion of the DGGG: Opinion on the Subject of Zikavirus Infection during Pregnancy, Effects on the Fetuses and Recommendations for Monitoring and Diagnostics - Geipel, Annegret; Enders, Martin; Mylonas, Ioannis; Seelbach-Goebel, Birgit; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2017)
EVALuna2:36136

Erratum: AGO Recommendations for the Surgical Therapy of the Axilla after Neoadjuvant Chemotherapy: 2021 Update (Geburtshilfe Frauenheilkd (2021) 81:10 (1112-1120) DOI: 10.1055/a-1499-8431) - Friedrich, Michael; Kühn, Thorsten; Janni, Wolfgang; Müller, Volkmar; Banys-Paluchowski, Maggie; Kolberg-Liedtke, Cornelia; Jackisch, Christian; Krug, David; Albert, Ute Susann; Bauerfeind, Ingo; Blohmer, Jens; Budach, Wilfried; et al. (Geburtshilfe und Frauenheilkunde, 2021)
In the above article, the name of the co-author was given incorrectly. Correct is: Maggie Banys-Paluchowski
CRIS-Team Scopus Importer:2021-11-19

Erratum: Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers (Nature communications (2021) 12 1 (1078)) - Coignard, Juliette; Lush, Michael; Beesley, Jonathan; O’Mara, Tracy A.; Dennis, Joe; Tyrer, Jonathan P.; Barnes, Daniel R.; McGuffog, Lesley; Leslie, Goska; Bolla, Manjeet K.; Agata, Simona; Ahearn, Thomas; et al. (Nature Communications, 2021)
A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.
CRIS-Team Scopus Importer:2021-06-04

Erratum: Correction to: Fresh and cryopreserved ovarian tissue transplantation for preserving reproductive and endocrine function: a systematic review and individual patient data meta-analysis (Human reproduction update (2022) 28 3 (400-416)) - Khattak, Hajra; Malhas, Rosamund; Craciunas, Laurentiu; Afifi, Yousri; Amorim, Christiani A.; Fishel, Simon; Silber, Sherman; Gook, Debra; Demeestere, Isabelle; Bystrova, Olga; Lisyanskaya, Alla; Manikhas, Georgy; et al. (Human Reproduction Update, 2022)
CRIS-Team Scopus Importer:2022-05-27

Erratum: Publisher Correction: Shared heritability and functional enrichment across six solid cancers (Nature communications (2019) 10 1 (431)) - Jiang, Xia; Finucane, Hilary K.; Schumacher, Fredrick R.; Schmit, Stephanie L.; Tyrer, Jonathan P.; Han, Younghun; Michailidou, Kyriaki; Lesseur, Corina; Kuchenbaecker, Karoline B.; Dennis, Joe; Conti, David V.; Casey, Graham; et al. (Nature Communications, 2019)
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
CRIS-Team Scopus Importer:2019-10-01

Erratum: SNiPER: A novel hypermethylation biomarker panel for liquid biopsy based early breast cancer detection (Oncotarget. (2019) 10 (6494-6508) DOI: 10.18632/oncotarget.27303) - Mijnes, Jolein; Tiedemann, Janina; Eschenbruch, Julian; Gasthaus, Janina; Bringezu, Sarah; Bauerschlag, Dirk; Maass, Nicolai; Arnold, Norbert; Weimer, Jörg; Anzeneder, Tobias; Fasching, Peter; Rübner, Matthias; et al. (Oncotarget, 2020)
TThis article has been corrected: The Grant section information has been updated with the following logos: (Figure Presented).
CRIS-Team Scopus Importer:2020-11-20

Erratum to: The integrative epigenomic-transcriptomic landscape of ER positive breast cancer - Gao, Yang; Jones, Allison; Fasching, Peter; Rübner, Matthias; Beckmann, Matthias; Widschwendter, Martin; Teschendorff, Andrew E. (Clinical Epigenetics, 2016)
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Establishment of the Certification System "Gynaecological Dysplasia" in Germany - Beckmann, Matthias; Quaas, J.; Bischofberger, A.; Kaemmerle, A.; Lux, Michael P.; Wesselmann, S. (Geburtshilfe und Frauenheilkunde, 2014)
Gynaecological cancer centres have been established nationwide in Germany since 2008 according to the certification system of the German Cancer Society (Deutsche Krebsgesellschaft e. V. [DKG]) and the German Society for Gynaecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe e. V. [DGGG]). However, patient access to the certified gynaecological cancer centres is currently only possible through direct referrals. A longitudinal structure with the corresponding long-term documentation of both the high-grade precursors as well as the cancers does not exist as yet. According to the aims of the National Cancer Plan, a corresponding structure for the cancer entity "cervix carcinoma" should be established. The foundations for such a structure are appropriate diagnostic units that are responsible, after nationwide screening, for clarification according to guideline-conform principles. On the basis of the vote of the certification commission for gynaecological cancer centres under the chairmanship of the DKG, the Working Group for Gynaecological Oncology (Arbeitsgemeinschaft Gynäkologische Onkologie e. V. [AGO]), the Committee on Cervical Pathology and Colposcopy (Arbeitsgemeinschaft Zervixpathologie & Kolposkopie [AG-CPC]) and the DGGG the certification system for gynaecological dysplasia has been established. As a general principle, a distinction is made between the certification of a consulting practice for gynaecological dysplasia and a gynaecological dysplasia facility in order to integrate both outpatient and inpatient health-care facilities into the certification system. In analogy to the further catalogue of requirements from the DKG, quantitative and qualitative minimum numbers are demanded. Furthermore, the requirements of the certification process include a summary of patient information, the applied guidelines, continuing and further training, interdisciplinary cooperation in tumour boards, contents or, respectively, procedure descriptions for consulting practices and the trial participations. Central components of the questionnaire are quality indicators that can be used as specific and measurable elements to evaluate the quality of treatment. After successful pilot certification, finalisation of the updated version of the questionnaire and a completed specialist auditor training course for the certification of gynaecological dysplasia, it will be possible to establish a nationwide treatment system for dysplasia within certified structures.
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Estrogen receptor beta rs1271572 polymorphism and invasive ovarian carcinoma risk: Pooled analysis within the ovarian cancer association consortium - Lurie, Galina; Wilkens, Lynne R.; Thompson, Pamela J.; Shvetsov, Yurii B.; Matsuno, Rayna K.; Carney, Michael E.; Palmieri, Rachel T.; Wu, Anna H.; Pike, Malcolm C.; Pearce, Celeste L.; Menon, Usha; Gentry-Maharaj, Aleksandra; et al. (PLoS ONE, 2011)
The association of ovarian carcinoma risk with the polymorphism rs1271572 in the estrogen receptor beta (ESR2) gene was examined in 4946 women with primary invasive ovarian carcinoma and 6582 controls in a pooled analysis of ten case-control studies within the Ovarian Cancer Association Consortium (OCAC). All participants were non-Hispanic white women. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression adjusted for site and age. Women with the TT genotype were at increased risk of ovarian carcinoma compared to carriers of the G allele (OR = 1.10; 95%; CI: 1.01-1.21; p = 0.04); the OR was 1.09 (CI: 0.99-1.20; p = 0.07) after excluding data from the center (Hawaii) that nominated this SNP for OCAC genotyping A stronger association of rs1271572 TT versus GT/GG with risk was observed among women aged ≤50 years versus older women (OR = 1.35; CI: 1.12-1.62; p = 0.002; p for interaction = 0.02) that remained statistically significant after excluding Hawaii data (OR = 1.34; CI: 1.11-1.61; p = 0.009). No heterogeneity of the association was observed by study, menopausal status, gravidity, parity, use of contraceptive or menopausal hormones, tumor histological type, or stage at diagnosis. This pooled analysis suggests that rs1271572 might influence the risk of ovarian cancer, in particular among younger women. © 2011 Lurie et al.
CRIS-Team Scopus Importer:2021-07-19

Europe-side external quality assessment (EQA) of RNA based testing of ER, PR, HER2 and Ki67 in invasive breast cancer - Erber, Ramona; Hartmann, Arndt; Fasching, Peter; Stöhr, Robert; Beckmann, Matthias; Zentgraf, M.; Rübner, Matthias; Hübner, Hanna; Fischer, J.; Guerini Rocco, E.; Viale, G.; Cayre, A.; et al. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-06-26

Evaluating the Effectiveness of Mobile Health in Breast Cancer Care: A Systematic Review - Flaucher, Madeleine; Zakreuskaya, Anastasiya; Nissen, Michael; Mocker, Alexander; Fasching, Peter; Beckmann, Matthias; Eskofier, Björn; Leutheuser, Heike (Oncologist, 2023)

Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study - Lee, Alice W.; Tyrer, Jonathan P.; Doherty, Jennifer A.; Stram, Douglas A.; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Spiewankiewicz, Beata; Myers, Emily J.; Chenevix-Trench, Georgia; Fasching, Peter A.; Beckmann, Matthias; et al. (Gynecologic Oncology, 2015)
Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted.Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations.We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive).Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.
EVALuna2:9278

Evaluation of a Marker Clip System in Sonographically Guided Core Needle Biopsy for Breast Cancer Localization Before and After Neoadjuvant Chemotherapy - Schulz-Wendtland, Rüdiger; Dankerl, P.; Bani, Mayada; Fasching, Peter; Heusinger, K.; Lux, Michael P.; Jud, Sebastian; Rauh, C.; Bayer, C. M.; Schrauder, M. G.; Beckmann, Matthias; Uder, M.; et al. (Geburtshilfe und Frauenheilkunde, 2017)
Introduction The placement of intramammary marker clips has proven to be helpful for tumor localization in patients undergoing neoadjuvant chemotherapy and breast-conserving surgery. The purpose of our study was to investigate the feasibility of using a clip marker system for breast cancer localization and its influence on the imaging assessment of treatment responses after neoadjuvant chemotherapy. Patients and Methods Between March and June 2015, a total of 25 patients (n = 25), with a suspicion of invasive breast cancer with diameters of at least 2 cm (cT2), underwent preoperative sonographically guided core needle biopsy using a single-use breast biopsy system (HistoCore(TM)) and intramammary clip marking using a directly adapted clip system based on the established O-Twist Marker(TM), before their scheduled preoperative neoadjuvant chemotherapy. Localization of the intramammary marker clip was controlled by sonography and digital breast tomosynthesis. Results Sonography detected no dislocation of intrammammary marker clips in 20 of 25 patients (80 %), while digital breast tomosynthesis showed accurate placement without dislocation in 24 patients (96 %) (p < 0.05). There was no evidence of significant clip migration during preoperative follow-up imaging after neoadjuvant chemotherapy. No complication related to the clip marking was noted and there was no difficulty in evaluating the treatment response to neoadjuvant chemotherapy. Among the breast-conserving surgeries performed, no cases were identified in which intraoperative loss of the marker clip had occurred. Conclusion Our study underscores the importance of intramammary marking clip systems before neoadjuvant chemotherapy. Placement of marker clips is advised to facilitate accurate tumor bed localization. With regard to digital breast tomosynthesis, its development continues to improve the quality of diagnostics and the therapy of breast cancer particularly for small breast cancer tumors or in neoadjuvant chemotherapy setting.
EVALuna2:14620

Evaluation of automated techniques for extraction of circulating cell-free DNA for implementation in standardized high-throughput workflows - Lehle, Sarah; Emons, Julius; Hack, Carolin; Heindl, Felix; Hein, Alexander; Preuß, Caroline; Seitz, Katharina; Zahn, Anna; Beckmann, Matthias; Fasching, Peter; Rübner, Matthias; Hübner, Hanna (Scientific Reports, 2023)
Analysis of circulating cell-free DNA (ccfDNA) is a suitable tool for detecting somatic mutations for the purpose of making decisions on treatment, monitoring treatment response, and predicting survival. High-throughput techniques for ccfDNA extraction are essential to implementing ccfDNA testing in the clinical setting. We set out to compare two automated techniques with regard to hands-on time, ccfDNA output and integrity, and circulating mitochondrial DNA (mtDNA). CcfDNA was isolated using the EZ1&2 ccfDNA field test kit (EZ2 kit, QIAGEN) and the Maxwell RSC ccfDNA plasma kit (Maxwell kit, Promega). DNA was extracted from plasma of 30 breast cancer patients enrolled in the iMODE-B (#325_19B; 12.10.2020) study. Real-time PCR, fluorescence-based detection and automated electrophoresis were used to assess ccfDNA concentrations. The ccfDNA yield was significantly higher when extracted with the EZ2 kit. The EZ2 kit enabled the isolation of a higher proportion of short fragments and a lower proportion of long fragments, resulting in lower DNA integrity. Significantly lower mtDNA quantities were detected in the Maxwell eluate than in the EZ2 eluate. Thus, decisions on which extraction method to use should proceed on the basis of the required input for downstream applications, the anticipated fragment size and minimum hands-on time.
CRIS-Team Scopus Importer:2023-01-20

Evaluation of ChatGPT’s Potential in Tailoring Gynecological Cancer Therapies - Krückel, Annika; Brückner, Lena; Psilopatis, Iason; Fasching, Peter; Beckmann, Matthias; Emons, Julius (In Vivo, 2024)
Background/Aim: Demographic change and increasing complexity of therapy decisions lead to a growing burden on the healthcare system, necessitating efforts to simplify and enhance the efficiency of patient care. The present study evaluates ChatGPT’s ability to provide therapy recommendations for gynecological malignancies that are both in line with the local guidelines and individually tailored to the patient. Patients and Methods: Sixteen patients with endometrial, cervical, and ovarian cancer who were treated in the gynecological clinic of the University Hospital Erlangen from January 2022 to August 2023 were included in the analysis. Data collected within clinical routine care were communicated to the chat-based AI model ChatGPT (version 3.5). ChatGPT’s performance generating treatment plans were evaluated using an answer scoring system and descriptive analysis. Results: According to the answer scoring system [range: –1 point (minimum) to 2 points (maximum)], ChatGPT demonstrated a good potential in generating therapy recommendations with an average score of 0.75 points for patients with ovarian cancer, 0.7 points for cervical and 1.5 points for endometrial cancer patients. The most common deductions in points were about incomplete therapy recommendations, whereas contraindicated treatment modalities were rarely suggested. Individual patient characteristics were regularly considered by ChatGPT. ChatGPT reliably indicated aftercare and provided detailed information on preventive measures as well as supportive treatment. Conclusion: ChatGPT is a promising tool for the generation of therapy suggestions for gynecological carcinomas with high flexibility in response to individual patient differences. At the current state, however, ChatGPT is not suitable for replacing expert panels.
CRIS-Team Scopus Importer:2024-07-12
Keywords: Artificial intelligence; cervical cancer; ChatGPT; endometrial cancer; ovarian cancer

Evaluation of endocervical curettage (ECC) in colposcopy for detecting cervical intraepithelial lesions - Behrens, Annika; Dietl, Anna; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Beckmann, Matthias; Mehlhorn, Grit; Koch, Martin C.; Schulmeyer, Carla; Seibold, Anja; Gaß, Paul; et al. (Archives of Gynecology and Obstetrics, 2024)
Purpose: Diagnostic challenges in colposcopy arise especially in women aged 50 or older, with postmenopausal status and transformation zone type 3 (TZ3). Endocervical curettage (ECC) is a valuable tool for diagnosing intracervical lesions. The aim of this retrospective analysis was to evaluate the use of ECC in colposcopy for detecting cervical intraepithelial lesions. Methods: A retrospective study was carried out of colposcopies performed in the certified Dysplasia Unit at Erlangen University Hospital between July 2016 and June 2023. Pap and human papillomavirus (HPV) results were correlated with the histologic findings via ECC, obtained during examinations or surgery. The primary outcome was the rate of accuracy between the colposcopic and histologic findings with regard to cytology, age of patients, and type of transformation zone (TZ). Results: A total of 429 colposcopies in 413 women with histologic samples obtained via ECC were included in the final analysis. In all, 355 women had TZ3. Among patients with TZ3, evidence of high-grade lesions and invasive carcinoma was also found in women with normal or low-grade abnormal cytology. For patients with normal colposcopic findings, cervical intraepithelial neoplasia (CIN) 2 and CIN 3/adenocarcinoma in situ (AIS) were found in 56 patients (16%), and invasive carcinoma was found in four patients (0.1%). Conclusion: This analysis suggests that ECC is a valuable tool in the diagnosis of cervical intraepithelial neoplasia, especially for patients who present with a normal colposcopy of the cervix and vagina but have either recurrent abnormal cytologic findings or high-grade abnormal cytology indicating CIN 2 +.
CRIS-Team Scopus Importer:2024-11-08
Keywords: Cervical cancer; Cervical cancer screening assessment; Cervical intraepithelial neoplasia; Colposcopy; Cytology; Endocervical curettage

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel - Levi, Hagai; Carmi, Shai; Rosset, Saharon; Yerushalmi, Rinat; Zick, Aviad; Yablonski-Peretz, Tamar; Wang, Qin; Bolla, Manjeet K.; Dennis, Joe; Michailidou, Kyriaki; Lush, Michael; Ahearn, Thomas; et al. (Journal of Medical Genetics, 2023)
To date, most BC GWASs have been performed Background Polygenic risk score (PRS), calculated in individuals of European (EUR) ancestry, and based on genome-wide association studies (GWASs), the generalisation of EUR-based PRS to other can improve breast cancer (BC) risk assessment. populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.
CRIS-Team Scopus Importer:2023-09-29
Keywords: Genomics; Polymorphism; Genetic

Evaluation of event-free survival as a surrogate for overall survival in early-stage triple-negative breast cancer following neoadjuvant therapy - Fasching, Peter; Huang, M.; Haiderali, A.; Xue, W.; Pan, W.; Karantza, V.; Yang, F.; Truscott, J.; Xin, Y.; O'Shaughnessy, J. (ANNALS OF ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-12-23

Evaluation of integrated hpv dna as individualized biomarkers for the detection of recurrent cin2/3 during post-treatment surveillance - Hoyer, Heike; Mehlhorn, Grit; Scheungraber, Cornelia; Hagemann, Ingke; Hirchenhain, Christine; Woelber, Linn; Stolte, Claudia; Hampl, Monika; Scherbring, Sarah; Denecke, Agnieszka; Bartels, Janina; Ebert, Andreas D.; et al. (Cancers, 2021)
Purpose: Post-treatment follow-up in women with cervical pre-cancers (CIN3) is mandatory due to relapse in up to 10% of patients. Standard follow-up based on hrHPV-DNA/cytology co-testing has high sensitivity but limited specificity. The aim of our prospective, multicenter, observational study was to test the hypothesis that an individualized viral-cellular-junction test (vcj-PCR) combined with cytology has a lower false positive rate for the prediction of recurrence compared to standard co-testing. Methods: Pre-surgical cervical swabs served for the identification of HPV16/18 DNA integration sites by next-generation-sequencing (NGS). Samples taken at 6, 12 and 24 months post-surgery were evaluated by cytology, hrHPV-DNA and the patients’ individual HPV-integration sites (vcj-PCR on the basis of NGS). Results: Integration sites were detected in 48 of 445 patients (10.8%), 39 of them had valid follow-up data. The false positive rate was 18.2% (95% CI 8.6–34.4%) for standard hrHPV/cytology at six months compared to 12.1% (95% CI 4.8–27.3%) for vcj-PCR/cytology, respectively (McNemar p = 0.50). Six patients developed recurrences (1 CIN2, 5 CIN3) during follow-up. Standard co-testing detected all, whereas vcj-PCR/cytology detected only five patients with recurrences. Data of 269 patients without evidence of HPV16/18 integration were subject to post-hoc analyses. Standard co-testing revealed a false positive rate of 15.7% (95% CI 11.7–20.7%) and predicted ten of fourteen recurrences at six months. Conclusions: Although highly specific on its own vcj-PCR could not detect all recurrent CIN2/3. Possible reasons for this unexpected result may be multifocal lesions, intratumoral heterogeneity with respect to HPV integration and/or incident CIN.
CRIS-Team Scopus Importer:2021-07-09
Keywords: CIN3; HPV DNA integration; Individualized molecular biomarker; Post treatment surveillance; Recurrence

Evaluation of newly adapted clip marker system in ultrasound-guided core needle biopsy for suspicion of breast cancer - Schulz-Wendtland, Rüdiger; Dankerl, Peter; Dilbat, G.; Bani, Mayada; Fasching, Peter; Heusinger, K.; Lux, Michael P.; Löhberg, Christian; Jud, Sebastian; Rauh, Claudia; Bayer, Christian M.; Beckmann, Matthias; et al. (Geburtshilfe und Frauenheilkunde, 2013)
Introduction: A newly adapted clip system for intramammary marking during ultrasound-guided core needle biopsy for suspicion of breast cancer is described and evaluated here. Material and Method: Fifty patients with suspicion of breast cancer (cT2) had ultrasound-guided core needle biopsy using a newly adapted clip marker system (HistoCore™ and O-Twist Marker™). Subsequently, ultrasound follow-up and tomosynthesis scans were done to determine the location of the marker clips. Results: No dislocation of the marker clip was detected on ultrasound in 45 of 50 patients (90%), and 5 patients (10%) had a maximum dislocation of 5 mm along the x-, y- or z-axis. Tomosynthesis scans demonstrated precise placement without dislocation of the clip markers in 48 patients (96%); 2 patients (4%) had a maximum dislocation of 3 mm along the x-, y- or z-axis. Conclusion: The newly developed clip marker system, a combination of a single-use breast biopsy needle and a precise, length-adapted intramammary marker clip, represents a further improvement in oncological therapy. This is of particular importance for patients requiring subsequent neoadjuvant chemotherapy, as in cases with complete tumour remission, there is no target point for preoperative, ultrasound-guided wire marking. © Georg Thieme Verlag KG Stuttgart New York.
CRIS-Team Scopus Importer:2023-03-08
Keywords: biopsy; breast; breast cancer; ultrasound

EVALUATION OF OPTOACOUSTIC IMAGING FOR ANALYSIS OF PLACENTAL VILLOUS VASCULARIZATION - Hübner, Hanna; Knieling, Ferdinand; Faschingbauer, Florian; Rübner, Matthias; Kehl, Sven; Beckmann, Matthias; Rascher, Wolfgang; Hartner, Andrea; Fahlbusch, Fabian (2018)
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Evaluation of pathological complete response as a trial-level surrogate for long-term survival outcomes among triple-negative breast cancer patients receiving neoadjuvant therapy - Huang, M.; Qi, C. Z.; Ramsey, S.; Briggs, A.; Zhao, J.; Haiderali, A.; Karantza, V.; Xie, J.; Gu, C.; Fasching, Peter (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-08-13

Evaluation of Pathologic Complete Response as a Surrogate for Long-Term Survival Outcomes in Triple-Negative Breast Cancer - Huang, Min; O'Shaughnessy, Joyce; Zhao, Jing; Haiderali, Amin; Cortes, Javier; Ramsey, Scott; Briggs, Andrew; Karantza, Vassiliki; Aktan, Gursel; Qi, Cynthia Z.; Gu, Chenyang; Xie, Jipan; et al. (Journal of the National Comprehensive Cancer Network : JNCCN, 2020)
BACKGROUND: Pathologic complete response (pCR) is a common efficacy endpoint in neoadjuvant therapy trials for triple-negative breast cancer (TNBC). Previous studies have shown that pCR is strongly associated with improved long-term survival outcomes, including event-free survival (EFS) and overall survival (OS). However, the trial-level associations between treatment effect on pCR and long-term survival outcomes are not well established. This study sought to evaluate these associations by incorporating more recent clinical trials in TNBC. METHODS: A literature review identified published randomized controlled trials (RCTs) of neoadjuvant therapy for TNBC that reported results for both pCR and EFS/OS. Meta-regression models were performed to evaluate the association of treatment effect on pCR and EFS/OS. Sensitivity analyses were conducted to assess the impact of divergent study designs. RESULTS: Ten comparisons from 8 RCTs (N=2,478 patients) were identified from the literature review. The log (odds ratio) of pCR was a significant predictor of the log (hazard ratio) of EFS (P=.003), with a coefficient of determination of 0.68 (95% CI, 0.41-0.95). There was a weaker association between pCR and OS (P=.18), with a coefficient of determination of 0.24 (95% CI, 0.01-0.77). Consistent results were found in the exploratory analysis and sensitivity analyses. CONCLUSIONS: This is the first study that has shown a trial-level association between pCR and survival outcomes in TNBC. By incorporating the most up-to-date RCTs, this study showed a significant trial-level association between pCR and EFS. A positive association between pCR and OS was also recorded.
CRIS-Team Scopus Importer:2020-08-14

Evaluation of serum epidermal growth factor receptor (EGFR) in correlation to circulating tumor cells in patients with metastatic breast cancer - Banys-Paluchowski, Malgorzata; Witzel, Isabell; Riethdorf, Sabine; Rack, Brigitte; Janni, Wolfgang; Fasching, Peter; Solomayer, Erich-Franz; Aktas, Bahriye; Kasimir-Bauer, Sabine; Pantel, Klaus; Fehm, Tanja; Mueller, Volkmar (Scientific Reports, 2017)
Overexpression of epidermal growth factor receptor in breast cancer is associated with estrogen receptor negativity, higher histological grade and larger tumors. The aim of the present study was to evaluate the clinical significance of serum EGFR (sEGFR) in relation to circulating tumor cells (CTCs) in metastatic breast cancer. 252 patients were enrolled in this prospective multicentre study. Blood was drawn before start of a new line of therapy. sEGFR was determined using a sandwich-type ELISA. CTCs were detected using CellSearch. sEGFR was determined in 48 healthy controls and 252 patients, with no significant differences between the two groups. Clinical-pathological parameters did not correlate with sEGFR, irrespective of the cutoff chosen. Patients with sEGFR levels above the 50th and 75th percentile were more likely to present with <5 CTCs per 7.5 ml blood (p = 0.007; p = 0.003). Patients with sEGFR ≥73 ng/ml had significantly longer overall survival than those with sEGFR <73 ng/ml (19.7 vs. 15.2 months; p = 0.007). In the multivariate analysis, presence of ≥5 CTCs, higher grading and higher line of therapy remained independent predictors of shorter OS, while only higher line of therapy and presence of ≥5 CTCs were independent predictors of shorter PFS.
EVALuna2:36177

Evaluation of soluble carbonic anhydrase IX as predictive marker for efficacy of bevacizumab: A biomarker analysis from the geparquinto phase III neoadjuvant breast cancer trial - Janning, Melanie; Müller, Volkmar; Vettorazzi, Eik; Cubas-Cordova, Miguel; Gensch, Victoria; Ben-Batalla, Isabel; zu Eulenburg, Christine; Schem, Christian; Fasching, Peter; Schnappauf, Benjamin; Karn, Thomas; Fehm, Tanja; et al. (International Journal of Cancer, 2019)
We analyzed the predictive potential of pretreatment soluble carbonic anhydrase IX levels (sCAIX) for the efficacy of bevacizumab in the phase III neoadjuvant GeparQuinto trial. sCAIX was determined by enzyme-linked immunosorbent assay (ELISA). Correlations between sCAIX and pathological complete response (pCR), disease-free and overall survival (DFS, OS) were assessed with logistic and Cox proportional hazard regression models using bootstrapping for robust estimates and internal validation. 1,160 HER2-negative patient sera were analyzed, of whom 577 received bevacizumab. Patients with low pretreatment sCAIX had decreased pCR rates (12.1 vs. 20.1%, p = 0.012) and poorer DFS (adjusted 5-year DFS 71.4 vs. 80.5 months, p = 0.010) compared to patients with high sCAIX when treated with neoadjuvant chemotherapy (NCT). For patients with low sCAIX, pCR rates significantly improved upon addition of bevacizumab to NCT (12.1 vs. 20.4%; p = 0.017), which was not the case in patients with high sCAIX (20.1% for NCT vs. 17.0% for NCT-B, p = 0.913). When analyzing DFS we found that bevacizumab improved 5-year DFS for patients with low sCAIX numerically but not significantly (71.4 vs. 78.5 months; log rank 0.234). In contrast, addition of bevacizumab worsened 5-year DFS for patients with high sCAIX (81 vs. 73.6 months, log-rank 0.025). By assessing sCAIX levels we identified a patient cohort in breast cancer that is potentially undertreated with NCT alone. Bevacizumab improved pCR rates in this group, suggesting sCAIX is a predictive biomarker for bevacizumab with regards to treatment response. Our data also show that bevacizumab is not beneficial in patients with high sCAIX.
CRIS-Team Scopus Importer:2019-05-03
Keywords: bevacizumab; breast cancer; carbonic anhydrase IX; neoadjuvant treatment; predictive biomarker

Evaluation of the MammaTyperVR as a molecular predictor for pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) and outcome in patients with different breast cancer (BC) subtypes - Fasching, Peter; Laible, M.; Weber, K. E.; Wirtz, R. M.; Denkert, C.; Schlombs, K.; Schmatloch, S.; Camara, O.; Lueck, H. J.; Huober, J.; Karn, T.; Van Mackelenbergh, M. T.; et al. (ANNALS OF ONCOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-08

Evaluation of Therapy Management and Patient Compliance in Postmenopausal Patients with Hormone Receptor-positive Breast Cancer Receiving Letrozole Treatment: The EvaluateTM Study - Fasching, Peter; Fehm, T.; Kellner, S.; De Waal, J.; Rezal, M.; Baler, B.; Baake, G.; Kolberg, H. -C; Guggenberger, M.; Warm, N.; Harbeck, N.; Wuerstlein, R.; et al. (Geburtshilfe und Frauenheilkunde, 2014)
Introduction: The EvaluateTM study (Evaluation of therapy management and patient compliance in postmenopausal hormone receptor-positive breast cancer patients receiving letrozole treatment) is a prospective, non-interventional study for the assessment of therapy management and compliance in the routine care of postmenopausal women with invasive hormone receptor-positive breast cancer receiving letrozole. The parameters for inclusion in the study are presented and discussed here. Material and Methods: Between January 2008 and December 2009 a total of 5045 patients in 310 study centers were recruited to the EvaluateTM study. Inclusion criteria were hormone receptor-positive breast cancer and adjuvant treatment or metastasis. 373 patients were excluded from the analysis for various reasons. Results: A total of 4420 patients receiving adjuvant treatment and 252 patients with metastasis receiving palliative treatment were included in the study. For 4181 patients receiving adjuvant treatment, treatment with the aromatase inhibitor letrozole commenced immediately after surgery (upfront). Two hundred patients had initially received tamoxifen and started aromatase inhibitor treatment with letrozole at 1-5 years after diagnosis (switch), und 39 patients only commenced letrozole treatment 5-10 years after diagnosis (extended endocrine therapy). Patient and tumor characteristics were within expected ranges, as were comorbidities and concurrent medication. Conclusion: The data from the EvaluateTM study will offer a good overview of therapy management in the routine care of postmenopausal women with hormone receptor-positive breast cancer. Planned analyses will look at therapy compliance and patient satisfaction with how information is conveyed and the contents of the conveyed informatio
EVALuna2:17459

Evaluation of two different analytical methods for circulating tumor cell detection in peripheral blood of patients with primary breast cancer - Jaeger, B. A. S.; Jueckstock, J.; Andergassen, U.; Salmen, J.; Schochter, F.; Fink, V.; Alunni-Fabbroni, M.; Rezai, M.; Beck, Th.; Beckmann, Matthias; Friese, K.; Friedl, T. W. P.; et al. (BioMed Research International, 2014)
Evidence is accumulating that circulating tumor cells (CTC) out of peripheral blood can serve as prognostic marker not only in metastatic but also in early breast cancer (BC). Various methods are available to detect CTC. Comparisons between the different techniques, however, are rare.We evaluate two different methods for CTC enrichment and detection in primary BC patients: the FDA-approved CellSearch System (CSS; Veridex, Warren, USA) and a manual immunocytochemistry (MICC). The cut-off value for positivity was >=1 CTC.The two different nonoverlapping patient cohorts evaluated with one or the other method were well balanced regarding common clinical parameters. Before adjuvant CHT 21.1% (416 out of 1972) and 20.6% (247 out of 1198) of the patients were CTC-positive, while after CHT 22.5% (359 out of 1598) and 16.6% (177 out of 1066) of the patients were CTC-positive using CSS or MICC, respectively. CTC positivity rate before CHT was thus similar and not significantly different (P = 0.749), while CTC positivity rate immediately after CHT was significantly lower using MICC compared to CSS (P < 0.001).Using CSS or MICC for CTC detection, we found comparable prevalence of CTC before but not after adjuvant CHT.
EVALuna2:17463

Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk - Stevens, K. N.; Garcia-Closas, Montserrat; Fredericksen, Z.; Kosel, M.; Pankratz, V. S.; Hopper, J. L.; Dite, G. S.; Apicella, C.; Southey, M. C.; Schmidt, M. K.; Broeks, A.; Van 'T Veer, L. J.; et al. (British Journal of Cancer, 2011)
Background: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. Methods: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). Results: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10 3), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139).Conclusion: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer. © 2011 Cancer Research UK All rights reserved.
CRIS-Team Scopus Importer:2021-07-19
Keywords: Association study; Genetic susceptibility; Neoplasms

Event-free survival by residual cancer burden with pembrolizumab in early-stage TNBC: exploratory analysis from KEYNOTE-522 - Pusztai, L.; Denkert, C.; O'Shaughnessy, J.; Cortes, J.; Dent, R.; McArthur, H.; Kümmel, S.; Bergh, J.; Park, Y. H.; Hui, R.; Harbeck, N.; Takahashi, M.; et al. (Annals of Oncology, 2024)
Background: KEYNOTE-522 demonstrated statistically significant improvements in pathological complete response (pCR) with neoadjuvant pembrolizumab plus chemotherapy and event-free survival (EFS) with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in patients with high-risk, early-stage triple-negative breast cancer (TNBC). Prior studies have shown the prognostic value of the residual cancer burden (RCB) index to quantify the extent of residual disease after neoadjuvant chemotherapy. In this preplanned exploratory analysis, we assessed RCB distribution and EFS within RCB categories by treatment group. Patients and methods: A total of 1174 patients with stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2 : 1 to pembrolizumab 200 mg or placebo every 3 weeks given with four cycles of paclitaxel + carboplatin, followed by four cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity. Primary endpoints are pCR and EFS. RCB is a prespecified exploratory endpoint. The association between EFS and RCB was assessed using a Cox regression model. Results: Pembrolizumab shifted patients into lower RCB categories across the entire spectrum compared with placebo. There were more patients in the pembrolizumab group with RCB-0 (pCR), and fewer patients in the pembrolizumab group with RCB-1, RCB-2, and RCB-3. The corresponding hazard ratios (95% confidence intervals) for EFS were 0.70 (0.38-1.31), 0.92 (0.39-2.20), 0.52 (0.32-0.82), and 1.24 (0.69-2.23). The most common first EFS events were distant recurrences, with fewer in the pembrolizumab group across all RCB categories. Among patients with RCB-0/1, more than half [21/38 (55.3%)] of all events were central nervous system recurrences, with 13/22 (59.1%) in the pembrolizumab group and 8/16 (50.0%) in the placebo group. Conclusions: Addition of pembrolizumab to chemotherapy resulted in fewer EFS events in the RCB-0, RCB-1, and RCB-2 categories, with the greatest benefit in RCB-2. These findings demonstrate that pembrolizumab not only increased pCR rates, but also improved EFS among most patients who do not have a pCR.
CRIS-Team Scopus Importer:2024-04-12
Keywords: chemotherapy; event-free survival; immunotherapy; pembrolizumab; residual cancer burden; triple-negative breast cancer

Event Report 11th Scientific Symposium of the AGO TraFo - Banys-Paluchowski, Malgorzata; Wunderle, Marius; Fehm, Tanja N.; Arnold, Norbert; Fasching, Peter (Geburtshilfe und Frauenheilkunde, 2019)
CRIS-Team WoS Importer:2020-01-17

Event Report 7th Scientific Symposium of AGO-TraFo - Niederacher, Dieter; Fasching, Peter; Fehm, Tanja N. (Geburtshilfe und Frauenheilkunde, 2016)
EVALuna2:33100

Event Report 8th Scientific Symposium of the AGO-TraFo - Banys-Paluchowski, Malgorzata; Hein, Alexander; Niederacher, Dieter; Fasching, Peter; Fehm, Tanja N. (Geburtshilfe und Frauenheilkunde, 2017)
EVALuna2:36207

EVI1 expression in early-stage breast cancer patients treated with neoadjuvant chemotherapy - Leichsenring, J.; Vladimirova, V.; Solbach, C.; Karn, T.; Ataseven, B.; Sinn, B.; Barinoff, J.; Mueller, V.; Blohmer, J-U.; Schem, C.; Engels, K.; Marme, F.; et al. (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-28

EVI1 expression in early-stage breast cancer patients treated with neoadjuvant chemotherapy - Leichsenring, Jonas; Vladimirova, Valentina; Solbach, Christine; Karn, Thomas; Ataseven, Beyhan; Sinn, Bruno Valentin; Barinoff, Jana; Mueller, Volkmar; Blohmer, Jens-Uwe; Schem, Christian; Engels, Knut; Marme, Frederik; et al. (BMC Cancer, 2022)
Background: Overexpression of the EVI1 (ecotropic viral integration site 1) oncogene has recently been implicated as a prognostic factor in breast cancer (BC), particularly in triple-negative BC (TNBC). In this study we aimed to investigate frequency and clinical relevance of EVI1 expression in newly diagnosed BC treated with neoadjuvant chemotherapy. Methods: EVI1 expression was determined by immunohistochemistry using H-score as a cumulative measurement of protein expression in pretherapeutic biopsies of BC patients treated with anthracycline/taxane based neoadjuvant chemotherapy within the GeparTrio trial. EVI1 was analyzed as a continuous variable and dichotomized into low or high based on median expression. Endpoints were pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Results: Of the 993 tumors analyzed, 882 had available subtype information: 50.8% were HR + /HER2-, 15% HR + /HER2 + , 9.8% HR-/HER2 + , and 24.5% TNBC. Median EVI1 H-score was 112.16 (range 0.5–291.4). High EVI1 expression was significantly associated with smaller tumor size (p = 0.002) but not with BC subtype. Elevated EVI1 levels were not significantly associated with therapy response and survival in the entire cohort or within BC subtypes. However, TNBC patients with high EVI1 showed a trend towards increased pCR rates compared to low group (37.7% vs 27.5%, p = 0.114; odds ratio 1.60 (95%CI 0.90–2.85, p = 0.110) and numerically better DFS (HR = 0.77 [95%CI 0.48–1.23], log-rank p = 0.271) and OS (HR = 0.76 [95% 0.44–1.31], log-rank p = 0.314) without reaching statistical significance. Conclusion: EVI1 was not associated with response to neoadjuvant therapy or patient survival in the overall cohort. Further analyses are needed to verify our findings especially in the pathological work-up of early-stage HER2-negative BC patients. Trial registration: NCT00544765.
CRIS-Team Scopus Importer:2022-10-21
Keywords: Breast cancer; EVI1; Neoadjuvant chemotherapy

Evidence for a shared genetic basis between breast cancer and mammographic density phenotypes - Chen, Hongjie; Douglas, Julie; Gordon, William; Thompson, Deborah; Couch, Fergus; Fasching, Peter; Hall, Per; Hopper, John; Maskarenic, Gertraud; Pollan, Marina; Stone, Jennifer; Tamimi, Rulla; et al. (CANCER RESEARCH, 2018)
CRIS-Team WoS Importer:2019-06-18

Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study - Koebel, M.; Madore, J.; Ramus, S. J.; Clarke, B. A.; Pharoah, P. D. P.; Deen, S.; Bowtell, D. D.; Odunsi, K.; Menon, U.; Morrison, C.; Lele, S.; Bshara, W.; et al. (British Journal of Cancer, 2014)
Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa.Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival.FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94).FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.
EVALuna2:6660

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation - Ghoussaini, Maya; Edwards, Stacey L.; Michailidou, Kyriaki; Nord, Silje; Lari, Richard Cowper-Sal; Desai, Kinjal; Kar, Siddhartha; Hillman, Kristine M.; Kaufmann, Susanne; Glubb, Dylan M.; Beesley, Jonathan; Dennis, Joe; et al. (Nature Communications, 2014)
GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biolog
EVALuna2:9236

Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation - Ghoussaini, Maya; French, Juliet D.; Michailidou, Kyriaki; Nord, Silje; Beesley, Jonathan; Canisus, Sander; Hillman, Kristine M.; Kaufmann, Susanne; Sivakumaran, Haran; Marjaneh, Mandi Moradi; Lee, Jason S.; Dennis, Joe; et al. (American Journal of Human Genetics, 2016)
Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+= 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER-= 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+= 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.
EVALuna2:33316

Examination of the effect of seminal plasma on uterus contraction from two different donor collectives with normozoospermia - Hoffmann, Inge; Lotz, Laura; Beckmann, Matthias; Dittrich, Ralf (2017)
EVALuna2:36131

Expression and Regulation of Retinoic Acid Receptor Responders in the Human Placenta - Hübner, Hanna; Rascher, Wolfgang; Strick, Reiner; Kehl, Sven; Heindl, Felix; Wachter, David; Beckmann, Matthias; Fahlbusch, Fabian B.; Rübner, Matthias; Hartner, Andrea (Reproductive Sciences, 2017)
INTRODUCTION: Retinoic acid (RA) signaling through its receptors (RARA, RARB, RARG, and the retinoic X receptor RXRA) is essential for healthy placental and fetal development. An important group of genes regulated by RA are the RA receptor responders (RARRES1, 2, and 3). We set out to analyze their expression and regulation in healthy and pathologically altered placentas of preeclampsia (PE) and intrauterine growth restriction (IUGR) as well as in trophoblast cell lines. METHODS: We performed immunohistochemical staining on placental sections and analyzed gene expression by real-time polymerase chain reaction. Additionally, we performed cell culture experiments and stimulated Swan71 and Jeg-3 cells with different RA derivates and 2'-deoxy-5-azacytidine (AZA) to induce DNA demethylation. RESULTS: RARRES1, 2, and 3 and RARA, RARB, RARG, and RXRA are expressed in the extravillous part of the placenta. RARRES1, RARA, RARG, and RXRA were additionally detected in villous cytotrophoblasts. RARRES gene expression was induced via activation of RARA, RARB, and RARG in trophoblast cells. RARRES1 was overexpressed in villous trophoblasts and the syncytiotrophoblast from PE placentas, but not in IUGR without PE. Promoter methylation was detectable for RARRES1 and RARB based on their sensitivity toward AZA treatment of trophoblast cell lines. DISCUSSION: RARRES1, 2 and 3 are expressed in the functional compartments of the human placenta and can be regulated by RA. We hypothesize that the epigenetic suppression of trophoblast RARRES1 and RARB expression and the upregulation of RARRES1 in PE trophoblast cells suggest an involvement of environmental factors (eg, maternal vitamin A intake) in the pathogenesis of this pregnancy complication.
EVALuna2:34222

Expression of disialoganglioside GD2 in breast cancer subtypes - Gaß, Paul; Kailayangiri, Sareetha; Hübner, Hanna; Rübner, Matthias; Hartmann, Arndt; Häberle, Lothar; Völkl, Simon; Mackensen, Andreas; Landgraf, Laura; Schulz-Wendtland, Rüdiger; Farwick, Nicole; Roessig, Claudia; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

Expression of neuroendocrine markers in different molecular subtypes of breast carcinoma - Wachter, David; Hartmann, Arndt; Beckmann, Matthias; Fasching, Peter; Hein, Alexander; Bayer, Christian M.; Agaimy, Abbas (BioMed Research International, 2014)
Carcinomas of the breast with neuroendocrine features are incorporated in the World Health Organization classification since 2003 and include well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas/small cell carcinomas, and invasive breast carcinomas with neuroendocrine differentiation. Neuroendocrine differentiation is known to be more common in certain low-grade histologic special types and has been shown to mainly cluster to the molecular (intrinsic) luminal A subtype.We analyzed the frequency of neuroendocrine differentiation in different molecular subtypes of breast carcinomas of no histologic special type using immunohistochemical stains with specific neuroendocrine markers (chromogranin A and synaptophysin).We found neuroendocrine differentiation in 20% of luminal B-like carcinomas using current WHO criteria (at least 50% of tumor cells positive for synaptophysin or chromogranin A). In contrast, no neuroendocrine differentiation was seen in luminal A-like, HER2 amplified and triple-negative carcinomas. Breast carcinomas with neuroendocrine differentiation presented with advanced stage disease and showed aggressive behavior.We conclude that neuroendocrine differentiation is more common than assumed in poorly differentiated luminal B-like carcinomas. Use of specific neuroendocrine markers is thus encouraged in this subtype to enhance detection of neuroendocrine differentiation and hence characterize the biological and therapeutic relevance of this finding in future studies.
EVALuna2:6612

Expression of secreted protein acidic and rich in cysteine (SPARC) in breast cancer and response to neoadjuvant chemotherapy - Lindner, J. L.; Loibl, S.; Denkert, Carsten; Ataseven, B.; Fasching, Peter; Pfitzner, B. M.; Gerber, B.; Gade, S.; Darb-Esfahani, S.; Sinn, B. V.; Huober, J.; Engels, K.; et al. (Annals of Oncology, 2015)
Secreted protein acidic and rich in cysteine (SPARC) has been suggested as a new biomarker and therapeutic target in breast cancer, as well as other tumor types.We evaluated the frequency of SPARC expression among different molecular breast cancer subtypes and its role for therapy response after neoadjuvant chemotherapy. In this study, pretherapeutic core biopsies of 667 patients from the neoadjuvant GeparTrio trial were evaluated for SPARC expression by immunohistochemistry using a standardized immunoreactive score (IRS).An increased SPARC expression (IRS >=6) was observed in 26% of all tumors. In triple-negative tumors, SPARC expression was increased in 37% of tumors, compared with other molecular subtypes (23% HR+/HER2-, 29% HR+/HER2+ and 22% HR-/HER2+; P = 0.038). Increased SPARC expression was associated with an increased pathological complete response (pCR) rate of 27%, compared with 15% in tumors with low SPARC expression (P < 0.001). In the triple-negative subgroup, pCR rates were 47% in tumors with high SPARC expression, compared with 26% in tumors with low SPARC expression (P = 0.032). In multivariable analysis, SPARC was independently predictive in the overall population (P = 0.010) as well as the triple-negative subgroup (P = 0.036).SPARC is frequently expressed in breast cancer with triple-negative breast cancer revealing the highest expression rate. High SPARC expression of the primary tumor is associated with a higher chance of achieving a pathological complete remission after TAC or TAC-NX chemotherapy. As SPARC is an albumin-binding protein and might mediate intratumoral accumulation of albumin bound drugs, SPARC should be further evaluated as a predictive marker especially for response to albumin-bound drugs like nab-paclitaxel.NCT00544765.
EVALuna2:17559

Expression of the Immunohistochemical Markers CK5, CD117, and EGFR in Molecular Subtypes of Breast Cancer Correlated with Prognosis - Schulmeyer, Carla; Fasching, Peter; Häberle, Lothar; Meyer, Julia; Schneider, Michael; Wachter, David; Rübner, Matthias; Pöschke, Patrik; Beckmann, Matthias; Hartmann, Arndt; Erber, Ramona; Gaß, Paul (Diagnostics, 2023)
Molecular-based subclassifications of breast cancer are important for identifying treatment options and stratifying the prognosis in breast cancer. This study aimed to assess the prognosis relative to disease-free survival (DFS) and overall survival (OS) in patients with triple-negative breast cancer (TNBC) and other subtypes, using a biomarker panel including cytokeratin 5 (CK5), cluster of differentiation 117 (CD117), and epidermal growth factor receptor (EGFR). This cohort–case study included histologically confirmed breast carcinomas as cohort arm. From a total of 894 patients, 572 patients with early breast cancer, sufficient clinical data, and archived tumor tissue were included. Using the immunohistochemical markers CK5, CD117, and EGFR, two subgroups were formed: one with all three biomarkers negative (TBN) and one with at least one of those three biomarkers positive (non-TBN). There were significant differences between the two biomarker subgroups (TBN versus non-TBN) in TNBC for DFS (p = 0.04) and OS (p = 0.02), with higher survival rates (DFS and OS) in the non-TBN subgroup. In this study, we found the non-TBN subgroup of TNBC lesions with at least one positive biomarker of CK5, CD117, and/or EGFR, to be associated with longer DFS and OS.
CRIS-Team Scopus Importer:2023-02-24
Keywords: CD117; CK5; early breast cancer; EGFR; prognosis; therapy; triple-negative breast cancer

External Beam Accelerated Partial Breast Irradiation in Early Breast Cancer and the Risk for Radiogenic Pneumonitis - Ott, Oliver; Stillkrieg, Wilhelm; Lambrecht, Ulrike; Sauer, Tim-Oliver; Schweizer, Claudia; Lamrani, Allison; Strnad, Vratislav; Hack, Carolin; Beckmann, Matthias; Uder, Michael; Fietkau, Rainer; Distel, Luitpold (Cancers, 2022)
Simple Summary Accelerated partial breast irradiation represents a well-established and safe treatment alternative for selected patients with early stage breast cancer after breast-conserving surgery. In a prospective trial on external beam partial breast irradiation, the risk for radiogenic pneumonitis is analyzed. After a median follow-up of 56 (1-129) months, radiogenic pneumonitis grade 2 appeared in only 1/170 (0.6%) patients. Compared to standard whole breast irradiation, the radiation doses applied to the lungs were very low. The patient with the radiogenic pneumonitis was found to have a generally increased radiation susceptibility. Using accelerated partial breast irradiation, the risk of radiogenic pneumonitis appeared quite low and may be limited to very exceptional cases associated with innate risk factors with an increased radiation susceptibility. In order to evaluate the risk for radiation-associated symptomatic pneumonitis in a prospective external beam accelerated partial breast irradiation (APBI) trial, between 2011 and 2021, 170 patients with early stage breast cancer were enclosed in the trial. Patients were eligible for study participation if they had a histologically confirmed breast cancer or an exclusive ductal carcinoma in situ (DCIS), a tumor size <= 3 cm, free safety margins >= 2 mm, no involved axillary lymph nodes, tumor bed clips, and were >= 50 years old. Patients received APBI with 38 Gy with 10 fractions in 10 consecutive working days. The trial was registered at the German Clinical Trials Registry, DRKS-ID: DRKS00004417. Median follow-up was 56 (1-129) months. Ipsilateral lung MLD, V20, and V30 were 4.3 +/- 1.4 Gy, 3.0 +/- 2.0%, and 1.0 +/- 1.0%, respectively. Radiogenic pneumonitis grade 2 appeared in 1/170 (0.6%) patients two months after radiotherapy. Ipsilateral MLD, V20, and V30 were 6.1 Gy, 7, and 3% in this patient. Additionally, individual radiosensitivity was increased in this specific patient. Compared to WBI, APBI leads to lower lung doses. Using APBI, the risk of symptomatic radiogenic pneumonitis is very low and may be limited, with an ipsilateral V20 < 3% to very exceptional cases associated with innate risk factors with an increased radiation susceptibility.
CRIS-Team WoS Importer:2022-08-12

External-Beam-Accelerated Partial-Breast Irradiation Reduces Organ-at-Risk Doses Compared to Whole-Breast Irradiation after Breast-Conserving Surgery - Ott, Oliver; Stillkrieg, Willy; Lambrecht, Ulrike; Schweizer, Claudia; Lamrani, Allison; Sauer, Tim-Oliver; Strnad, Vratislav; Bert, Christoph; Hack, Carolin; Beckmann, Matthias; Fietkau, Rainer (Cancers, 2023)
In order to evaluate organ-at-risk (OAR) doses in external-beam-accelerated partial-breast irradiation (APBI) compared to standard whole-breast irradiation (WBI) after breast-conserving surgery. Between 2011 and 2021, 170 patients with early breast cancer received APBI within a prospective institutional single-arm trial. The prescribed dose to the planning treatment volume was 38 Gy in 10 fractions on 10 consecutive working days. OAR doses for the contralateral breast, the ipsilateral, contralateral, and whole lung, the whole heart, left ventricle (LV), and the left anterior descending coronary artery (LAD), and for the spinal cord and the skin were assessed and compared to a control group with real-world data from 116 patients who underwent WBI. The trial was registered at the German Clinical Trials Registry, DRKS-ID: DRKS00004417. Compared to WBI, APBI led to reduced OAR doses for the contralateral breast (0.4 ± 0.6 vs. 0.8 ± 0.9 Gy, p = 0.000), the ipsilateral (4.3 ± 1.4 vs. 9.2 ± 2.5 Gy, p = 0.000) and whole mean lung dose (2.5 ± 0.8 vs. 4.9 ± 1.5 Gy, p = 0.000), the mean heart dose (1.6 ± 1.6 vs. 1.7 ± 1.4 Gy, p = 0.007), the LV V23 (0.1 ± 0.4 vs. 1.4 ± 2.6%, p < 0.001), the mean LAD dose (2.5 ± 3.4 vs. 4.8 ± 5.5 Gy, p < 0.001), the maximum spinal cord dose (1.5 ± 1.1 vs. 4.5 ± 5.7 Gy, p = 0.016), and the maximum skin dose (39.6 ± 1.8 vs. 49.1 ± 5.8 Gy, p = 0.000). APBI should be recommended to suitable patients to minimize the risk of secondary tumor induction and the incidence of consecutive major cardiac events.
CRIS-Team Scopus Importer:2023-08-25
Keywords: accelerated partial-breast irradiation; breast cancer; mean heart dose; mean lung dose; organs-at-risk

Ex Vivo Chromosomal Radiosensitivity Testing in Patients with Pathological Germline Variants in Breast Cancer High-Susceptibility Genes BReast CAncer 1 and BReast CAncer 2 - Zuhair Kassem, Tara; Wunderle, Marius; Kuhlmann, Lukas; Rübner, Matthias; Hübner, Hanna; Hoyer, Juliane; Reis, André; Fasching, Peter; Beckmann, Matthias; Hack, Carolin; Fietkau, Rainer; Distel, Luitpold (Current Issues in Molecular Biology, 2023)
Background: Individual radiosensitivity is an important factor in the occurrence of undesirable consequences of radiotherapy. The potential for increased radiosensitivity has been linked to highly penetrant heterozygous mutations in DNA repair genes such as BRCA1 and BRCA2. By studying the chromosomal radiosensitivity of BRCA1/2 mutation carriers compared to the general population, we study whether increased chromosomal radiation sensitivity is observed in patients with BRCA1/2 variants. Methods: Three-color-fluorescence in situ hybridization was performed on ex vivo-irradiated peripheral blood lymphocytes from 64 female patients with a heterozygous germline BRCA1 or BRCA2 mutation. Aberrations in chromosomes #1, #2 and #4 were analyzed. Mean breaks per metaphase (B/M) served as the parameter for chromosomal radiosensitivity. The results were compared with chromosomal radiosensitivity in a cohort of generally healthy individuals and patients with rectal cancer or breast cancer. Results: Patients with BRCA1/2 mutations (n = 64; B/M 0.47) overall showed a significantly higher chromosomal radiosensitivity than general healthy individuals (n = 211; B/M 0.41) and patients with rectal cancer (n = 379; B/M 0.44) and breast cancer (n = 147; B/M 0.45) without proven germline mutations. Chromosomal radiosensitivity varied depending on the locus of the BRCA1/2 mutation. Conclusions: BRCA1/2 mutations result in slightly increased chromosomal sensitivity to radiation. A few individual patients have a marked increase in radiation sensitivity. Therefore, these patients are at a higher risk for adverse therapeutic consequences.
CRIS-Team Scopus Importer:2023-09-08
Keywords: BRCA1; BRCA2; breast cancer; chromosomal radiosensitivity; FISH assay; radiation oncology; radiation sensitivity testing; radiotherapy

Factors Influencing Decision-Making for or against Adjuvant and Neoadjuvant Chemotherapy in Postmenopausal Hormone Receptor-Positive Breast Cancer Patients in the EvAluate-TM Study - Gaß, Paul; Fasching, Peter; Fehm, Tanja; De Waal, Johann; Rezai, Mahdi; Baier, Bernd; Baake, Gerold; Kolberg, Hans-Christian; Guggenberger, Martin; Warm, Mathias; Harbeck, Nadia; Wuerstlein, Rachel; et al. (Breast Care, 2016)
BACKGROUND: Decision-making for or against neoadjuvant or adjuvant chemotherapy in postmenopausal patients with hormone receptor-positive breast cancer does not follow any clear guidelines, and some patients may unnecessarily undergo chemotherapy and be exposed to the associated toxicity. The aim of this study was to identify the patient population for whom this issue may bear relevance. METHODS: Patients being treated with letrozole in the prospective multicenter noninterventional EvAluate-TM study were recruited. The percentage of patients receiving chemotherapy and factors associated with chemotherapy administration were identified. RESULTS: In all, 3,924 (37.4%) patients received chemotherapy before treatment with letrozole. Of these, 293 (20%) underwent neoadjuvant therapy. Younger age was predictive for both adjuvant and neoadjuvant therapy. Overall, decisions in favor of administering chemotherapy are more likely to be made in patients with a higher body mass index (BMI), and neoadjuvant chemotherapy is administered at a higher rate in women with a lower BMI. Concomitant medication influenced the overall decision-making regarding chemotherapy, irrespective of whether it was given on a neoadjuvant or adjuvant basis. CONCLUSION: There is an ongoing debate as to whether all of the many patients who receive chemotherapy actually benefit from it. Neoadjuvant chemotherapy is frequently administered in this patient population, and this should encourage further research to resolve current clinical and research issues.
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Factors Predicting Discordance in HER2 Phenotype between Primary Tumor and Circulating Tumor Cells in Women with Metastatic Breast Cancer - Janni, W.; Schramm, A.; Friedl, T. W. P.; Schochter, E.; Huober, J.; Rack, B.; Alunni-Fabbroni, M.; Fasching, Peter; Taran, F-A.; Hortkopf, A.; Schneeweiss, A.; Mueller, V.; et al. (2016)
EVALuna2:33105

FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women - Figlioli, Gisella; Billaud, Amandine; Ahearn, Thomas U.; Antonenkova, Natalia N.; Becher, Heiko; Beckmann, Matthias; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Blok, Marinus J.; Bogdanova, Natalia; Bonanni, Bernardo; et al. (European Journal of Human Genetics, 2023)
Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.
CRIS-Team WoS Importer:2023-04-07

Fatal events during clinical trials: an evaluation of deaths during breast cancer studies - Furlanetto, Jenny; von Minckwitz, Gunter; Lederer, Bianca; Möbus, Volker; Schneeweiss, Andreas; Huober, Jens; Fasching, Peter; Gerber, Bernd; Bauerfeind, Ingo; Nitz, Ulrike; Lück, Hans Joachim; Hanusch, Claus; et al. (Breast Cancer, 2019)
Background: Information on deaths occurring during oncological clinical trials has never been systematically assessed. Here, we examine the incidence of death and the profile of patients who died during randomized clinical breast cancer (BC) trials. Methods: Information on fatal events during German Breast Group (GBG) led BC trials was prospectively captured. Data were derived from the trial databases and death narratives. All deaths were evaluated for possible causes, underlying conditions, treatment relatedness, time point and rate of autopsies. Results: From 12/1996 to 01/2017, 23,387 patients were treated within 32 trials. Of those 88 (0.4%) died on therapy within 17 trials. Median age was 64 [range 35–84] years, 63.2% of patients had a body mass index (BMI) ≥ 25 kg/m2; 65.9% 1–3 and 22.7% ≥ 4 comorbidities; 61.4% 1–2 cardiovascular risk factors (CRFs); 26.4% took > 3 drugs; 81.7% had ECOG 0; 50.0% stage III, 76.7% luminal BC. The main causes of death were infection (38.6%; of those, 82.3% sepsis, 17.6% pneumonia), heart failure (14.8%), and pulmonary embolism (13.6%). Fatal events mainly occurred within the first 4 therapy cycles (55.7%), in the investigational arm (66.7%) and under anthracycline–taxane-based chemotherapy (51.1%). A relationship with the treatment was declared in 27.3% of the cases. An autopsy was performed in 13.6% of patients. Conclusions: Death during study treatment was mainly related to infections, and patients with advanced disease, high BMI, underlying comorbidities, CRFs and concomitant medications. If considered for study participation these patients need careful monitoring due to their higher risk for death on study.
CRIS-Team Scopus Importer:2019-07-12
Keywords: Cause of death; Chemotherapy-related death; Death in clinical trial; Rate of autopsy; Serious adverse events

Favorable impact of therapy management by an interactive eHealth system on severe adverse events in patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer treated by palbociclib and endocrine therapy - Harbeck, Nadia; Kates, Ronald; Schinköthe, Timo; Schumacher, Johannes; Wuerstlein, Rachel; Degenhardt, Tom; Lüftner, Diana; Räth, Philip; Hoffmann, Oliver; Lorenz, Ralf; Decker, Thomas; Reinisch, Mattea; et al. (Cancer Treatment Reviews, 2023)
Background: Oral cancer medications offer advantages but also pose challenges for therapy management and adherence. An eHealth-based platform such as CANKADO can help to support therapy management by probing the patient's quality of life (QoL) continuously throughout the course of treatment. Material and Methods: AGO-B WSG PreCycle (NCT03220178) is a multicenter, randomized phase IV intergroup trial evaluating the impact of eHealth-based Patient-Reported Outcome (ePRO) assessment on QoL in patients with hormone receptor-positive (HR + )/HER2-negative (HER2-) advanced breast cancer treated with palbociclib and endocrine therapy. Patients were randomized (2:1) to CANKADO-active arm (supported by CANKADO PRO-React) or CANKADO-inform arm (drug intake documentation only) This exploratory analysis reports the impact of CANKADO PRO-React on safety. Time to first serious adverse event (SAE) was estimated taking competing risks into account. Results: While distributions of adverse events (AEs) were similar by arm overall, patients in the CANKADO-active arm had a favorable hazard ratio of 0.67 (95%CI 0.46–0.97; p = 0.04) for time to first SAE and were significantly less likely overall to suffer an SAE than patients in the inform arm. At 24 months, 22.9% [17.9%-27.8%] of patients in CANKADO-active had suffered an SAE vs. 30.3% [22.6%-38.0%] in CANKADO-inform. AE-related dose reductions affected approximately 20% of patients (CANKADO-active: 18.2%, CANKADO-inform: 21.1%). Conclusion: Exploratory safety analysis of PreCycle demonstrates for the first time in a randomized prospective trial that interactive autonomous eHealth-based support has a substantial favorable impact on the risk of SAEs and mitigates their severity for patients with advanced HR+/HER2- breast cancer on oral tumor therapy.
CRIS-Team Scopus Importer:2023-10-27
Keywords: CANKADO; CDK4/6 inhibitor; eHealth; Endocrine therapy; Metastatic breast cancer; Patient-reported outcomes; Quality of life; Serious adverse events

Feasibility and Acceptance of Self-Guided Mobile Ultrasound among Pregnant Women in Routine Prenatal Care - Pontones, Constanza; Titzmann, Adriana; Hübner, Hanna; Danzberger, Nina; Rübner, Matthias; Häberle, Lothar; Eskofier, Björn; Nissen, Michael; Kehl, Sven; Faschingbauer, Florian; Beckmann, Matthias; Fasching, Peter; et al. (Journal of Clinical Medicine, 2023)
Background and objectives: Mobile and remote ultrasound devices are becoming increasingly available. The benefits and possible risks of self-guided ultrasound examinations conducted by pregnant women at home have not yet been well explored. This study investigated aspects of feasibility and acceptance, as well as the success rates of such examinations. Methods: In this prospective, single-center, interventional study, forty-six women with singleton pregnancies between 17 + 0 and 29 + 6 weeks of gestation were included in two cohorts, using two different mobile ultrasound systems. The participants examined the fetal heartbeat, fetal profile and amniotic fluid. Aspects of feasibility and acceptance were evaluated using a questionnaire. Success rates in relation to image and video quality were evaluated by healthcare professionals. Results: Two thirds of the women were able to imagine performing the self-guided examination at home, but 87.0% would prefer live support by a professional. Concerns about their own safety and that of the child were expressed by 23.9% of the women. Success rates for locating the target structure were 52.2% for videos of the fetal heartbeat, 52.2% for videos of the amniotic fluid in all four quadrants and 17.9% for videos of the fetal profile. Conclusion: These results show wide acceptance of self-examination using mobile systems for fetal ultrasonography during pregnancy. Image quality was adequate for assessing the amniotic fluid and fetal heartbeat in most participants. Further studies are needed to determine whether ultrasound self-examinations can be implemented in prenatal care and how this would affect the fetomaternal outcome.
CRIS-Team Scopus Importer:2023-07-28
Keywords: acceptance; feasibility; mobile ultrasound; pregnancy; prenatal care; self-guided ultrasound

Feasibility of internal inguinoperitoneal drainage after inguinofemoral lymphadenectomy in vulvar cancer - Dall, Peter; Hildebrandt, Thomas; Du Bois, Andreas; Boetel, Eric; Ahlfaenger, Janine; Beckmann, Matthias; Bommert, Mareike (Archives of Gynecology and Obstetrics, 2020)
Purpose: Despite the introduction of sentinel node biopsy in patients with vulvar cancer, still approximately 50% of all patients have to undergo an inguinofemoral lymphadenectomy. This is associated with a high incidence of postoperative complications, which may be influenced by inguinal drain management. The aim of this study was to investigate the feasibility of a new surgical technique regarding drain management with an inguinoperitoneal drainage. Methods: A retrospective analysis of 21 vulvar cancer patients with inguinofemoral lymphadenectomy was conducted. A silicone drain was circularly placed with the perforated end in the groin and the other end in the space of Douglas. The removal after 3 months was performed under local anesthesia. All patients were questioned during clinical follow-up regarding their personal experiences with the procedure, the occurrence of complications, and side effects using a clinical questionnaire. Results: In 100% of the patients, the procedure was feasible. Regarding the number of groin punctures due to lymphocyst formation, 15 (71.4%) patients did not need any intervention and 3 (14.3%) patients needed 1–3 punctures. The patient satisfaction with the internal drainage was ranked as good by 17 (81.0%) patients and as moderate by 1 (4.8%) patient. In 3 (14.3%) patients, information about the number of groin punctures and the patient satisfaction were missing. Conclusion: Inguinoperitoneal drainage after inguinofemoral lymphadenectomy in vulvar cancer patients is feasible and safe and a patient satisfaction of 81% is promising. For definitive conclusions regarding the efficacy of this technique, further investigations and prospective multicenter trials are needed.
CRIS-Team Scopus Importer:2020-05-05
Keywords: Inguinofemoral lymphadenectomy; Inguinoperitoneal drainage; Postoperative complications; Vulvar cancer

Female reproductive organs tissue engineering - Liverani, Liliana; Bleisinger, Nathalie; Beckmann, Matthias; Dittrich, Ralf (Elsevier, 2021)
The present chapter is focused on the tissue engineering approach applied to female reproductive organs. This field was quite often presented as urogenital applications, but recently the interest of the scientific community has been more oriented on the reproductive organs and to the evaluation of tissue engineering-based approaches focusing on the selection of biomaterials and scaffold fabrication technologies to develop suitable biomimetic three-dimensional constructs.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Biomaterials; Fallopian tubes; Ovary; Reproductive organs; REPROTEN; Tissue engineering; Uterus

Femoral Placement of Totally Implantable Venous Access Ports in Patients with Bilateral Breast Cancer - Almási-Sperling, Veronika; Hieber, Sabrina; Lermann, J.; Strahl, Olga; Beckmann, Matthias; Lang, Werner; Sagban, T. A. (Geburtshilfe und Frauenheilkunde, 2016)
Purpose: Aim of this study was to determine the rate of complications following femoral placement of totally implantable venous access ports (f-TIVAP) in women with bilateral breast cancer, with a special focus on long-term function, deep vein thrombosis (DVT), and port infection. Methods: 73 patients with bilateral breast cancer treated between October 2000 and January 2013 with placement of an f-TIVAP using a transfemoral approach were retrospectively reviewed. All patients were followed up, and all complications of f-TIVAP were recorded. Results: The median age was 62.5 years (range: 35-86 years). Four patients received f-TIVAP under local anesthesia, and 69 underwent placement under general anesthesia. Mean follow-up was 33.7 months (SD 25.9; range: 0.2-93.5 months). Complications over the entire period of observation included infections in 21 %, DVT in 19 % and catheter occlusion in 12 %. Patients receiving chemotherapy who developed leukopenia were more likely to experience DVT at the access site (p = 0.037). There was a trend towards a higher infection rate when the device was used more often (p = 0.084). Conclusion: Although the rates of complications in the longer term, especially device infections and DVTs, appeared to be relatively high, TIVAP implantation using femoral vein access is recommended in patients with bilateral breast cancer not suitable for cephalic vein cut-down.
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FemZone trial: a randomized phase II trial comparing neoadjuvant letrozole and zoledronic acid with letrozole in primary breast cancer patients - Fasching, Peter; Jud, Sebastian; Hauschild, Maik; Kuemmel, Sherko; Schuette, Martin; Warm, Matthias; Hanf, Volker; Grab, Dieter; Krocker, Jutta; Stickeler, Elmar; Kreienberg, Rolf; Mueller, Thomas; et al. (BMC Cancer, 2014)
The objective of this prospectively randomized phase II trial (Trial registration: EUCTR2004-004007-37-DE) was to compare the clinical response of primary breast cancer patients to neoadjuvant therapy with letrozole alone (LET) or letrozole and zoledronic acid (LET + ZOL).Patients were randomly assigned to receive either LET 2.5 mg/day (n = 79) or the combination of LET 2.5 mg/day and a total of seven infusions of ZOL 4 mg every 4 weeks (n = 89) for 6 months. Primary endpoint was clinical response rate as assessed by mammogram readings. The study was terminated prematurely due to insufficient recruitment. We report here on an exploratory analysis of this data.Central assessment of tumor sizes during the treatment period was available for 131 patients (66 LET, 65 LET + ZOL). Clinical responses (complete or partial) were seen in 54.5% (95% CI: 41.8-66.9) of the patients in the LET arm and 69.2% (95% CI: 56.6-80.1) of those in the LET + ZOL arm (P = 0.106). A multivariate model showed an OR of 1.72 (95% CI: 0.83-3.59) for the experimental arm.No increase in the clinical response rate was observed with the addition of ZOL to a neoadjuvant treatment regimen with LET. However a trend towards a better reponse in the LET + ZOL arm could be observed. This trend is consistent with previous studies that have investigated the addition of ZOL to chemotherapy, and it may support the evidence for a direct antitumor action of zoledronic acid.
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Fertilitätserhalt bei Kindern und Jugendlichen - Lotz, Laura; Hoffmann, Inge; Dittrich, Ralf (Pädiatrische Praxis, 2022)
Auch bei Kindern und Jugendlichen stellen fertilitätserhaltende Maßnahmen ein relevantes Thema dar. Vor einer gonadotoxischen Therapie oder bei genetischer Prädisposition für eine Unfruchtbarkeit können zum Erhalt der Fruchtbarkeit etablierte und experimentelle Maßnahmen ergriffen werden. Dabei müssen viele Faktoren, wie Alter bzw. pubertärer Reifestatus und Zeit bis zum Therapiestart, bedacht werden.
CRIS-Team Scopus Importer:2024-12-16
Keywords: chemotherapy; children; cryopreservation; fertility preservation; oncological therapy; Chemotherapie; Fertilitätserhaltende Maßnahmen; Kinder; Kryokonservierung; onkologische Therapie

Fertilitätserhalt bei Kindern und Jugendlichen - Lotz, Laura; Hoffmann, Inge; Dittrich, Ralf (gynäkologische praxis, 2023)
Fertility preservation measures are a relevant issue in children and adolescents before gonadotoxic therapy, in cases of genetic predisposition to infertility or benign diseases that may limit fertility. Counseling these young patients is an interdisciplinary challenge in which many factors, such as age or pubertal maturation status, time for counseling, and time to initiation of therapy, play an important role. Since some fertility preserving measures in prepubertal girls and boys are experimental, these measures should only be used in centres with sufficient expertise in the field of reproductive medicine.
CRIS-Team Scopus Importer:2023-10-20
Keywords: Chemotherapy; Children; Cryopreservation; Fertility preservation; Oncological therapy

Fertilität und Fertilitätserhalt der Frau - Dittrich, Ralf; Lotz, Laura (Die Dermatologie, 2023)
Background: Advances in the treatment of cancer and in reproductive medicine make it possible for many patients to start their family planning even after cytotoxic therapy. Depending on the age of the patient, the planned oncological therapy and its urgency, various methods can be used to preserve the fertility of affected women. Objectives: Presentation of facts about fertility, as well as information about fertility-preserving methods for women, so that they can be discussed with and offered to patients. Materials and methods: Presentation and discussion of basic research, clinical data, and expert recommendations on fertility and fertility preservation. Results: Well-established fertility-protective techniques now exist for women that offer a realistic chance of subsequent pregnancy. These include transposition of the gonads prior to radiotherapy, gonadal protection with gonadotropin-releasing hormone (GnRH) analogues and cryopreservation of fertilized and unfertilized oocytes, as well as cryopreservation of ovarian tissue. Conclusions: Fertility-protective techniques are an integral part of oncological treatments for prepubertal girls and patients of reproductive age. The various measures must be discussed individually with the patient as part of a multimodal concept. Prompt and timely collaboration with a specialized center is essential.
CRIS-Team Scopus Importer:2023-07-07
Keywords: Cancer treatment; Cryopreservation; Oocytes; Ovarian tissue; Pharmacologic ovarian protection

Fertility-preservation counselling and treatment for medical reasons: data from a multinational network of over 5000 women - Von Wolff, Michael; Dittrich, Ralf; Liebenthron, Jana; Nawroth, Frank; Schuering, Andreas N.; Bruckner, Thomas; Germeyer, Ariane (Reproductive Biomedicine Online, 2015)
Fertility-preservation techniques for medical reasons are increasingly offered in national networks. Knowledge of the characteristics of counselled patients and techniques used are essential. The FertiPROTEKT network registry was analysed between 2007 and 2013, and included up to 85 university and non-university centres in Germany, Austria and Switzerland; 5159 women were counselled and 4060 women underwent fertility preservation. In 2013, fertility-preservation counselling for medical reasons increased significantly among nullipara and women aged between 21 and 35 years (n = 1043; P < 0.001). Frequency of GnRH applications slowly decreased, whereas tissue, oocytes and zygote cryopreservation increased. In 2013, women with breast cancer mainly opted for tissue freezing, whereas women with lymphoma opted for GnRH agonist. Women younger than 20 years predominantly opted for GnRH agonists and ovarian tissue cryopreservation; women aged between 20 and 40 years underwent a variety of techniques; and women over 40 years opted for GnRH agonists. The average number of aspirated oocytes per stimulation cycle decreased as age increased (< 30 years: 12.9; 31-35 years: 12.3; 36-46: 9.0; > 41 years: 5.7). For ovarian tissue cryopreservation, removal and cryopreservation of fewer than one ovary was preferred and carried out in 97% of cases in 2013.
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Fertility Preservation for Patients with Malignant Disease. Guideline of the DGGG, DGU and DGRM (S2k-Level, AWMF Registry No. 015/082, November 2017) - Recommendations and Statements for Girls and Women - Dittrich, Ralf; Kliesch, Sabine; Schuering, Andreas; Balcerek, Magdalena; Baston-Buest, Dunja M.; Beck, Ramona; Beckmann, Matthias; Behringer, Karolin; Borgmann-Staudt, Anja; Cremer, Wolfgang; Denzer, Christian; Diemer, Thorsten; et al. (Geburtshilfe und Frauenheilkunde, 2018)
The aim of this official guideline published by the German Society of Gynecology and Obstetrics (DGGG) and coordinated with the German Society of Urology (DGU) and the German Society of Reproductive Medicine (DGRM) is to provide consensus-based recommendations, obtained by evaluating the relevant literature, on counseling and fertility preservation for prepubertal girls and boys as well as patients of reproductive age. Statements and recommendations for girls and women are presented below. Statements or recommendations for boys and men are not the focus of this guideline.This S2k guideline was developed at the suggestion of the guideline commission of the DGGG, DGU and DGRM and represents the structured consensus of representative members from various professional associations (n = 40).The guideline provides recommendations on counseling and fertility preservation for women and girls which take account of the patient's personal circumstances, the planned oncologic therapy and the individual risk profile as well as the preferred approach for selected tumor entities.
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Fertility preservation in breast cancer patients by embryo cryopreservation after ovarian stimulation with letrozole and FSH - Beckmann, Matthias; Findeklee, Sebastian (Strahlentherapie und Onkologie, 2015)
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Fertility Preservation: Optimization of Follicle Extraction before Cultivation in the Artificial Ovary - Keckstein, P.; Fattahi, Amir; Liverani, Liliana; Dittrich, Ralf; Hoffmann, I; Boccaccini, Aldo R.; Beckmann, Matthias; Bleisinger, Nathalie (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

Fertility protection: complications of surgery and results of removal and transplantation of ovarian tissue - Beckmann, Matthias; Dittrich, Ralf; Lotz, Laura; Van Der Ven, Karin; Van Der Ven, Hans H.; Liebenthron, Jana; Korell, Matthias; Frambach, Torsten; Suetterlin, Marc; Schwab, Roxana; Seitz, Stefan; Mueller, Andreas; et al. (Reproductive Biomedicine Online, 2018)
Fertility-preserving measures are becoming important for patients receiving oncological treatment. One method involves cryopreservation of ovarian tissue and transplanting it when treatment is completed. We report complications resulting from surgical and fertility medicine, and the results of procedures for the removal and transplantation of ovarian tissue carried out within the FertiProtekt network. A survey using a structured questionnaire was conducted among the FertiProtekt network centres between November 2015 and June 2016. The analysis included surgical techniques used to remove and transplant ovarian tissue, surgical complications and results. Laparoscopic removal and transplantation of ovarian tissue have a low risk of complications. Surgical complications occurred in three of the network's 1373 ovarian tissue removals (n = 1302) and transplantations (n = 71); two complications (0.2%) occurred during removal and one during transplantation. Menstruation resumed in 47 out of 58 women (81%) who underwent ovarian tissue transplantation. Hormonal activity occurred in 63.2% of transplantations with a follow-up of 6 months or over. Sixteen pregnancies occurred in 14 patients, with nine births. The risks and complications of removal and transplantation of ovarian tissue are similar to those of standard laparoscopy. These procedures are becoming standard for fertility protection in cancer patients.
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Fertility Protection FertiPROTEKT in Germany - yesterday, today, tomorrow - Von Wolff, Michael; Dittrich, Ralf; Germeyer, Ariane; Liebenthron, Jana; Nawroth, Frank; Schuering, Andreas; Suerdieck, Moritz (Geburtshilfe und Frauenheilkunde, 2016)
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Fertility Protection in Female Oncology Patients: How Should Patients Be Counseled? - Findeklee, S.; Lotz, Laura; Heusinger, K.; Hoffmann, I.; Dittrich, Ralf; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2015)
Protecting the fertility of patients with oncologic disease is becoming more and more important, as fulfilling the wish to have children is increasingly occurring at a later stage in life and long-term survival rates after cancer are continuing to improve. A number of fertility-preserving options exist. In addition to techniques which have been around for some time such as medical ovarian suppression, ovarian transposition, and organ-preserving surgery, there are other, more recent, innovative methods which have developed over the last few years such as cryopreservation of oocytes or ovarian tissue transplantation after completing cancer therapy. As every procedure has its specific advantages and disadvantages, informed patient consent is essential. The physician's aim must be to select the optimal procedure for each patient. The extent of patients' information about the options to preserve fertility in women with oncologic disease remains limited. One of the main reasons for this is that clinicians are not sure how to inform patients about existing procedures and methods. The aim of this review article is to provide help in clinical practice.
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Fetal Re-Identification in Multiple Pregnancy Ultrasound Images Using Deep Learning - Gabler, Elisabeth; Nissen, Michael; Altstidl, Thomas Robert; Titzmann, Adriana; Packhäuser, Kai; Maier, Andreas; Fasching, Peter; Eskofier, Björn; Leutheuser, Heike (2023 45th Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC), 2023)
Ultrasound examinations during pregnancy can detect abnormal fetal development, which is a leading cause of perinatal mortality. In multiple pregnancies, the position of the fetuses may change between examinations. The individual fetus cannot be clearly identified. Fetal re-identification may improve diagnostic capabilities by tracing individual fetal changes. This work evaluates the feasibility of fetal re-identification on FETAL-PLANES-DB, a publicly available dataset of singleton pregnancy ultrasound images. Five dataset subsets with 6,491 images from 1,088 pregnant women and two re-identification frameworks (Torchreid, FastReID) are evaluated. FastReID achieves a mean average precision of 68.77% (68.42%) and mean precision at rank 10 score of 89.60% (95.55%) when trained on images showing the fetal brain (abdomen). Visualization with gradient-weighted class activation mapping shows that the classifiers appear to rely on anatomical features. We conclude that fetal re-identification in ultrasound images may be feasible. However, more work on additional datasets, including images from multiple pregnancies and several subsequent examinations, is required to ensure and investigate performance stability and explainability.Clinical relevance - To date, fetuses in multiple pregnancies cannot be distinguished between ultrasound examinations. This work provides the first evidence for feasibility of fetal re-identification in pregnancy ultrasound images. This may improve diagnostic capabilities in clinical practice in the future, such as longitudinal analysis of fetal changes or abnormalities.
Created from Fastlane, Scopus look-up
Keywords: Pregnancy; Deep learning; Visualization; Ultrasonic imaging; Fetus; Stability analysis; Biology

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium - Agarwal, D.; Pineda, S.; Michailidou, K.; Herranz, J.; Pita, G.; Moreno, L. T.; Alonso, M. R.; Dennis, J.; Wang, Q.; Bolla, M. K.; Meyer, K. B.; Menendez-Rodriguez, P.; et al. (British Journal of Cancer, 2014)
Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.
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Fiber alignment in 3D collagen networks as a biophysical marker for cell contractility - Böhringer, David; Bauer, Andreas; Moravec, Ivana; Bischof, Lars; Kah, Delf-Thorge Eric; Mark, Christoph; Grundy, Thomas J.; Görlach, Ekkehard; O'Neill, Geraldine M.; Budday, Silvia; Strissel, Pamela; Strick, Reiner; et al. (Matrix Biology, 2023)
Cells cultured in 3D fibrous biopolymer matrices exert traction forces on their environment that induce deformations and remodeling of the fiber network. By measuring these deformations, the traction forces can be reconstructed if the mechanical properties of the matrix and the force-free matrix configuration are known. These requirements limit the applicability of traction force reconstruction in practice. In this study, we test whether force-induced matrix remodeling can instead be used as a proxy for cellular traction forces. We measure the traction forces of hepatic stellate cells and different glioblastoma cell lines and quantify matrix remodeling by measuring the fiber orientation and fiber density around these cells. In agreement with simulated fiber networks, we demonstrate that changes in local fiber orientation and density are directly related to cell forces. By resolving Rho-kinase (ROCK) inhibitor-induced changes of traction forces, fiber alignment, and fiber density in hepatic stellate cells, we show that the method is suitable for drug screening assays. We conclude that differences in local fiber orientation and density, which are easily measurable, can be used as a qualitative proxy for changes in traction forces. The method is available as an open-source Python package with a graphical user interface.
CRIS-Team Scopus Importer:2023-12-22
Keywords: Biopolymer Networks; Fiber Orientation; Mechanobiology; Traction Force Microscopy

Filarial extract of Litomosoides sigmodontis induces a type 2 immune response and attenuates plaque development in hyperlipidemic ApoE-knockout mice - Kühn, Constanze; Tauchi, Miyuki; Furtmair, Roman; Urschel, Katharina; Raaz-Schrauder, Dorette; Neumann, Anna Lena; Frohberger, Stefan J.; Hoerauf, Achim; Regus, Susanne; Lang, Werner; Sagban, Tolga Atilla; Stumpfe, Florian Matthias; et al. (The FASEB Journal, 2019)
A type 1 immune response is involved in atherosclerosis progression, whereas the role of a type 2 polarization, especially with regard to an enhanced T helper (Th)2 cell differentiation, is still unclear. Helminths trigger type 2 immune responses, protecting the host from inflammatory disorders. We investigated whether an increased type 2 polarization by administration of Litomosoides sigmodontis adult worm extract (LsAg) affects atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Injections of 50 µg LsAg, i.p. into ApoE-/- mice induced a type 2 immune response shown by increased frequencies of peritoneal eosinophils and alternatively activated macrophages. To analyze the effect of LsAg on atherosclerosis initiation, ApoE-/- mice received a high-fat diet for 12 wk and weekly injections of 50 µg LsAg from wk 5 to 12. Therapeutic effects on advanced atherosclerosis were analyzed in mice that were fed a high-fat diet for 12 wk followed by 12 wk of normal chow and weekly LsAg injections. Both preventive and therapeutic LsAg application significantly decreased plaque size. Therapeutic treatment even caused regression of plaque size and macrophage density in the aortic root and reduced Th1-specific gene expression and intraplaque inflammation. In addition, plaque size after therapeutic treatment was inversely correlated with plaque-infiltrated alternatively activated macrophages. In vitro, LsAg treatment of HUVECs reduced intracellular levels of phosphorylated NF-κB-p65, IκB-α, and JNK1/2. In bifurcation flow-through slides, THP-1 cell adhesion to a HUVEC monolayer was decreased by LsAg in regions of nonuniform shear stress. Applying inhibitors of the respective kinases suggests JNK1/2 inhibition is involved in the suppressed cell adhesion. A switch to an enhanced type 2 immune response by LsAg exerts antiatherogenic effects on murine plaque development, indicating a protective role of a hampered type 1 polarization. In vitro, LsAg affects endothelial signaling pathways, among which JNK1/2 inhibition seems to be involved in the suppression of monocytic cell adhesion under proatherogenic shear stress.-Constanze, K., Tauchi, M., Furtmair, R., Urschel, K., Raaz-Schrauder, D., Neumann, A.-L., Frohberger, S. J., Hoerauf, A., Regus, S., Lang, W., Sagban, T. A., Stumpfe, F. M., Achenbach, S., Hübner, M. P., Dietel, B. Filarial extract of Litomosoides sigmodontis induces a type 2 immune response and attenuates plaque development in hyperlipidemic ApoE-knockout mice.
CRIS-Team Scopus Importer:2019-05-21
Keywords: atherosclerosis; endothelial activation; helminth; inflammation; JNK

Filtration based assessment of CTCs and CellSearch® based assessment are both powerful predictors of prognosis for metastatic breast cancer patients - Hübner, Hanna; Fasching, Peter; Gumbrecht, Walter; Jud, Sebastian; Rauh, Claudia; Matzas, Mark; Paulicka, Peter; Friedrich, Katja; Lux, Michael P.; Volz, Bernhard; Gaß, Paul; Häberle, Lothar; et al. (BMC Cancer, 2018)
The assessment of circulating tumor cells (CTCs) has been shown to enable monitoring of treatment response and early detection of metastatic breast cancer (MBC) recurrence. The aim of this study was to compare a well-established CTC detection method based on immunomagnetic isolation with a new, filtration-based platform.In this prospective study, two 7.5 ml blood draws were obtained from 60 MBC patients and CTC enumeration was assessed using both the CellSearch® and the newly developed filtration-based platform. We analyzed the correlation of CTC-positivity between both methods and their ability to predict prognosis. Overall survival (OS) was calculated and Kaplan-Meier curves were estimated with thresholds of >=1 and >=5 detected CTCs.The CTC positivity rate of the CellSearch® system was 56.7% and of the filtration-based platform 66.7%. There was a high correlation of CTC enumeration obtained with both methods. The OS for patients without detected CTCs, regardless of the method used, was significantly higher compared to patients with one or more CTCs (p < 0.001). The median OS of patients with no CTCs vs. >= 1 CTC assessed by CellSearch® was 1.83 years (95% CI: 1.63-2.02) vs. 0.74 years (95% CI: 0.51-1.52). If CTCs were detected by the filtration-based method the median OS times were 1.88 years (95% CI: 1.74-2.03) vs. 0.59 years (95% CI: 0.38-0.80).The newly established EpCAM independently filtration-based system is a suitable method to determine CTC counts for MBC patients. Our study confirms CTCs as being strong predictors of prognosis in our population of MBC patients.
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Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2 - Orr, Nick; Dudbridge, Frank; Dryden, Nicola; Maguire, Sarah; Novo, Daniela; Perrakis, Eleni; Johnson, Nichola; Ghoussaini, Maya; Hopper, John L.; Southey, Melissa C.; Apicella, Carmel; Stone, Jennifer; et al. (Human Molecular Genetics, 2015)
We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans 14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-?, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basi
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Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus - Horne, Hisani N.; Chung, Charles C.; Zhang, Han; Yu, Kai; Prokunina-Olsson, Ludmila; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Hopper, John L.; Southey, Melissa C.; Schmidt, Marjanka K.; et al. (PLoS ONE, 2016)
The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.
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Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk - Painter, Jodie N.; O'Mara, Tracy A.; Batra, Jyotsna; Cheng, Timothy; Lose, Felicity A.; Dennis, Joe; Michailidou, Kyriaki; Tyrer, Jonathan P.; Ahmed, Shahana; Ferguson, Kaltin; Healey, Catherine S.; Kaufmann, Susanne; et al. (Human Molecular Genetics, 2015)
Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.
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Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer - Shi, Jiajun; Zhang, Yanfeng; Zheng, Wei; Michailidou, Kyriaki; Ghoussaini, Maya; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Lush, Michael; Milne, Roger L.; Shu, Xiao-Ou; Beesley, Jonathan; et al. (International Journal of Cancer, 2016)
Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.
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Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs) - Darabi, Hatef; Beesley, Jonathan; Droit, Arnaud; Kar, Siddhartha; Nord, Silje; Marjaneh, Mahdi Moradi; Soucy, Penny; Michailidou, Kyriaki; Ghoussaini, Maya; Wahl, Hanna Fues; Bolla, Manjeet K.; Wang, Qin; et al. (Scientific Reports, 2016)
Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.
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Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk - Guo, Xingyi; Long, Jirong; Zeng, Chenjie; Michailidou, Kyriaki; Ghoussaini, Maya; Bolla, Manjeet K.; Wang, Qin; Milne, Roger L.; Shu, Xiao-Ou; Cai, Qiuyin; Beesley, Jonathan; Kar, Siddhartha P.; et al. (Cancer Epidemiology Biomarkers & Prevention, 2015)
A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored.We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium.Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 × 10(-4); OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r(2) >= 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue.Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2.Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.
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Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1 - Glubb, Dylan M.; Maranian, Mel J.; Michailidou, Kyriaki; Pooley, Karen A.; Meyer, Kerstin B.; Kar, Siddhartha; Carlebur, Saskia; O'Reilly, Martin; Betts, Joshua A.; Hillman, Kristine M.; Kaufmann, Susanne; Beesley, Jonathan; et al. (American Journal of Human Genetics, 2015)
Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell surviva
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First Results of the Detect IVA Study -Everolimus Treatment in Patients with HER2-Negative, Hormone-Receptor Positive Metastatic Breast (MBC) Cancer and Circulating Tumor Cells (CTC) - Friedl, Thomas W. P.; Krause, Sabrina; Fasching, Peter; Schneeweiss, Andreas; Mueller, Volkmar; Riethdorf, Sabine; Taran, Florin-Andrei; Schochter, Fabienne; Polasik, Arkadius; Tzschaschel, Marie; De Gregorio, Amelie; Meier-Stiegen, Franziska; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

Five endometrial cancer risk loci identified through genome-wide association analysis - Cheng, Timothy H. T.; Thompson, Deborah J.; O'Mara, Tracy A.; Painter, Jodie N.; Glubb, Dylan M.; Flach, Susanne; Lewis, Annabelle; French, Juliet D.; Freeman-Mills, Luke; Church, David; Gorman, Maggie; Martin, Lynn; et al. (Nature Genetics, 2016)
We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.
EVALuna2:9326

Fresh and cryopreserved amniotic membrane secrete the trefoil factor family peptide 3 that is well known to promote wound healing - Schulze, Ute; Hampel, Ulrike; Sel, Saadettin; Goecke, Tamme W.; Thaele, Volker; Garreis, Fabian; Paulsen, Friedrich (Histochemistry and Cell Biology, 2012)
Amniotic membrane (AM) is often used for the treatment of ocular surface ulcerations and other corneal defects. Trefoil factor family (TFF) peptide 3 is produced by conjunctival goblet cells, participates in tear film physiology and has also been shown to be involved in ocular surface restitution after corneal injury. In the present study, we questioned whether AM also might be a source of TFF3 and if yes whether the secretion rate of TFF3 is changed by proinflammatory cytokines or by cryoconservation of AM. By means of RT-PCR, the mRNA expression of all three known TFF peptides could be detected in AM. Immunohistochemistry on paraffin-embedded sections localized TFF3 protein and also TFF2 in AM cells and Western blot analysis revealed TFF3 protein in AM. Stimulation experiments with proinflammatory cytokines and subsequent TFF3 ELISA measurements revealed that the secretion rate of fresh or cryoconserved AM was not significantly changed. The results indicate that TFF peptides are produced by AM. TFF3 may contribute to ocular surface wound healing after AM transplantation, but its production by AM is not further inducible by proinflammatory stimuli. Cryopreservation has no effect on the secretion rate of TFF3 supporting the use of cryopreserved AM for transplantation.
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Fresh and cryopreserved ovarian tissue transplantation for preserving reproductive and endocrine function: a systematic review and individual patient data meta-analysis - Khattak, Hajra; Malhas, Rosamund; Craciunas, Laurentiu; Afifi, Yousri; Amorim, Christiani A.; Fishel, Simon; Silber, Sherman; Gook, Debra; Demeestere, Isabelle; Bystrova, Olga; Lisyanskaya, Alla; Manikhas, Georgy; et al. (Human Reproduction Update, 2022)
BACKGROUND Ovarian tissue cryopreservation involves freezing and storing of surgically retrieved ovarian tissue in liquid or vapour nitrogen below -190 degrees C. The tissue can be thawed and transplanted back with the aim of restoring fertility or ovarian endocrine function. The techniques for human ovarian tissue freezing and transplantation have evolved over the last 20 years, particularly in the context of fertility preservation in pre-pubertal cancer patients. Fresh ovarian tissue transplantation, using an autograft or donor tissue, is a more recent development; it has the potential to preserve fertility and hormonal function in women who have their ovaries removed for benign gynaecological conditions. The techniques of ovarian tissue cryopreservation and transplantation have progressed rapidly since inception; however, the evidence on the success of this intervention is largely based on case reports and case series. OBJECTIVE AND RATIONALE The aim of this study was to systematically review the current evidence by incorporating study-level and individual patient-level meta-analyses of women who received ovarian transplants, including frozen-thawed transplant, fresh or donor graft. SEARCH METHODS The review protocol was registered with PROSPERO (CRD42018115233). A comprehensive literature search was performed using MEDLINE, EMBASE, CINAHL and Cochrane Central Register of Controlled Trials from database inception to October 2020. Authors were also contacted for individual patient data if relevant outcomes were not reported in the published manuscripts. Meta-analysis was performed using inverse-variance weighting to calculate summary estimates using a fixed-effects model. OUTCOMES The review included 87 studies (735 women). Twenty studies reported on >= 5 cases of ovarian transplants and were included in the meta-analysis (568 women). Fertility outcomes included pregnancy, live birth and miscarriage rates, and endocrine outcomes included oestrogen, FSH and LH levels. The pooled rates were 37% (95% CI: 32-43%) for pregnancy, 28% (95% CI: 24-34%) for live birth and 37% (95% CI: 30-46%) for miscarriage following frozen ovarian tissue transplantation. Pooled mean for pre-transplant oestrogen was 101.6 pmol/l (95% CI: 47.9-155.3), which increased post-transplant to 522.4 pmol/l (95% CI: 315.4-729; mean difference: 228.24; 95% CI: 180.5-276). Pooled mean of pre-transplant FSH was 66.4 IU/l (95% CI: 52.8-84), which decreased post-transplant to 14.1 IU/l (95% CI: 10.9-17.3; mean difference 61.8; 95% CI: 57-66.6). The median time to return of FSH to a value <25 IU/l was 19 weeks (interquartile range: 15-26 weeks; range: 0.4-208 weeks). The median duration of graft function was 2.5 years (interquartile range: 1.4-3.4 years; range: 0.7-5 years). The analysis demonstrated that ovarian tissue cryopreservation and transplantation could restore reproductive and hormonal functions in women. Further studies with larger samples of well-characterized populations are required to define the optimal retrieval, cryopreservation and transplantation processes. WIDER IMPLICATIONS Ovarian tissue cryopreservation and transplantation may not only be effective in restoring fertility but also the return of reproductive endocrine function. Although this technology was developed as a fertility preservation option, it may have the scope to be considered for endocrine function preservation.
CRIS-Team WoS Importer:2022-03-11

From the Past to the Future The 1st Volume of "Obstetrics and Women's Medicine - Research Findings for Practice". A Review of the 75th Birthday - Ebert, Andreas D.; Beckmann, Matthias; Wallwiener, Diethelm; David, Matthias (Geburtshilfe und Frauenheilkunde, 2016)
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Frühes Mammakarzinom: Aktuelle Strategien in der System- und Radiotherapie: 17. Internationale St.-Gallen-Konsensuskonferenz vor dem Hintergrund deutscher Therapieempfehlungen diskutiert - Schneeweiss, Andreas; Huober, Jens; Brucker, Sara Y.; Budach, Wilfried; Denkert, Carsten; Fasching, Peter; Haidinger, Renate; Harbeck, Nadia; Jackisch, Christian; Janni, Wolfgang; Krug, David; Kühn, Thorsten; et al. (Onkologe, 2021)
Background: The St. Gallen (SG) International Consensus Conference on the treatment of patients with primary breast cancer (SG-BCC) has been held regularly for more than 30 years. As the international panel of the St. Gallen conference consists of experts from different countries and different disciplines, the consensus voting that results from these meetings represents an international cross-section of opinions. Rationale: From the German perspective it is considered useful to discuss the results of the consensus voting with respect to the clinical routine in Germany. Basis: The discussion is based on the German treatment guidelines of the Working Group of Gynecologic Oncology of the German Cancer Society (AGO 2021) which are updated annually and the German S3 guideline. Results: The topic of this year’s 17th St. Gallen Consensus Conference was “Customizing local and systemic therapies for women with early breast cancer”. The rationale behind this is that each treatment decision must also consider the cancer-specific situation of the individual patient. In this article, the most important results of the SG-BCC in systemic treatment and radiotherapy are discussed.
CRIS-Team Scopus Importer:2021-07-09
Keywords: Consensus recommendations 2021; Local treatment; Systemic treatment; Treatment de-escalation; Treatment of early breast cancer

Früh- und Spättoxizitäten sowie sozialmedizinisch-relevante Folgestörungen bei Brustkrebs-Patientinnen als Basis der Abschätzung des Reha-Bedarfes - Hass, Holger G.; Seywald, Marianne; Stepien, Jürgen; Muco, Blerta; Tanriverdi, Miro; Beckmann, Matthias; Kunzmann, Volker; Wöckel, Achim (Rehabilitation (Germany), 2021)
Introduction Reasonable to the improved prognosis of breast cancer (BC) long-term toxicities and side effects of oncological therapy gain more importance for work ability and social life of BC patients. Aim of this study was the analysis of occurence and differences of treatment-related side effects in relation to type of rehabilitation (so-called AHB vs. later rehabilitation) after therapy for BC. Methods Clinical and patient related data as early and late toxicities after oncological treatment of 8.000 patients with BC (55.7±10.4y) were analyzed and compared with current literature. Results In 23.9% a mastectomy was performed, in 87.3% radiotherapy. In most cases an additional systemic treatment (57,6% CTX, 15,1% anti-Her2, 71% antihormonal treatment) was carried out. In 8.1% women suffered from recurrent or metastatic BC. As most common side effects of multimodal treatment weakness/fatigue (73,6%), insomnia (51,9%), CIPN (33%), lymph edema (13,9%) and drug-induced arthralgia (24,8%) were detected. In addition, 60.4% of women reported high levels of psychological distress. Shortly after therapy typical side effects were drug-induced toxicities (Leucopenia, p<0.0001; anemia, p<0.001; weakness/fatigue p<0.001; CIPN, p<0.0001), whereas in a later course chronic lymphedema (p<0.0001), chronic or recurrent disease (p<0.0001), status after mastectomy (p<0.0001) and psychological distress (p<0.0001) were significantly more often seen. Moreover, in this collective patients were significantly younger (53,7±9,8 vs. 56,3±10,7y). Conclusions In BC patients, significantly different impairments and toxicities were documented between patients with early rehabilitation and patients with later onset of rehabilitation. These data may help to establish more individual and focused rehabilitation concepts in specialized centers.
CRIS-Team Scopus Importer:2021-04-30
Keywords: breast cancer; CIPN; fatigue; indoor rehabilitation; psychological distress

Full field digital mammography (FFDM) versus cmos technology, specimen radiography system (SRS) and tomosynthesis (DBT) - Which system can optimise surgical therapy? - Schulz-Wendtland, Rüdiger; Dilbat, G.; Bani, Mayada; Fasching, Peter; Heusinger, K.; Lux, Michael P.; Löhberg, Christian; Brehm, Barbara; Hammon, Matthias; Saake, Marc; Dankerl, Peter; Jud, Sebastian; et al. (Geburtshilfe und Frauenheilkunde, 2013)
Aim: This prospective clinical study aimed to evaluate whether it would be possible to reduce the rate of re-excisions using CMOS technology, a specimen radiography system (SRS) or digital breast tomosynthesis (DBT) compared to a conventional full field digital mammography (FFDM) system. Material and Method: Between 12/2012 and 2/2013 50 patients were diagnosed with invasive breast cancer (BI-RADS™ 5). After histological verification, all patients underwent breast-conserving therapy with intraoperative imaging using 4 different systems and differing magnifications: 1. Inspiration™ (Siemens, Erlangen, Germany), amorphous selenium, tungsten source, focus 0.1 mm, resolution 85 m pixel pitch, 8 lp/mm; 2. BioVision™ (Bioptics, Tucson, AZ, USA), CMOS technology, photodiode array, flat panel, tungsten source, focus 0.05, resolution 50 m pixel pitch, 12 lp/mm; 3. the Trident™ specimen radiography system (SRS) (Hologic, Bedford, MA, USA), amorphous selenium, tungsten source, focus 0.05, resolution 70 m pixel pitch, 7.1 lp/mm; 4. tomosynthesis (Siemens, Erlangen, Germany), amorphous selenium, tungsten source, focus 0.1 mm, resolution 85 m pixel pitch, 8 lp/mm, angular range 50 degrees, 25 projections, scan time > 20 s, geometry: uniform scanning, reconstruction: filtered back projection. The 600 radiographs were prospectively shown to 3 radiologists. Results: Of the 50 patients with histologically proven breast cancer (BI-RADS™ 6), 39 patients required no further surgical therapy (re-excision) after breast-conserving surgery. A retrospective analysis (n = 11) showed a significant (p < 0.05) increase of sensitivity with the BioVision™, the Trident™ and tomosynthesis compared to the Inspiration™ at a magnification of 1.0: 2.0 or 1.0: 1.0 (tomosynthesis) (2.6, 3.3 or 3.6 %), i.e. re-excision would not have been necessary in 2, 3 or 4 patients, respectively, compared to findings obtained with a standard magnification of 1.0: 1.0. Conclusion: The sensitivity of the BioVision™, the Trident™ and tomosynthesis was significantly (p < 0.05) higher and the rate of re-excisions was reduced compared to FFDM using a conventional detector at a magnification of 2.0 but without zooming. © Georg Thieme Verlag KG Stuttgart New York.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Breast; breast cancer; breast malignancy; mammography

Fully automated nipple detection in 3D breast ultrasound images - Wang, Lei; Böhler, Tobias; Zöhrer, Fabian; Georgii, Joachim; Rauh, Claudia; Fasching, Peter; Brehm, Barbara; Schulz-Wendtland, Rüdiger; Beckmann, Matthias; Uder, Michael; Hahn, Horst K. (Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), 2014)
Nipple position provides useful diagnostic informations in reading automated 3D breast ultrasound (ABUS) images. The identification of nipples is required to localize and determine the quadrants of breast lesions. Additionally, the nipple position serves as an effective landmark to register an ABUS image to other imaging modalities, such as digital mammography, breast magnet resonance imaging (MRI), or tomosynthesis. Nevertheless, the presence of speckle noise induced by interference waves and variant imaging directions in ultrasonography poses challenges to the task. In this work, we propose a fast and automated algorithm to detect nipples in 3D breast ultrasound images. The method fully takes advantages of the consistent characteristics of ultrasonographic signals observed at nipples and employs a multi-scale Laplacian-based blob detector to eventually identify nipple positions. The accuracy of the proposed method was tested on 113 ABUS images, resulting in a distance error of 6.6±8.9 mm (mean ±std). © 2014 Springer International Publishing.
CRIS-Team Scopus Importer:2023-03-08

Fully automatic HER2 tissue segmentation for interpretable HER2 scoring - Öttl, Mathias; Steenpaß, Jana; Wilm, Frauke; Qiu, Jingna; Rübner, Matthias; Lang-Schwarz, Corinna; Taverna, Cecilia; Tava, Francesca; Hartmann, Arndt; Hübner, Hanna; Beckmann, Matthias; Fasching, Peter; et al. (Journal of Pathology Informatics, 2025)
Breast cancer is the most common cancer in women, with HER2 (human epidermal growth factor receptor 2) overexpression playing a critical role in regulating cell growth and division. HER2 status, assessed according to established scoring guidelines, offers important information for treatment selection. However, the complexity of the task leads to variability in human rater assessments. In this work, we propose a fully automated, interpretable HER2 scoring pipeline based on pixel-level semantic segmentations, designed to align with clinical guidelines. Using polygon annotations, our method balances annotation effort with the ability to capture fine-grained details and larger structures, such as non-invasive tumor tissue. To enhance HER2 segmentation, we propose the use of a Wasserstein Dice loss to model class relationships, ensuring robust segmentation and HER2 scoring performance. Additionally, based on observations of pathologists' behavior in clinical practice, we propose a calibration step to the scoring rules, which positively impacts the accuracy and consistency of automated HER2 scoring. Our approach achieves an F1 score of 0.832 on HER2 scoring, demonstrating its effectiveness. This work establishes a potent segmentation pipeline that can be further leveraged to analyze HER2 expression in breast cancer tissue.
CRIS-Team Scopus Importer:2025-04-11
Keywords: Deep learning; HER2; HER2 scoring; Histopathology; Semantic segmentation

Fumarate hydratase (FH) deficiency in uterine leiomyomas: recognition by histological features versus blind immunoscreening - Siegler, Lisa; Erber, Ramona; Burghaus, Stefanie; Brodkorb, Tobias; Wachter, David; Wilkinson, Nafisa; Bolton, James; Stringfellow, Helen; Haller, Florian; Beckmann, Matthias; Hartmann, Arndt; Agaimy, Abbas (Virchows Archiv, 2018)
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is a rare autosomal dominant disease caused by germline mutations in the fumarate hydratase (FH) gene. Affected individuals develop cutaneous and uterine leiomyomas and aggressive RCC. To date, only few publications described the frequency and morphology of FH-deficient uterine leiomyomas. We reviewed 22 cases collected over 8 years from routine and consultation files based on distinctive histological features. In addition, we screened 580 consecutive uterine leiomyomas from 484 patients, 23 extra-uterine and 8 uterine leiomyosarcomas, and 6 leiomyomas with bizarre nuclei for FH loss using immunohistochemistry (IHC) on tissue microarrays (TMAs). All 22 FH-deficient cases were suspected on H&E sections and confirmed by FH IHC. Patients' ages ranged from 25 to 70 years (median 36). Seventeen patients had multiple nodules (2-14) measuring up to 11.8 cm. None of the patients had stigmata or family history of the HLRCC syndrome. Histologically, all FH-deficient tumors showed consistent and reproducible features as reported previously. FH loss was detected in 2/534 evaluable leiomyomas (0.4%), but in none of leiomyosarcomas. Two of six leiomyomas with bizarre nuclei were FH-deficient. FH-deficient uterine leiomyomas are rare in routine material (= 0.4%). They can be reliably identified or suspected by consistent morphological features. Our data showed predictive morphology to be superior to blind IHC screening for detecting them. The relationship of FH-deficient uterine smooth muscle tumors to the HLRCC syndrome needs further clarification.
EVALuna2:33962

Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus - Buckley, Melissa A.; Woods, Nicholas T.; Tyrer, Jonathan P.; Mendoza-Fandino, Gustavo; Lawrenson, Kate; Hazelett, Dennis J.; Najafabadi, Hamed S.; Gjyshi, Anxhela; Carvalho, Renato S.; Lyra, Paulo C.; Coetzee, Simon G.; Shen, Howard C.; et al. (Cancer Research, 2019)
Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/ matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer.
CRIS-Team WoS Importer:2019-02-21

Functional Heterogeneity of Umbilical Cord Blood Monocyte-Derived Dendritic Cells - Schweiger, Petra; Hamann, Livia; Strobel, Julian; Weisbach, Volker; Wandersee, Alexandra; Christ, Julia; Kehl, Sven; Weidenthaler, Filip; Antoniadis, Sophia; Hackstein, Holger; Cunningham, Sarah (Journal of Immunology, 2024)
Human umbilical cord blood (UCB) represents a unique resource for hematopoietic stem cell transplantation for children and patients lacking suitable donors. UCB harbors a diverse set of leukocytes such as professional APCs, including monocytes, that could act as a novel source for cellular therapies. However, the immunological properties of UCB monocytes and monocyte-derived dendritic cells (MoDCs) are not fully characterized. In this study, we characterized the phenotype and functions of UCB-MoDCs to gauge their potential for future applications. UCB exhibited higher frequencies of platelets and lymphocytes as well as lower frequencies of neutrophils in comparison with adult whole blood. Leukocyte subset evaluation revealed significantly lower frequencies of granulocytes, NK cells, and CD14+CD16− monocytes. Surface marker evaluation revealed significantly lower rates of costimulatory molecules CD80 and CD83 while chemokine receptors CCR7 and CXCR4, as well as markers for Ag presentation, were similarly expressed. UCB-MoDCs were sensitive to TLR1–9 stimulation and presented quantitative differences in the release of proinflammatory cytokines. UCB-MoDCs presented functional CCR7-, CXCR4-, and CCR5-associated migratory behavior as well as adequate receptor- and micropinocytosis-mediated Ag uptake. When cocultured with allogeneic T lymphocytes, UCB-MoDCs induced weak CD4+ T lymphocyte proliferation, CD71 expression, and release of IFN-γ and IL-2. Taken together, UCB-MoDCs present potentially advantageous properties for future medical applications.<br

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus - Lawrenson, Kate; Kar, Siddhartha; Mccue, Karen; Kuchenbaeker, Karoline; Michailidou, Kyriaki; Tyrer, Jonathan; Beesley, Jonathan; Ramus, Susan J.; Li, Qiyuan; Delgado, Melissa K.; Lee, Janet M.; Aittomaki, Kristiina; et al. (Nature Communications, 2016)
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
EVALuna2:33322

Galactography with Tomosynthesis Technique (Galactomosynthesis) - Renaissance of a Method? - Schulz-Wendtland, Rüdiger; Preuss, Caroline; Fasching, Peter; Löhberg, Christian; Lux, Michael P.; Emons, Julius; Beckmann, Matthias; Uder, Michael; Mueller-Schimpfle, Markus (Geburtshilfe und Frauenheilkunde, 2018)
Introduction: For decades, conventional galactography was the only imaging technique capable of showing the mammary ducts. Today, diagnosis is based on a multimodal concept which combines high-resolution ultrasound with magnetic resonance (MR) mammography and ductoscopy/galactoscopy and has a sensitivity and specificity of up to 95%. This study used tomosynthesis in galactography for the first time and compared the synthetic digital 2D full-field mammograms generated with this technique with the images created using the established method of ductal sonography. Both methods should be able to detect invasive breast cancers and their precursors such as ductal carcinoma in situ (DCIS) as well as being able to identify benign findings. Material and Methods: Five patients with pathological nipple discharge were examined using ductal sonography, contrast-enhanced 3D galactography with tomosynthesis and the synthetic digital 2D full-field mammograms generated with the latter method. Evaluation of the images created with the different imaging modalities was done by three investigators with varying levels of experience with complementary breast diagnostics (1, 5 and 15 years), and their evaluations were compared with the histological findings. Results: All 3 investigators independently evaluated the images created with ductal sonography, contrast-enhanced 3D galactography with tomosynthesis, and generated synthetic digital 2D full-field mammograms. Their evaluations were compared with the histopathological assessment of the surgical specimens resected from the 5 patients. There was 1 case of invasive breast cancer, 2 cases with ductal carcinoma in situ and 2 cases with benign findings. All 3 investigators made more mistakes when they used the standard imaging technique of ductal sonography to diagnose suspicious lesions than when they used contrast-enhanced galactography with tomosynthesis and the generated synthetic digital 2D full-field mammograms. Conclusion: This is the first time breast tomosynthesis was used in galactography (galactomosynthesis) to create digital 3-dimensional images of suspicious findings. When used together with the generated synthetic digital 2D full-field mammograms, it could be a useful complementary procedure for the diagnosis of breast anomalies and could herald a renaissance of this method. Compared with high-resolution ductal ultrasound, the investigators achieved better results with contrast-enhanced galactography using tomosynthesis and the generated synthetic digital 2D full-field mammograms, as confirmed by histopathological findings.
EVALuna2:34697

Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer—results from the randomized phase III SUCCESS-A trial - de Gregorio, Amelie; Häberle, Lothar; Fasching, Peter; Müller, Volkmar; Schrader, Iris; Lorenz, Ralf; Forstbauer, Helmut; Friedl, Thomas W.P.; Bauer, Emanuel; de Gregorio, Nikolaus; Deniz, Miriam; Fink, Visnja; et al. (Breast Cancer Research, 2020)
Background: When chemotherapy is indicated in patients with early breast cancer, regimens that contain anthracyclines and taxanes are established standard treatments. Gemcitabine has shown promising effects on the response and prognosis in patients with metastatic breast cancer. The SUCCESS-A trial (NCT02181101) examined the addition of gemcitabine to a standard chemotherapy regimen in high-risk early breast cancer patients. Methods: A total of 3754 patients with at least one of the following characteristics were randomly assigned to one of the two treatment arms: nodal positivity, tumor grade 3, age ≤ 35 years, tumor larger than 2 cm, or negative hormone receptor status. The treatment arms received either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by three cycles of docetaxel (FEC → Doc); or three cycles of FEC followed by three cycles of docetaxel and gemcitabine (FEC → Doc/Gem). The primary study aim was disease-free survival (DFS), and the main secondary objectives were overall survival (OS) and safety. Results: No differences were observed in the 5-year DFS or OS between FEC → Doc and FEC → Doc/Gem. The hazard ratio was 0.93 (95% CI, 0.78 to 1.12; P = 0.47) for DFS and 0.94 (95% CI, 0.74 to 1.19; P = 0.60) for OS. For patients treated with FEC → Doc and FEC → Doc/Gem, the 5-year probabilities of DFS were 86.6% and 87.2%, and the 5-year probabilities of OS were 92.8% and 92.5%, respectively. Conclusion: Adding gemcitabine to a standard chemotherapy does not improve the outcomes in patients with high-risk early breast cancer and should therefore not be included in the adjuvant treatment setting. Trial registration: Clinicaltrials.gov NCT02181101 and EU Clinical Trials Register EudraCT 2005-000490-21. Registered September 2005.
CRIS-Team Scopus Importer:2020-10-30
Keywords: Chemotherapy; Early breast cancer; Gemcitabine

Gene-environment interactions involving functional variants: Results from the Breast Cancer Association Consortium - Barrdahl, Myrto; Rudolph, Anja; Hopper, John L.; Southey, Melissa C.; Broeks, Annegien; Fasching, Peter; Beckmann, Matthias; Gago-Dominguez, Manuela; Castelao, J. Esteban; Guenel, Pascal; Truong, Therese; Bojesen, Stig E.; et al. (International Journal of Cancer, 2017)
Investigating the most likely causal variants identified by fine-mapping analyses may improve the power to detect gene-environment interactions. We assessed the interplay between 70 single nucleotide polymorphisms identified by genetic fine-scale mapping of susceptibility loci and 11 epidemiological breast cancer risk factors in relation to breast cancer. Analyses were conducted on up to 58,573 subjects (26,968 cases and 31,605 controls) from the Breast Cancer Association Consortium, in one of the largest studies of its kind. Analyses were carried out separately for estrogen receptor (ER) positive (ER+) and ER negative (ER-) disease. The Bayesian False Discovery Probability (BFDP) was computed to assess the noteworthiness of the results. Four potential gene-environment interactions were identified as noteworthy (BFDP < 0.80) when assuming a true prior interaction probability of 0.01. The strongest interaction result in relation to overall breast cancer risk was found between CFLAR-rs7558475 and current smoking (ORint = 0.77, 95% CI: 0.67-0.88, pint = 1.8 × 10-4 ). The interaction with the strongest statistical evidence was found between 5q14-rs7707921 and alcohol consumption (ORint =1.36, 95% CI: 1.16-1.59, pint = 1.9 × 10-5 ) in relation to ER- disease risk. The remaining two gene-environment interactions were also identified in relation to ER- breast cancer risk and were found between 3p21-rs6796502 and age at menarche (ORint = 1.26, 95% CI: 1.12-1.43, pint =1.8 × 10-4 ) and between 8q23-rs13267382 and age at first full-term pregnancy (ORint = 0.89, 95% CI: 0.83-0.95, pint = 5.2 × 10-4 ). While these results do not suggest any strong gene-environment interactions, our results may still be useful to inform experimental studies. These may in turn, shed light on the potential interactions observed.
EVALuna2:36122

Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies? - Park, Jooyong; Choi, Ji-Yeob; Choi, Jaesung; Chung, Seokang; Song, Nan; Park, Sue K.; Han, Wonshik; Noh, Dong-Young; Ahn, Sei-Hyun; Lee, Jong Won; Kim, Mi Kyung; Jee, Sun Ha; et al. (Cancers, 2021)
Simple Summary
CRIS-Team WoS Importer:2021-06-04

Gene expression and epigenetic aberrations in F1-placentas fathered by obese males - Mitchell, Megan; Strick, Reiner; Strissel, Pamela; Dittrich, Ralf; Mcpherson, Nicole O.; Lane, Michelle; Pliushch, Galyna; Potabattula, Ramya; Haaf, Thomas; El Hajj, Nady (Molecular Reproduction and Development, 2017)
Gene expression and/or epigenetic deregulation may have consequences for sperm and blastocysts, as well as for the placenta, together potentially contributing to problems observed in offspring. We previously demonstrated specific perturbations of fertilization, blastocyst formation, implantation, as well as aberrant glucose metabolism and adiposity in offspring using a mouse model of paternal obesity. The current investigation analyzed gene expression and methylation of specific CpG residues in F1 placentas of pregnancies fathered by obese and normal-weight male mice, using real-time PCR and bisulfite pyrosequencing. Our aim was to determine if paternal obesity deregulated placental gene expression and DNA methylation when compared to normal-weight males. Gene methylation of sperm DNA was analyzed and compared to placentas to address epigenetic transmission. Of the 10 paternally expressed genes (Pegs), 11 genes important for development and transport of nutrients, and the long-terminal repeat Intracisternal A particle (IAP) elements, derived from a member of the class II endogenous retroviral gene family, we observed a significant effect of paternal diet-induced obesity on deregulated expression of Peg3, Peg9, Peg10, and the nutrient transporter gene Slc38a2, and aberrant DNA methylation of the Peg9 promoter in F1 placental tissue. Epigenetic changes in Peg9 were also found in sperm from obese fathers. We therefore propose that paternal obesity renders changes in gene expression and/or methylation throughout the placental genome, which could contribute to the reproductive problems related to fertility and to the metabolic, long-term health impact on offspring.
EVALuna2:36349

Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes. - Meagher, Nicola S.; Gorringe, Kylie L.; Wakefield, Matthew J.; Bolithon, Adelyn; Pang, Chi Nam Ignatius; Chiu, Derek S.; Anglesio, Michael S.; Mallitt, Kylie-Ann; Doherty, Jennifer A.; Harris, Holly R.; Schildkraut, Joellen M.; Berchuck, Andrew; et al. (Clinical Cancer Research, 2022)
PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.
EVALuna2:513963

Gene Expression Signatures of BRCAness and Tumor Inflammation Define Subgroups of Early-Stage Hormone Receptor-Positive Breast Cancer Patients - Schroth, Werner; Buettner, Florian A.; Kandabarau, Siarhei; Hoppe, Reiner; Fritz, Peter; Kumbrink, Joerg; Kirchner, Thomas; Brauer, Heather A.; Ren, Yuqi; Henderson, David; Madden, Stephen F.; Sauer, Georg; et al. (Clinical Cancer Research, 2020)
Purpose: Patients with estrogen receptor- and/or progesterone receptor-positive, early breast cancer benefit from hormonal treatment, yet high global death burdens due to high prevalence and long-term recurrence risk call for biomarkers to guide additional treatment approaches.
CRIS-Team WoS Importer:2021-02-05

Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2 - Kraus, Cornelia; Hoyer, Juliane; Vasileiou, Georgia; Wunderle, Marius; Lux, Michael P.; Fasching, Peter; Krumbiegel, Mandy; Uebe, Steffen; Reuter, Miriam; Beckmann, Matthias; Reis, André (International Journal of Cancer, 2017)
Breast and ovarian cancer (BC/OC) predisposition has been attributed to a number of high- and moderate to low-penetrance susceptibility genes. With the advent of next generation sequencing (NGS) simultaneous testing of these genes has become feasible. In this monocentric study, we report results of panel-based screening of 14 BC/OC susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, CHEK2, PALB2, ATM, NBN, CDH1, TP53, MLH1, MSH2, MSH6 and PMS2) in a group of 581 consecutive individuals from a German population with BC and/or OC fulfilling diagnostic criteria for BRCA1 and BRCA2 testing including 179 with a triple-negative tumor. Altogether we identified 106 deleterious mutations in 105 (18%) patients in 10 different genes, including seven different exon deletions. Of these 106 mutations, 16 (15%) were novel and only six were found in BRCA1/2. To further characterize mutations located in or nearby splicing consensus sites we performed RT-PCR analysis which allowed confirmation of pathogenicity in 7 of 9 mutations analyzed. In PALB2, we identified a deleterious variant in six cases. All but one were associated with early onset BC and a positive family history indicating that penetrance for PALB2 mutations is comparable to BRCA2. Overall, extended testing beyond BRCA1/2 identified a deleterious mutation in further 6% of patients. As a downside, 89 variants of uncertain significance were identified highlighting the need for comprehensive variant databases. In conclusion, panel testing yields more accurate information on genetic cancer risk than assessing BRCA1/2 alone and wide-spread testing will help improve penetrance assessment of variants in these risk genes.
EVALuna2:9340

Generalization of a deep learning model for HER2 status predictions on H&E-stained whole slide images derived from 3 neoadjuvant clinical studies - Haegele, M.; Mueller, K-R.; Denkert, C.; Schneeweiss, Andreas; Sinn, B. V.; Untch, M.; Van Mackelenbergh, M. T.; Jackisch, C.; Nekljudova, V.; Karn, T.; Alber, M.; Marme, F.; et al. (ANNALS OF ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-12-23

Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent - Guo, Yan; Andersen, Shaneda Warren; Shu, Xiao-Ou; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Garcia-Closas, Montserrat; Milne, Roger L.; Schmidt, Marjanka K.; Chang-Claude, Jenny; Dunning, Allison; Bojesen, Stig E.; et al. (Plos Medicine, 2016)
BACKGROUND: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. METHODS: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. RESULTS: In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31-0.62, p = 9.91 × 10-8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46-0.71, p = 1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60-0.84, p = 1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. CONCLUSIONS: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.
EVALuna2:33324

Genetic Breast Cancer Susceptibility Variants and Prognosis in the Prospectively Randomized SUCCESS A Study - Hein, Alexander; Rack, B.; Li, L.; Ekici, Arif Bülent; Reis, André; Lux, Michael P.; Cunningham, J. M.; Rübner, Matthias; Fridley, B. L.; Schneeweiss, A.; Tesch, H.; Lichtenegger, W.; et al. (Geburtshilfe und Frauenheilkunde, 2017)
Large-scale genotyping studies have identified over 70 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. However, knowledge regarding genetic risk factors associated with the prognosis is limited. The aim of this study was therefore to investigate the prognostic effect of nine known breast cancer risk SNPs. BC patients (n = 1687) randomly sampled in an adjuvant, randomized phase III trial (SUCCESS A study) were genotyped for nine BC risk SNPs: rs17468277 (CASP8) , rs2981582 (FGFR2) , rs13281615(8q24), rs3817198 (LSP1) , rs889312 (MAP3K1) , rs3803662 (TOX3) , rs13387042(2q35), rs4973768 (SLC4A7) , rs6504950 (COX11) . Cox proportional hazards models were used to test the SNPs' association with overall survival (OS) and progression-free survival (PFS). Additional analyses were carried out for molecular subgroups. rs3817198 in LSP1 (lymphocyte-specific protein 1) was the only SNP that significantly influenced OS (p = 0.01) and PFS (p < 0.01) in the likelihood ratio test comparing the genetic survival model with the clinical survival model. In the molecular subgroups, triple-negative patients with two minor alleles in rs3817198 had a much better prognosis relative to OS (adjusted HR 0.03; 95% CI 0.002 - 0.279) and PFS (HR 0.09; 95% CI 0.02 - 0.36) than patients with the common alleles. The same effect on PFS was shown for patients with luminal A tumors (HR 0.19; 95% CI 0.05 - 0.84), whereas patients with luminal B tumors had a poorer PFS with two minor alleles (HR 2.13; 95% CI 1.02 - 4.40). The variant in rs3817198 has a prognostic effect particularly in the subgroup of patients with triple-negative BC, suggesting a possible link with immunomodulation and BC.
EVALuna2:9355

Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk - Yang, Yaohua; Wu, Lang; Shu, Xiang; Lu, Yingchang; Shu, Xiao-Ou; Cai, Qiuyin; Beeghly-Fadiel, Alicia; Li, Bingshan; Ye, Fei; Berchuck, Andrew; Anton-Culver, Hoda; Banerjee, Susana; et al. (Cancer Research, 2019)
DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 x 10(-7). Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression.
CRIS-Team WoS Importer:2019-02-21

Genetic modifiers of CHEK2*1100delC-associated breast cancer risk - Muranen, Taru A.; Greco, Dario; Blomqvist, Carl; Aittomaki, Kristiina; Khan, Sofia; Hogervorst, Frans; Verhoef, Senno; Pharoah, Paul D. P.; Dunning, Alison M.; Shah, Mitul; Luben, Robert; Bojesen, Stig E.; et al. (Genetics in Medicine, 2017)
PURPOSE: CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). METHODS: Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. RESULTS: The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average. CONCLUSION: Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.
EVALuna2:36144

Genetic overlap between endometriosis and endometrial cancer: evidence from cross-disease genetic correlation and GWAS meta-analyses - Painter, Jodie N.; O'Mara, Tracy A.; Morris, Andrew P.; Cheng, Timothy H. T.; Gorman, Maggie; Martin, Lynn; Hodson, Shirley; Jones, Angela; Martin, Nicholas G.; Gordon, Scott; Henders, Anjali K.; Attia, John; et al. (Cancer Medicine, 2018)
Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg = 0.23, P = 9.3 × 10-3 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10-3 ) and concordance in effect direction (P = 2.0 × 10-3 ) between the two diseases. Cross-disease GWAS meta-analysis highlighted 13 distinct loci associated at P ≤ 10-5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10-8 , OR = 1.11, 95% CI = 1.07-1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross-disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.
EVALuna2:34631

Genetic Polymorphisms and Correlation with Treatment-Induced Cardiotoxicity and Prognosis in Patients with Breast Cancer - Peddi, Parvin F.; Fasching, Peter; Liu, Duan; Quinaux, Emmanuel; Robert, Nicholas J.; Valero, Vicente; Crown, John; Falkson, Carla; Brufsky, Adam; Cunningham, Julie M.; Weinshilboum, Richard M.; Pienkowski, Tadeusz; et al. (Clinical Cancer Research, 2022)
PURPOSE: Cardiac toxicity is a serious potential complication of HER2-directed therapies and anthracyclines. HER2 codon 655 and SLC28A3 gene polymorphisms have been reported to be associated with cardiac toxicity from anti-HER2 and anthracycline therapy, respectively. Association of the polymorphism at HER2 codon 655 with prognosis has also been reported. EXPERIMENTAL DESIGN: Whole blood samples from patients treated on a randomized adjuvant breast cancer trial (BCIRG-006) that compared chemotherapy with or without trastuzumab plus either anthracycline or nonanthracycline chemotherapy were tested for genetic polymorphisms in HER2 codon 655 and SLC28A3. Genotypes were correlated with cardiac function and disease-free survival (DFS) outcomes. RESULTS: Of 3,222 patients enrolled in BCIRG-006, 662 patient samples were successfully genotyped for the rs1136201 allele in HER2 (codon 655): 424 (64%) were AA, 30 (4.5%) were GG, and 208 (31%) were AG genotype. In addition, 665 patient samples were successfully genotyped for the rs7853758 allele in the SLC28A3 gene: 19 (3%) were AA, 475 (71%) were GG, and 171 (26%) were AG genotype. Follow-up time was 10 years. No correlation between DFS, cardiac event rate, or mean left ventricular ejection fraction (LVEF) and rs1136201 genotype was seen in the trastuzumab-treated or non-trastuzumab-treated patients. Moreover, mean LVEF and cardiac event rates were similar in all rs7853758 genotype groups treated with anthracycline-based therapy. CONCLUSIONS: In the largest study to date to evaluate whether two polymorphisms are associated with DFS and/or cardiac toxicity in HER2-positive breast cancer treated with trastuzumab and/or anthracyclines, we observed no correlation.
CRIS-Team Scopus Importer:2022-05-20

Genetic predictors of chemotherapy-related amenorrhea in women with breast cancer - Ruddy, Kathryn J.; Schaid, Daniel J.; Partridge, A. H.; Larson, Nicholas B.; Batzler, Anthony; Häberle, Lothar; Dittrich, Ralf; Widschwendter, P.; Fink, Visnja; Bauer, Emanuel; Schwitulla, Judith; Rübner, Matthias; et al. (Fertility and Sterility, 2019)
Objective: To study how genetics may play a role in determining risk of chemotherapy-related amenorrhea (CRA) in young women with breast cancer. Design: Genome-wide association study. Setting: Not applicable. Patient(s): Premenopausal women ≤45 years of age enrolled in one of these three trials were included if they had at least one menstrual case report form after chemotherapy ended and if they were of European ancestry. Forms during and up to 3 months after receipt of GnRH agonist were excluded. Intervention(s): None. Main Outcome Measure(s): The association of single-nucleotide polymorphisms with post-chemotherapy menstruation adjusted for trial and arm, age, tamoxifen use, and nodal status. Result(s): The median age of the 1,168 women was 41 years (range 19–45). Among these, 457 (39%) never resumed menses after chemotherapy. Older age, tamoxifen use, and node-negative disease were associated with increased risk of CRA. Adjusting for these, rs147451859, in an intron of PPCDC (phosphopantothenoylcysteine decarboxylase), and rs17587029, located 5′ upstream of RPS20P11 (ribosomal protein S20 pseudogene 11), were associated with post-chemotherapy menstruation. Conclusion(s): Genetic variation may contribute to risk of CRA. Better prediction of who will experience CRA may inform reproductive and treatment decision making in young women with cancer.
CRIS-Team Scopus Importer:2019-08-06
Keywords: amenorrhea; Breast neoplasms; drug therapy; toxicity

Genetic predisposition to ductal carcinoma in situ of the breast - Petridis, Christos; Brook, Mark N.; Shah, Vandna; Kohut, Kelly; Gorman, Patricia; Caneppele, Michele; Levi, Dina; Papouli, Efterpi; Orr, Nick; Cox, Angela; Cross, Simon S.; Dos-Santos-Silva, Isabel; et al. (Breast Cancer Research, 2016)
BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci. METHODS: To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip. RESULTS: Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing. Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC. We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10(-8). CONCLUSION: In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist.
EVALuna2:33330

Genetic predisposition to in situ and invasive lobular carcinoma of the breast - Sawyer, Elinor; Roylance, Rebecca; Petridis, Christos; Brook, Mark N.; Nowinski, Salpie; Papouli, Efterpi; Fletcher, Olivia; Pinder, Sarah; Hanby, Andrew; Kohut, Kelly; Gorman, Patricia; Caneppele, Michele; et al. (PLoS Genetics, 2014)
Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.
EVALuna2:9234

Genetic risk factors for ovarian cancer and their role for endometriosis risk - Burghaus, Stefanie; Fasching, Peter; Haeberle, Lothar; Rübner, Matthias; Buechner, Kathrin; Blum, Simon; Engel, Anne; Ekici, Arif Bülent; Hartmann, Arndt; Hein, Alexander; Beckmann, Matthias; Renner, Stefan (Gynecologic Oncology, 2017)
Several genetic variants have been validated as risk factors for ovarian cancer. Endometriosis has also been described as a risk factor for ovarian cancer. Identifying genetic risk factors that are common to the two diseases might help improve our understanding of the molecular pathogenesis potentially linking the two conditions.In a hospital-based case-control analysis, 12 single nucleotide polymorphisms (SNPs), validated by the Ovarian Cancer Association Consortium (OCAC) and the Collaborative Oncological Gene-environment Study (COGS) project, were genotyped using TaqMan® OpenArray(TM) analysis. The cases consisted of patients with endometriosis, and the controls were healthy individuals without endometriosis. A total of 385 cases and 484 controls were analyzed. Odds ratios and P values were obtained using simple logistic regression models, as well as from multiple logistic regression models with adjustment for clinical predictors.rs11651755 in HNF1B was found to be associated with endometriosis in this case-control study. The OR was 0.66 (95% CI, 0.51 to 0.84) and the P value after correction for multiple testing was 0.01. None of the other genotypes was associated with a risk for endometriosis.As rs11651755 in HNF1B modified both the ovarian cancer risk and also the risk for endometriosis, HNF1B may be causally involved in the pathogenetic pathway leading from endometriosis to ovarian cancer.
EVALuna2:6871

Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer - Painter, Jodie N.; O'Mara, Tracy A.; Marquart, Louise; Webb, Penelope M.; Attia, John; Medland, Sarah E.; Cheng, Timothy; Dennis, Joe; Holliday, Elizabeth G.; Mcevoy, Mark; Scott, Rodney J.; Ahmed, Shahana; et al. (Cancer Epidemiology Biomarkers & Prevention, 2016)
The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls.Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable.The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10(-17)). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m(2) of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44-1.68, per 5 kg/m(2)). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10-1.39; P = 5.3 × 10(-4)). There was evidence of directional pleiotropy (P = 1.5 × 10(-4)). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10(-4)), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS.BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI.The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503-10. ©2016 AACR.
EVALuna2:9342

Genetic variants in the genes of the sex steroid hormone metabolism and depressive symptoms during and after pregnancy - Schneider, Michael; Pretscher, Jutta; Goecke, Tamme; Häberle, Lothar; Engel, Anne; Kornhuber, Johannes; Eichler, Anna; Ekici, Arif Bülent; Beckmann, Matthias; Fasching, Peter; Schwenke, Eva (Archives of Gynecology and Obstetrics, 2022)
Purpose: The aim of this study was to conduct an association analysis of depressive symptoms and polymorphisms in the ESR1, PGR, CYP19A1, and COMT genes in pregnant and postpartum women. Methods: The Franconian Maternal Health Evaluation Study (FRAMES) recruited healthy pregnant women prospectively for assessment of maternal and fetal health. The German version of the 10-item Edinburgh Postnatal Depression Scale (EPDS) was completed at three time points in this prospective cohort study. Visit 1 was at study entry in the third trimester of pregnancy, visit 2 was shortly after birth, and visit 3 was 6–8 months after birth. Germline DNA and depression measurements from 361 pregnant women were available for analysis. Six single nucleotide polymorphisms (SNPs) in the above-mentioned genes were genotyped. After reconstruction of haplotypes for PGR (rs1042838 and rs10895068) and CYP19A1 (rs10046 and rs4646), a multifactorial linear mixed model was applied to the data to describe the association between haplotypes and depression values. The single SNPs for ESR1 (rs488133) and COMT (rs4680) were analyzed separately using linear mixed models analogously. Results: The mean antepartum EPDS measurement was 5.1, the mean postpartal measurement after 48–72 h was 3.5, and the mean value 6–8 months postpartum was 4.2. The SNPs in PGR were reconstructed into three haplotypes. The most common haplotype was GG, with 63.43% of patients carrying two copies and 33.52% carrying one copy. For haplotype GA, the group of carriers of two copies (0.28%) was combined with the carriers of one copy (9.70%). Haplotype reconstruction using CYP19A1 SNPs resulted in three haplotypes. The most common haplotype was TC, with 25.48% of patients carrying two copies and 51.52% one copy. None of the haplotype blocks and neither of the two single SNPs showed any significant associations with EPDS values. Conclusions: The candidate haplotypes analyzed in PGR and CYP19A1 and single SNPs in ESR1 and COMT did not show any association with depression scores as assessed by EPDS in this cohort of healthy unselected pregnant women.
CRIS-Team Scopus Importer:2022-06-17
Keywords: COMT; CYP19A1; Depression; EPDS; ESR1; PGR; Single nucleotide polymorphisms

Genetic variants in the genes of the stress hormone signalling pathway and depressive symptoms during and after pregnancy - Schneider, Michael; Engel, Anne; Fasching, Peter; Haeberle, Lothar; Binder, Elisabeth B.; Voigt, Franziska; Grimm, Jennifer; Faschingbauer, Florian; Eichler, Anna; Dammer, Ulf; Rebhan, Dirk; Amann, Manuela; et al. (BioMed Research International, 2014)
The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in genes of the stress hormone signaling pathway, specifically FKBP5, NR3C1, and CRHR1, are associated with depressive symptoms during and after pregnancy.The Franconian Maternal Health Evaluation Study (FRAMES) recruited healthy pregnant women prospectively for the assessment of maternal and fetal health including the assessment of depressiveness. The German version of the 10-item Edinburgh Postnatal Depression Scale (EPDS) was completed at three time points in this prospective cohort study. Visit 1 was at study entry in the third trimester of the pregnancy, visit 2 was shortly after birth, and visit 3 was 6-8 months after birth. Germline DNA was collected from 361 pregnant women. Nine SNPs in the above mentioned genes were genotyped. After construction of haplotypes for each gene, a multifactorial linear mixed model was performed to analyse the depression values over time.EPDS values were within expected ranges and comparable to previously published studies. Neither did the depression scores differ for comparisons among haplotypes at fixed time points nor did the change over time differ among haplotypes for the examined genes. No haplotype showed significant associations with depressive symptoms severity during pregnancy or the postpartum period.The analysed candidate haplotypes in FKBP5, NR3C1, and CRHR1 did not show an association with depression scores as assessed by EPDS in this cohort of healthy unselected pregnant women.
EVALuna2:17356

Genetic variants in the glucocorticoid pathway genes and birth weight - Schneider, Michael; Hübner, Theresa; Pretscher, Jutta; Goecke, Tamme W.; Schwitulla, Judith; Häberle, Lothar; Kornhuber, Johannes; Ekici, Arif Bülent; Beckmann, Matthias; Fasching, Peter; Schwenke, Eva (Archives of Gynecology and Obstetrics, 2020)
Purpose: The aim of this study was to examine associations between single nucleotide polymorphisms (SNPs) that tag genetic variation in the glucocorticoid pathways (particularly in maternal genes FKBP5, NR3C1, and CRHR1) and birth weight. Methods: The Franconian Maternal Health Evaluation Study (FRAMES) recruited healthy pregnant women prospectively for the assessment of maternal and fetal health. Germline DNA was collected from 375 pregnant women. Nine SNPs in the above-mentioned genes were genotyped. After reconstruction of haplotypes for each gene, a linear regression model was applied to the data to describe the association between haplotypes and birth weight. Results: Female sex in the newborn (compared to male) was associated with lower birth weight, whereas a later week of gestation, higher body mass index pre-pregnancy, and higher parity were associated with higher birth weight. No association with birthweight was shown for the haplotypes of the selected SNPs. Conclusions: In this cohort of healthy unselected pregnant women, the analyzed candidate haplotypes in FKBP5, NR3C1, and CRHR1 did not show any association with birth weight. This might be in line with several other studies that have found no influence of fetal polymorphisms in the glucocorticoid receptor gene or triggers of the maternal HPA axis such as stress and psychosocial problems on birth weight. However, the small sample size in this study and the lack of consideration of individual risk factors and levels of stress in this cohort needs to be taken into account when interpreting the results.
CRIS-Team Scopus Importer:2020-09-11
Keywords: Birth weight; CRHR1; FKBP5; NR3C1; Single nucleotide polymorphisms

Genetic variants in VEGF pathway genes in neoadjuvant breast cancer patients receiving bevacizumab: Results from the randomized phase III GeparQuinto study - Hein, Alexander; Lambrechts, Diether; Von Minckwitz, Gunter; Haeberle, Lothar; Eidtmann, Holger; Tesch, Hans; Untch, Michael; Hilfrich, Joern; Schem, Christian; Rezai, Mahdi; Gerber, Bernd; Costa, Serban Dan; et al. (International Journal of Cancer, 2015)
Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression-free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2-negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre-planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF-A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49-3.75), 1.20 (95% CI, 0.88-1.64) and 0.61 (95% CI, 0.34-1.12). Notably, some SNPs in VEGF-A exhibited a more pronounced effect in the triple-negative subgroup. Several SNPs in VEGF-A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.
EVALuna2:9285

Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study - Johnson, Nichola; Dudbridge, Frank; Orr, Nick; Gibson, Lorna; Jones, Michael E.; Schoemaker, Minouk J.; Folkerd, Elizabeth J.; Haynes, Ben P.; Hopper, John L.; Southey, Melissa C.; Dite, Gillian S.; Apicella, Carmel; et al. (Breast Cancer Research, 2014)
We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age <=50 years.We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics.We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P(trend) = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P(trend) = 0.005) but not cases (P(trend) = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P(het) = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age >=15 years (OR(het) = 0.84, 95% CI 0.75, 0.94; OR(hom) = 0.81, 95% CI 0.51, 1.30; P(trend) = 0.002) but not for those who had their menarche age <=11 years (OR(het) = 1.06, 95% CI 0.95, 1.19, OR(hom) = 1.07, 95% CI 0.67, 1.72; P(trend) = 0.29).To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.
EVALuna2:9240

Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade - Purrington, Kristen S.; Slettedahl, Seth; Bolla, Manjeet K.; Michailidou, Kyriaki; Czene, Kamila; Nevanlinna, Heli; Bojesen, Stig E.; Andrulis, Irene L.; Cox, Angela; Hall, Per; Carpenter, Jane; Yannoukakos, Drakoulis; et al. (Human Molecular Genetics, 2014)
Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.
EVALuna2:6629

Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium - Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B.; Behrens, Sabine; Goode, Ellen L.; Bolla, Manjeet K.; Dennis, Joe; Dunning, Alison M.; Easton, Douglas F.; Wang, Qin; Benitez, Javier; Hopper, John L.; et al. (Human genetics, 2016)
Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 × 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10(-3) and 7.0 × 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10(-3), 4.5 × 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.
EVALuna2:33106

Genetic variations in estrogen and progesterone pathway genes in preeclampsia patients and controls in Bavaria - Pretscher, Jutta; Rübner, Matthias; Ekici, Arif Bülent; Rödl, Melanie; Hübner, Hanna; Schwitulla, Judith; Titzmann, Adriana; Hartwig, Charlotte; Beckmann, Matthias; Fasching, Peter; Schneider, Michael; Schwenke, Eva (Archives of Gynecology and Obstetrics, 2020)
Purpose: Hypertensive pregnancy disorders and preeclampsia are major causes of maternal and fetal morbidity and mortality worldwide. Many different organs are involved in the diseases’ clinical phenotype. The underlying mechanism is still unknown, with a possible genetic component. This case–control study investigated effects on the risk of preeclampsia of genetic variations (single nucleotide polymorphisms, SNPs) in the estrogen and progesterone pathway genes. Methods: The study included 167 patients with preeclampsia and 115 healthy controls from the “Franconian Maternal Health Evaluation Studies” (FRAMES). All patients completed an epidemiological questionnaire, data from which were correlated with prospective data on pregnancy and labor. DNA was isolated from blood samples and genotyping was done by PCR. Variants in the aromatase gene CYP19A1 (rs10046, rs4646), progesterone receptor gene (rs1042838, rs10895068), and estrogen receptor-α gene (rs488133) were examined, and the genotype distribution in the two groups was analyzed statistically. Results: A significant difference in the distribution frequency of genotypes between preeclampsia patients and controls was identified in one of the five SNPs. For rs10895068 in the progesterone receptor gene, genotype G/A was significantly more frequent among cases than controls (P = 0.023). No significant differences between the two cohorts were found in the other SNPs. Conclusions: This study showed a significant association between only one SNP in the progesterone receptor and preeclampsia. Other studies have also noted genetic aspects of preeclampsia. The underlying mechanism and causal relationship are not yet known, and further research is needed to explain the extent of genetic variations and the causal relationship in preeclampsia.
CRIS-Team Scopus Importer:2020-10-09
Keywords: Genetic marker; Preeclampsia; Pregnancy; Single nucleotide polymorphism (SNP)

Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium - Johnatty, Sharon E.; Tyrer, Jonathan P.; Kar, Siddhartha; Beesley, Jonathan; Lu, Yi; Gao, Bo; Fasching, Peter; Hein, Alexander; Ekici, Arif Bülent; Beckmann, Matthias; Lambrechts, Diether; Van Nieuwenhuysen, Els; et al. (Clinical Cancer Research, 2015)
Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome.We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with >=4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis.Five SNPs were significantly associated (P <= 1.0 × 10(-5)) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P <= 7.1 × 10(-6)). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA <=6 × 10(-3)).We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264-76. ©2015 AACR.
EVALuna2:9298

Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci - Chen, Hongjie; Fan, Shaoqi; Stone, Jennifer; Thompson, Deborah J.; Douglas, Julie; Li, Shuai; Scott, Christopher; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Michailidou, Kyriaki; Li, Christopher; et al. (Breast Cancer Research, 2022)
BACKGROUND: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. METHODS: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. RESULTS: We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes. CONCLUSIONS: Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.
CRIS-Team Scopus Importer:2022-04-22
Keywords: Breast cancer; Genome-wide association study (GWAS); Mammographic density; Transcriptome-wide association study (TWAS)

Genome-Wide Association Analyses of HPV16 and HPV18 Seropositivity Identify Susceptibility Loci for Cervical Cancer - Beckhaus, Theresa; Kachuri, Linda; Nakase, Taishi; Schürmann, Peter; Eisenblätter, Rieke; Geerts, Maya; Böhmer, Gerd; Strauß, Hans Georg; Hirchenhain, Christine; Schmidmayr, Monika; Müller, Florian; Fasching, Peter; et al. (Journal of Medical Virology, 2025)
Infection by high-risk human papillomavirus is known to exacerbate cervical cancer development. The host immune response is crucial in disease regression. Large-scale genetic association studies for cervical cancer have identified few susceptibility variants, mainly at the human leukocyte antigen locus on chromosome 6. We hypothesized that the host immune response modifies cervical cancer risk and performed three genome-wide association analyses for HPV16, HPV18 and HPV16/18 seropositivity in 7814, 7924, and 7924 samples from the UK Biobank, followed by validation genotyping in the German Cervigen case-control series of cervical cancer and dysplasia. In GWAS analyses, we identified two loci associated with HPV16 seropositivity (6p21.32 and 15q26.2), two loci associated with HPV18 seropositivity (5q31.2 and 14q24.3), and one locus for HPV16 and/or HPV18 seropositivity (at 6p21.32). MAGMA gene-based analysis identified HLA-DQA1 and HLA-DQB1 as genome-wide significant (GWS) genes. In validation genotyping, the genome-wide significant lead variant at 6p21.32, rs9272293 associated with overall cervical disease (OR = 0.86, p = 0.004, 95% CI = 0.78–0.95, n = 3710) and HPV16 positive invasive cancer (OR = 0.73, p = 0.005, 95% CI = 0.59–0.91, n = 1431). This variant was found to be a robust eQTL for HLA-DRB1, HLA-DQB1-AS1, C4B, HLA-DRB5, HLA-DRB6, HLA-DQB1, and HLA-DPB1 in a series of cervical epithelial tissue samples. We additionally genotyped twenty-four HPV seropositivity variants below the GWS threshold out of which eleven variants were found to be associated with cervical disease in our cohort, suggesting that further seropositivity variants may determine cervical disease outcome. Our study identifies novel genomic risk loci that associate with HPV type-specific cervical cancer and dysplasia risk and provides evidence for candidate genes at one of the risk loci.
CRIS-Team Scopus Importer:2025-02-14
Keywords: cervical carcinoma; eQTL; human papillomavirus; infection; SNP

Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease - Ramachandran, Dhanya; Tyrer, Jonathan P.; Kommoss, Stefan; DeFazio, Anna; Riggan, Marjorie J.; Webb, Penelope M.; Fasching, Peter; Lambrechts, Diether; García, María J.; Rodríguez-Antona, Cristina; Goodman, Marc T.; Modugno, Francesmary; et al. (npj Genomic Medicine, 2024)
Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10−8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.
CRIS-Team Scopus Importer:2024-06-14

Genome-wide association analysis identifies three new breast cancer susceptibility loci - Ghoussaini, Maya; Fletcher, Olivia; Michailidou, Kyriaki; Turnbull, Clare; Schmidt, Marjanka K.; Dicks, Ed; Dennis, Joe; Wang, Qin; Humphreys, Manjeet K.; Luccarini, Craig; Baynes, Caroline; Conroy, Don; et al. (Nature Genetics, 2012)
Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for 8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in 70,000 cases and 68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
EVALuna2:9145

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer - Michailidou, Kyriaki; Beesley, Jonathan; Lindstrom, Sara; Canisius, Sander; Dennis, Joe; Lush, Michael J.; Maranian, Mel J.; Bolla, Manjeet K.; Wang, Qin; Shah, Mitul; Perkins, Barbara J.; Czene, Kamila; et al. (Nature Genetics, 2015)
Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining 14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO
EVALuna2:17570

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer - Ferreira, Manuel A.; Gamazon, Eric R.; Al-Ejeh, Fares; Aittomaki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Arason, Adalgeir; Arndt, Volker; Aronson, Kristan J.; Arun, Banu K.; Asseryanis, Ella; Azzollini, Jacopo; et al. (Nature Communications, 2019)
Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
CRIS-Team WoS Importer:2019-04-30

Genome-wide association study and functional follow-up identify 14q12 as a candidate risk locus for cervical cancer - Ramachandran, Dhanya; Dennis, Joe; Fachal, Laura; Schurmann, Peter; Bousset, Kristine; Huelse, Fabienne; Mao, Qianqian; Wang, Yingying; Jentschke, Matthias; Boehmer, Gerd; Strauss, Hans-Georg; Hirchenhain, Christine; et al. (Human Molecular Genetics, 2022)
Cervical cancer is among the leading causes of cancer-related death in females worldwide. Infection by human papillomavirus (HPV) is an established risk factor for cancer development. However, genetic factors contributing to disease risk remain largely unknown. We report on a genome-wide association study (GWAS) on 375 German cervical cancer patients and 866 healthy controls, followed by a replication study comprising 658 patients with invasive cervical cancer, 1361 with cervical dysplasia and 841 healthy controls. Functional validation was performed for the top GWAS variant on chromosome 14q12 (rs225902, close to PRKD1). After bioinformatic annotation and in silico predictions, we performed transcript analysis in a cervical tissue series of 317 samples and demonstrate rs225902 as an expression quantitative trait locus (eQTL) for FOXG1 and two tightly co-regulated long non-coding RNAs at this genomic region, CTD-2251F13 (lnc-PRKD1-1) and CTD-2503I6 (lnc-FOXG1-6). We also show allele-specific effects of the 14q12 variants via luciferase assays. We propose a combined effect of genotype, HPV status and gene expression at this locus on cervical cancer progression. Taken together, this work uncovers a potential candidate locus with regulatory functions and contributes to the understanding of genetic susceptibility to cervical cancer.
CRIS-Team WoS Importer:2022-05-06

Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer - Purrington, Kristen S.; Slager, Susan; Eccles, Diana; Yannoukakos, Drakoulis; Fasching, Peter A.; Miron, Penelope; Carpenter, Jane; Chang-Claude, Jenny; Martin, Nicholas G.; Montgomery, Grant W.; Kristensen, Vessela; Anton-Culver, Hoda; et al. (Carcinogenesis, 2014)
Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
EVALuna2:6530

Genome-wide association study identifies a common variant associated with risk of endometrial cancer - Spurdle, Amanda B.; Thompson, Deborah J.; Ahmed, Shahana; Ferguson, Kaltin; Healey, Catherine S.; O'Mara, Tracy; Walker, Logan C.; Montgomery, Stephen B.; Dermitzakis, Emmanouil T.; Fahey, Paul; Montgomery, Grant W.; Webb, Penelope M.; et al. (Nature Genetics, 2011)
Endometrial cancer is the most common malignancy of the female genital tract in developed countries. To identify genetic variants associated with endometrial cancer risk, we performed a genome-wide association study involving 1,265 individuals with endometrial cancer (cases) from Australia and the UK and 5,190 controls from the Wellcome Trust Case Control Consortium. We compared genotype frequencies in cases and controls for 519,655 SNPs. Forty seven SNPs that showed evidence of association with endometrial cancer in stage 1 were genotyped in 3,957 additional cases and 6,886 controls. We identified an endometrial cancer susceptibility locus close to HNF1B at 17q12 (rs4430796, P = 7.1 × 10-10) that is also associated with risk of prostate cancer and is inversely associated with risk of type 2 diabetes. © 2011 Nature America, Inc. All rights reserved.
CRIS-Team Scopus Importer:2021-07-19

Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk - Lindstroem, Sara; Thompson, Deborah J.; Paterson, Andrew D.; Li, Jingmei; Gierach, Gretchen L.; Scott, Christopher; Stone, Jennifer; Douglas, Julie A.; Dos-Santos-Silva, Isabel; Fernandez-Navarro, Pablo; Verghase, Jajini; Smith, Paula; et al. (Nature Communications, 2014)
Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5 × 10(-8)) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B and SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23 and TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease-susceptibility loci.
EVALuna2:17508

Genome-wide association study of germline variants and breast cancer-specific mortality - Escala-Garcia, Maria; Guo, Qi; Doerk, Thilo; Canisius, Sander; Keeman, Renske; Dennis, Joe; Beesley, Jonathan; Lecarpentier, Julie; Bolla, Manjeet K.; Wang, Qin; Abraham, Jean; Andrulis, Irene L.; et al. (British Journal of Cancer, 2019)
BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.
CRIS-Team WoS Importer:2019-03-29

Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA - Earp, Madalene A.; Kelemen, Linda E.; Magliocco, Anthony M.; Swenerton, Kenneth D.; Chenevix-Trench, Georgia; Lu, Yi; Hein, Alexander; Ekici, Arif Bülent; Beckmann, Matthias; Fasching, Peter; Lambrechts, Diether; Despierre, Evelyn; et al. (Human genetics, 2014)
Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.
EVALuna2:9208

Genome-Wide DNA Methylation Patterns in Children Exposed to Nonpharmacologically Treated Prenatal Depressive Symptoms: Results From 2 Independent Cohorts - Stonawski, Valeska; Roetner, Jakob; Goecke, Tamme W.; Fasching, Peter; Beckmann, Matthias; Kornhuber, Johannes; Kratz, Oliver; Moll, Gunther; Eichler, Anna; Heinrich, Hartmut; Frey, Stefan (Epigenetics Insights, 2020)
Background: Maternal depressive symptoms are a common phenomenon during pregnancy and are related to negative outcomes for child development and health. Modifications in child DNA methylation are discussed as an underlying mechanism for the association between prenatal depressive symptoms and alterations in child outcomes. However, formerly reported genome-wide associations have yet to be replicated. Methods: In an epigenome-wide association study (EWAS), alterations of DNA methylation related to maternal prenatal depressive symptoms were investigated in buccal cell samples from 174 children (n = 52 exposed to prenatal depressive symptoms; 6-9 years old) of the German longitudinal study FRAMES-FRANCES. Whole blood samples from the independent, age-comparable ARIES subsample of the ARIES/ALSPAC study (n = 641; n = 159 exposed to prenatal depressive symptoms; 7-8 years old) were examined as a confirmation sample. Depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale. DNA methylation was analyzed with the Infinium Human Methylation 450k BeadChip. Modifications in single CpGs, regions, and biological pathways were investigated. Results were adjusted for age and birth outcomes as well as postnatal and current maternal depressive symptoms. Analyses were performed for the whole sample as well as separated for sex. Results: The EWAS yielded no differentially methylated CpG or region as well as no accordance between samples withstanding correction for multiple testing. In pathway analyses, no overlapping functional domain was found to be enriched for either sample. A comparison of current and former findings suggests some overlapping methylation modifications from infancy to childhood. Results suggest that there might be sex-specific differential methylation, which should be further investigated in additional studies. Conclusions: The current, mainly nonsignificant, results challenge the assumption of consistent modifications of DNA methylation in children exposed to prenatal depressive symptoms. Despite the relatively small sample size used in this study, this lack of significant results may reflect diverse issues of environmental epigenetic studies, which need to be addressed in future research.
CRIS-Team Scopus Importer:2020-06-26
Keywords: ALSPAC; ARIES; DNA methylation; epigenetics; FRANCES; Pregnancy; prenatal depression

Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types - Kar, Siddhartha P.; Beesley, Jonathan; Al Olama, Ali Amin; Michailidou, Kyriaki; Tyrer, Jonathan; Kote-Jarai, Zsofi A.; Lawrenson, Kate; Lindstrom, Sara; Ramus, Susan J.; Thompson, Deborah J.; Kibel, Adam S.; Dansonka-Mieszkowska, Agnieszka; et al. (Cancer Discovery, 2016)
Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis.We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.
EVALuna2:9322

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk - Day, Felix R.; Thompson, Deborah J.; Helgason, Hannes; Chasman, Daniel I.; Finucane, Hilary; Sulem, Patrick; Ruth, Katherine S.; Whalen, Sean; Sarkar, Abhishek K.; Albrecht, Eva; Altmaier, Elisabeth; Amini, Marzyeh; et al. (Nature Genetics, 2017)
The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10-8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.
EVALuna2:36141

Genomic analysis of advanced breast cancer tumors from talazoparib-treated gBRCA1/2mut carriers in the ABRAZO study - Turner, Nicholas C.; Laird, A. Douglas; Telli, Melinda L.; Rugo, Hope S.; Mailliez, Audrey; Ettl, Johannes; Grischke, Eva Maria; Mina, Lida A.; Balmaña, Judith; Fasching, Peter; Hurvitz, Sara A.; Hopkins, Julia F.; et al. (npj Breast Cancer, 2023)
These analyses explore the impact of homologous recombination repair gene mutations, including BRCA1/2 mutations and homologous recombination deficiency (HRD), on the efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor talazoparib in the open-label, two-cohort, Phase 2 ABRAZO trial in germline BRCA1/2-mutation carriers. In the evaluable intent-to-treat population (N = 60), 58 (97%) patients harbor ≥1 BRCA1/2 mutation(s) in tumor sequencing, with 95% (53/56) concordance between germline and tumor mutations, and 85% (40/47) of evaluable patients have BRCA locus loss of heterozygosity indicating HRD. The most prevalent non-BRCA tumor mutations are TP53 in patients with BRCA1 mutations and PIK3CA in patients with BRCA2 mutations. BRCA1- or BRCA2-mutated tumors show comparable clinical benefit within cohorts. While low patient numbers preclude correlations between HRD and efficacy, germline BRCA1/2 mutation detection from tumor-only sequencing shows high sensitivity and non-BRCA genetic/genomic events do not appear to influence talazoparib sensitivity in the ABRAZO trial. ClinicalTrials.gov identifier: NCT02034916.
CRIS-Team Scopus Importer:2023-10-20

GeparPiPPa- A randomized, open-label, phase II trial comparing neoadjuvant trastuzumab, pertuzumab and endocrine therapy +/- the PI3K inhibitor inavolisib in patients (pts) with HER2+/HR+, PIK3CA mutant early breast cancer (BC) - Loibl, Sibylle; Reinisch, Mattea; Denkert, Carsten; Schneeweiss, Andreas; Seiler, Sabine; Fasching, Peter; Hanusch, Claus; Link, Theresa; Bjelic-Radisic, Vesna; Huober, Jens; Untch, Michael; Jackisch, Christian; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

GeparX: Denosumab (Dmab) as add-on to different regimen of nab-paclitaxel (nP)-anthracycline based neoadjuvant chemotherapy (NACT) in early breast cancer (BC): Subgroup analyses by RANK expression and HR status - Link, T.; Blohmer, J-U.; Just, M.; Untch, M.; Stoetzer, O.; Fasching, Peter; Schneeweiss, A.; Wimberger, P.; Seiler, S.; Huober, J.; Schmitt, W. D.; Jackisch, C.; et al. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-10-30

Germline BRCA1/2 mutations and severe haematological toxicities in patients with breast cancer treated with neoadjuvant chemotherapy - Furlanetto, Jenny; Möbus, Volker; Schneeweiss, Andreas; Rhiem, Kerstin; Tesch, Hans; Blohmer, Jens Uwe; Lübbe, Kristina; Untch, Michael; Salat, Christoph; Huober, Jens; Klare, Peter; Schmutzler, Rita; et al. (European Journal of Cancer, 2021)
Background: BRCA1 and BRCA2 play a central role in DNA repair. Therefore, patients harbouring germline (g) BRCA1/2 mutations (m) treated with chemotherapy might be at higher risk of haematological toxicities. Methods: Patients from German Breast Group (GBG) and Arbeitsgemeinschaft Gynäkologische Onkologie-breast group studies with early triple-negative breast cancer (TNBC) and known gBRCA1/2m status treated with anthracycline-taxane-based neoadjuvant chemotherapy were analysed. Primary objective was the rate of neutropenia grade (G)III–IV in cycle 1 (C1). Secondary objectives included effects on overall and other haematological toxicities GIII-IV in C1, cumulative haematological toxicity across all cycles, relative total dose intensity, and granulocyte-colony stimulating factor prophylaxis. Haematological toxicities under taxanes, carboplatin, and cyclophosphamide were explored. Results: Two hundred nine of 1171 (17.8%) evaluated patients had gBRCA1/2m. In C1, 37.4% gBRCA1/2m versus 35.7% wild-type patients had neutropenia GIII-IV (P = 0.683). For C1, gBRCA1/2m predicted neither for neutropenia GIII-IV (odds ratio [OR]: 1.26, 95% confidence intervals [CI]: 0.87–1.82, P = 0.226) nor for other haematological toxicities GIII-IV (OR: 0.91, 95% CI: 0.64–1.31, P = 0.625) in multivariable regression models. Analyses of cumulative toxicities across all cycles yielded similar results except thrombocytopaenia GIII-IV, which was increased in gBRCA1m patients. In patients treated with taxanes, the rate of haematological toxicities GIII-IV was higher in gBRCA1/2m compared with wild-type (59.5% versus 43.1%; p < 0.001). No difference was seen under cyclophosphamide or platinum-containing chemotherapies. Conclusions: gBRCA1/2m was not associated with higher risk of overall severe haematological toxicities in the first cycle or cumulatively across all cycles under standard chemotherapy for TNBC. Under taxane, patients with gBRCA1/2m might have a higher risk of haematological toxicities GIII-IV, requiring further research.
CRIS-Team Scopus Importer:2021-01-15
Keywords: Carboplatin; gBRCA1/2 mutation; Hematological toxicities; Neoadjuvant chemotherapy; Neutropenia; Taxanes

Germline copy number variants and endometrial cancer risk - Stylianou, Cassie E.; Wiggins, George A.R.; Lau, Vanessa L.; Dennis, Joe; Shelling, Andrew N.; Wilson, Michelle; Sykes, Peter; Amant, Frederic; Annibali, Daniela; De Wispelaere, Wout; Easton, Douglas F.; Fasching, Peter; et al. (Human genetics, 2024)
Known risk loci for endometrial cancer explain approximately one third of familial endometrial cancer. However, the association of germline copy number variants (CNVs) with endometrial cancer risk remains relatively unknown. We conducted a genome-wide analysis of rare CNVs overlapping gene regions in 4115 endometrial cancer cases and 17,818 controls to identify functionally relevant variants associated with disease. We identified a 1.22-fold greater number of CNVs in DNA samples from cases compared to DNA samples from controls (p = 4.4 × 10–63). Under three models of putative CNV impact (deletion, duplication, and loss of function), genome-wide association studies identified 141 candidate gene loci associated (p < 0.01) with endometrial cancer risk. Pathway analysis of the candidate loci revealed an enrichment of genes involved in the 16p11.2 proximal deletion syndrome, driven by a large recurrent deletion (chr16:29,595,483-30,159,693) identified in 0.15% of endometrial cancer cases and 0.02% of control participants. Together, these data provide evidence that rare copy number variants have a role in endometrial cancer susceptibility and that the proximal 16p11.2 BP4-BP5 region contains 25 candidate risk gene(s) that warrant further analysis to better understand their role in human disease.
CRIS-Team Scopus Importer:2024-11-15

Germline (G)BRCA1/2 Mutations (M) and Hematological Toxicities in Patients (PTS) with Triple Negative Breast Cancer (TNBC) Treated with Neoadjuvant Chemotherapy (NACT) - Furlanetto, Jenny; Moebus, Volker; Schneeweiss, Andreas; Rhiem, Kerstin; Tesch, Hans; Blohmer, Jens-Uwe; Luebbe, Kristina; Untch, Michael; Salat, Christoph; Huober, Jens; Klare, Peter; Schmutzler, Rita; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

Germline genome-wide association studies in women receiving neoadjuvant chemotherapy with or without bevacizumab - Ingle, James N.; Kalari, Krishna R.; Wickerham, Donald Lawrence; Von Minckwitz, Gunter; Fasching, Peter; Furukawa, Yoichi; Mushiroda, Taisei; Goetz, Matthew P.; Barman, Poulami; Carlson, Erin E.; Rastogi, Priya; Costantino, Joseph P.; et al. (Pharmacogenetics and Genomics, 2018)
Neoadjuvant chemotherapy (NAC) for breast cancer is widely utilized, and we performed genome-wide association studies (GWAS) to determine whether germ-line genetic variability was associated with benefit in terms of pathological complete response (pCR), disease-free survival, and overall survival in patients entered on the NSABP B-40 NAC trial, wherein patients were randomized to receive, or not, bevacizumab in addition to chemotherapy. Patient DNA samples were genotyped with the Illumina OmniExpress BeadChip. Replication was attempted with genotyping data from 1398 HER2-negative patients entered on the GeparQuinto NAC study in which patients were also randomized to receive, or not, bevacizumab in addition to chemotherapy. A total of 920 women from B-40 were analyzed, and 237 patients achieved a pCR. GWAS with three phenotypes (pCR, disease-free survival, overall survival) revealed no single nucleotide polymorphisms (SNPs) that were genome-wide significant (i.e. P≤5E-08) signals; P values for top SNPs were 2.04E-07, 5.61E-08, and 5.63E-08, respectively, and these SNPs were not significant in the GeparQuinto data. An ad-hoc GWAS was performed in the patients randomized to bevacizumab (457 patients with 128 pCR) who showed signals on chromosome 6, located within a gene, CDKAL1, that approached, but did not reach, genome-wide significance (top SNP rs7453577, P=2.97E-07). However, this finding was significant when tested in the GeparQuinto data set (P=0.04). In conclusion, we identified no SNPs significantly associated with NAC. The observation, in a hypothesis-generating GWAS, of an SNP in CDKAL1 associated with pCR in the bevacizumab arm of both B-40 and GeparQuinto requires further validation and study.
EVALuna2:210016

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk - Liu, Jingjing; Prager-van der Smissen, Wendy J.C.; Collée, J. Margriet; Bolla, Manjeet K.; Wang, Qin; Michailidou, Kyriaki; Dennis, Joe; Ahearn, Thomas U.; Aittomäki, Kristiina; Ambrosone, Christine B.; Andrulis, Irene L.; Anton-Culver, Hoda; et al. (Scientific Reports, 2020)
In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.
CRIS-Team Scopus Importer:2020-06-26

Germline mutations in new susceptibility genes for non-high-grade serous ovarian cancer. - Pavanello, Marina; Dicks, Ed; Song, Honglin; Ariff, Amir; Bolithon, Adelyn; Intermaggio, Maria P.; Pinese, Mark; Moysich, Kirsten; Odunsi, Kunle O.; Goode, Ellen; Bowtell, David D.; Fasching, Peter; et al. (CLINICAL CANCER RESEARCH, 2020)
CRIS-Team WoS Importer:2020-07-24

Germline Mutation Status and Therapy Response in High-Risk Early-Stage Breast Cancer: a Secondary Analysis of the Geparocto Randomized Clinical Trial (NCT02125344) - Pohl-Rescigno, Esther; Hauke, Jan; Rhiem, Kerstin; Moebus, Volker; Furlanetto, Jenny; Denkert, Carsten; Fasching, Peter; Hanusch, Claus; Tesch, Hans; Weber-Lassalle, Nana; Mueller, Volkmar; Untch, Michael; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

Germline mutation status and therapy response in patients with homologous recombination deficient, HER2-negative early breast cancer: Results of the GeparOLA study (NCT02789332) - Hauke, J.; Ernst, C.; Fasching, Peter; Jackisch, C.; Seither, F.; Klare, P.; Rhiem, K. E.; Schmatloch, S.; Huober, J.; Stefek, A.; Seiler, S.; Uleer, C.; et al. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-10-30

Germline mutation status and therapy response in patients with triple-negative breast cancer (TNBC): Results of the GeparOcto study - Pohl, E.; Schneeweiss, A.; Hauke, J.; Moebus, V.; Furlanetto, J.; Denkert, C.; Fasching, Peter; Hanusch, C.; Tesch, H.; Weber-Lassalle, N.; Mueller, V.; Rhiem, K.; et al. (ANNALS OF ONCOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-08

Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial - Hahnen, Eric; Lederer, Bianca; Hauke, Jan; Loibl, Sibylle; Kroeber, Sandra; Schneeweiss, Andreas; Denkert, Carsten; Fasching, Peter; Blohmer, Jens U.; Jackisch, Christian; Paepke, Stefan; Gerber, Bernd; et al. (JAMA Oncology, 2017)
Importance: The GeparSixto trial provided evidence that the addition of neoadjuvant carboplatin to a regimen consisting of anthracycline, taxane, and bevacizumab increases pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Whether BRCA1 and BRCA2 germline mutation status affects treatment outcome remains elusive. Objective: To determine whether BRCA1 and BRCA2 germline mutation status affects therapy response in patients with TNBC. Design, Setting, and Participants: This secondary analysis of a randomized clinical trial used archived DNA samples and cancer family history of 315 patients with TNBC enrolled between August 1, 2011, and December 31, 2012, in the GeparSixto trial. In all, 291 participants (92.4%) were included in this multicenter prospective investigation. DNA samples were analyzed for germline mutations in BRCA1, BRCA2, and 16 other cancer predisposition genes. The pCR rates between the carboplatin and noncarboplatin arms were compared. Genetic analyses were performed at the Center for Familial Breast and Ovarian Cancer in Cologne, Germany; data analysis, November 1 through December 31, 2015. Main Outcomes and Measures: Proportion of patients who achieved pCR and disease-free survival after neoadjuvant treatment according to BRCA1 and BRCA2 germline mutation status. For pCR rates, the ypT0/is ypN0 definition was used as a primary end point. Results: Of the 291 patients with TNBC, all were women; the mean (SD) age was 48 (11) years. The pCR rate in the carboplatin group was 56.8% (83 of 146) and 41.4% (60 of 145) in the noncarboplatin group (odds ratio [OR], 1.87; 95% CI, 1.17-2.97; P = .009). Pathogenic BRCA1 and BRCA2 germline mutations were present in 50 of the 291 patients (17.2%). In the noncarboplatin arm, the pCR rate was 66.7% (16 of 24) for patients with BRCA1 and BRCA2 mutations and 36.4% (44 of 121) for patients without (OR, 3.50; 95% CI, 1.39-8.84; P = .008). The high pCR rate observed in BRCA1 and BRCA2 mutation carriers (16 of 24 [66.7%]) was not increased further by adding carboplatin (17 of 26 [65.4%]). In contrast, carboplatin increased response rates in patients without BRCA1 and BRCA2 mutations: 66 of the 120 patients (55%) without BRCA1 and BRCA2 mutations achieved pCR in the carboplatin arm vs 44 of the 121 patients (36.4%) in the noncarboplatin arm (OR, 2.14; 95% CI, 1.28-3.58; P = .004). Patients without pathogenic BRCA1 and BRCA2 alterations showed elevated disease-free survival rates when carboplatin was added (without carboplatin, 73.5%; 95% CI, 64.1%-80.8% vs with carboplatin, 85.3%; 95% CI, 77.0%-90.8%; hazard ratio, 0.53; 95% CI, 0.29-0.96; P = .04). Conclusions and Relevance: Under the nonstandard GeparSixto polychemotherapy regimen, patients without BRCA1 and BRCA2 germline mutations benefited from the addition of carboplatin and those with BRCA1 and BRCA2 mutations showed superior response rates without additive effects observed for carboplatin. Trial Registration: clinicaltrials.gov Identifier: NCT01426880.
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Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer - French, Juliet D.; Johnatty, Sharon E.; Lu, Yi; Beesley, Jonathan; Gao, Bo; Kalimutho, Murugan; Henderson, Michelle J.; Russell, Amanda J.; Kar, Siddhartha; Chen, Xiaoqing; Hillman, Kristine M.; Kaufmann, Susanne; et al. (Oncotarget, 2016)
Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression.
EVALuna2:9320

Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis - Escala-Garcia, Maria; Canisius, Sander; Keeman, Renske; Beesley, Jonathan; Anton-Culver, Hoda; Arndt, Volker; Augustinsson, Annelie; Becher, Heiko; Beckmann, Matthias; Behrens, Sabine; Bermisheva, Marina; Bojesen, Stig E.; et al. (Scientific Reports, 2021)
Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 x 10(-8) and 4.42 x 10(-8)). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.
CRIS-Team WoS Importer:2021-10-15

Germline variants of homology-directed repair or mismatch repair genes in cervical cancer - Kokemüller, Lara; Ramachandran, Dhanya; Schürmann, Peter; Geffers, Robert; Jentschke, Matthias; Böhmer, Gerd; Strauß, Hans Georg; Hirchenhain, Christine; Schmidmayr, Monika; Müller, Florian; Fasching, Peter; Luyten, Alexander; et al. (International Journal of Cancer, 2024)
While cervical cancer is associated with a persistent human papillomavirus (HPV) infection, the progression to cancer is influenced by genomic risk factors that have remained largely obscure. Pathogenic variants in genes of the homology-directed repair (HDR) or mismatch repair (MMR) are known to predispose to diverse tumour entities including breast and ovarian cancer (HDR) or colon and endometrial cancer (MMR). We here investigate the spectrum of HDR and MMR germline variants in cervical cancer, with particular focus on the HPV status and histological subgroups. We performed targeted next-generation sequencing for 5 MMR genes and 12 HDR genes on 728 German patients with cervical dysplasia or invasive cancer. In total, 4% of our patients carried a pathogenic germline variant, based on ClinVar classifications and additional ESM1b and AlphaMissense predictions. These included 15 patients with truncating variants in HDR genes (BARD1, BRCA1, BRCA2, BRIP1, FANCM, RAD51D and SLX4). MMR-related gene variants were less prevalent and mainly of the missense type. While MMR-related gene variants tended to associate with adenocarcinomas, HDR gene variants were commonly observed in squamous cancers. While one patient with HPV-negative cancer carried a pathogenic MMR gene variant (in MSH6), the HDR germline variants were found in patients with HPV-positive cancers and tended to associate with HPV18. Taken together, our study supports a potentially risk-modifying role of MMR and HDR germline variants in cervical cancer but no association with HPV-negative status. These variants may be exploitable in future therapeutic managements.
CRIS-Team Scopus Importer:2024-11-01
Keywords: cervical carcinoma; homologous recombination; human papillomavirus; mismatch repair; targeted sequencing

Germline variation in ADAMTSL1 is associated with prognosis following breast cancer treatment in young women - Kadalayil, Latha; Khan, Sofia; Nevanlinna, Heli; Fasching, Peter; Couch, Fergus J.; Hopper, John L.; Liu, Jianjun; Maishman, Tom; Durcan, Lorraine; Gerty, Sue; Blomqvist, Carl; Rack, Brigitte; et al. (Nature Communications, 2017)
To identify genetic variants associated with breast cancer prognosis we conduct a meta-analysis of overall survival (OS) and disease-free survival (DFS) in 6042 patients from four cohorts. In young women, breast cancer is characterized by a higher incidence of adverse pathological features, unique gene expression profiles and worse survival, which may relate to germline variation. To explore this hypothesis, we also perform survival analysis in 2315 patients aged ≤ 40 years at diagnosis. Here, we identify two SNPs associated with early-onset DFS, rs715212 (P meta = 3.54 × 10-5) and rs10963755 (P meta = 3.91 × 10-4) in ADAMTSL1. The effect of these SNPs is independent of classical prognostic factors and there is no heterogeneity between cohorts. Most importantly, the association with rs715212 is noteworthy (FPRP <0.2) and approaches genome-wide significance in multivariable analysis (P multivariable = 5.37 × 10-8). Expression quantitative trait analysis provides tentative evidence that rs715212 may influence AREG expression (P eQTL = 0.035), although further functional studies are needed to confirm this association and determine a mechanism.
EVALuna2:36180

Gestational and Non-gestational Trophoblastic Disease. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry No. 032/049, December 2015) - Tempfer, C.; Horn, L. -C.; Ackermann, S.; Beckmann, Matthias; Dittrich, Ralf; Einenkel, J.; Guenthert, A.; Haase, H.; Kratzsch, J.; Kreissl, M. C.; Polterauer, S.; Ebert, A. D.; et al. (Geburtshilfe und Frauenheilkunde, 2016)
Purpose: The aim was to establish an official interdisciplinary guideline, published and coordinated by the German Society of Gynecology and Obstetrics (DGGG). The guideline was developed for use in German-speaking countries. In addition to the Germany Society of Gynecology and Obstetrics, the guideline has also been approved by the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). The aim was to standardize diagnostic procedures and the management of gestational and non-gestational trophoblastic disease in accordance with the principles of evidence-based medicine, drawing on the current literature and the experience of the colleagues involved in compiling the guideline. Methods: This s2k guideline represents the consensus of a representative panel of experts with a range of different professional backgrounds commissioned by the DGGG. Following a review of the international literature and international guidelines on trophoblastic tumors, a structural consensus was achieved in a formalized, multi-step procedure. This was done using uniform definitions, objective assessments, and standardized management protocols. Recommendations: The recommendations of the guideline cover the epidemiology, classification and staging of trophoblastic tumors; the measurement of human chorionic gonadotropin (hCG) levels in serum, and the diagnosis, management, and follow-up of villous trophoblastic tumors (e.g., partial mole, hydatidiform mole, invasive mole) and non-villous trophoblastic tumors (placental site nodule, exaggerated placental site, placental site tumor, epitheloid trophoblastic tumor, and choriocarcinoma).
EVALuna2:32997

Gestational and Non-gestational Trophoblastic Neoplasia. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 032/049, April 2022). - Tempfer, Clemens; Horn, Lars Christian; Ackermann, Sven; Dittrich, Ralf; Einenkel, Jens; Günthert, Andreas; Haase, Heidemarie; Kratzsch, Jürgen; Kreiβl, Michael; Polterauer, Stephan; Ebert, Andreas; Steiner, Eric; et al. (Geburtshilfe und Frauenheilkunde, 2023)
Purpose The aim was to develop and update a guideline which would improve the quality of care offered to women with gestational and non-gestational trophoblastic disease, a group of diseases characterized by their rarity and biological heterogeneity. Methods In accordance with the method used to compile S2k-guidelines, the guideline authors carried out a search of the literature (MEDLINE) for the period 1/2020 to 12/2021 and evaluated the recent literature. No key questions were formulated. No structured literature search with methodical evaluation and assessment of the level of evidence was carried out. The text of the precursor version of the guideline from 2019 was updated based on the most recent literature, and new statements and recommendations were drafted. Recommendations The updated guideline contains recommendations for the diagnosis and therapy of women with hydatidiform mole (partial and complete moles), gestational trophoblastic neoplasia after pregnancy or without prior pregnancy, persistent trophoblastic disease after molar pregnancy, invasive moles, choriocarcinoma, placental site nodules, placental site trophoblastic tumor, hyperplasia at the implantation site und epithelioid trophoblastic tumor. Separate chapters cover the determination and assessment of human chorionic gonadotropin (hCG), histopathological evaluation of specimens, and the appropriate molecular pathological and immunohistochemical diagnostic procedures. Separate chapters on immunotherapy, surgical therapy, multiple pregnancies with simultaneous trophoblastic disease, and pregnancy after trophoblastic disease were formulated, and the corresponding recommendations agreed upon.
EVALuna2:545292

Global Phase 3 Study of Adagloxad Simolenin (OBI-822) and OBI-821 Versus Placebo Treatment for High Risk Early Stage Triple Negative Breast Cancer Patients (TNBC) Following Neoadjuvant or Adjuvant Chemotherapy - Rugo, Hope; Chow, Louis W. C.; Cortes, Javier; Fasching, Peter; He, Xu-Bing; Hsu, Pei; Huang, Chiun-Sheng; Kim, Sung-Bae; Lu, Yen-Shen; Melisko, Michelle; Nanda, Rita; Pearce, Tillman E.; et al. (CANCER RESEARCH, 2021)
CRIS-Team WoS Importer:2021-03-26

Going Digital: A Survey on Digitalization and Large-Scale Data Analytics in Healthcare - Tresp, Volker; Overhage, J. Marc; Bundschus, Markus; Rabizadeh, Shahrooz; Fasching, Peter; Yu Shipeng, (Proceedings of the IEEE, 2016)
We provide an overview of the recent trends toward digitalization and large-scale data analytics in healthcare. It is expected that these trends are instrumental in the dramatic changes in the way healthcare will be organized in the future. We discuss the recent political initiatives designed to shift care delivery processes from paper to electronic, with the goals of more effective treatments with better outcomes; cost pressure is a major driver of innovation. We describe newly developed networks of healthcare providers, research organizations, and commercial vendors to jointly analyze data for the development of decision support systems. We address the trend toward continuous healthcare where health is monitored by wearable and stationary devices; a related development is that patients increasingly assume responsibility for their own health data. Finally, we discuss recent initiatives toward a personalized medicine, based on advances in molecular medicine, data management, and data analytics.
EVALuna2:33056

Growth Hormone: A Potential Treatment of Patients with Refractory Thin Endometrium: A Clinical Trial Study - Aghdam, Soghra Hosseini; Ghasemzadeh, Alyeh; Farzadi, Laya; Hamdi, Kobra; Navali, Nazli; Hakimi, Parvin; Baradaran-Binazir, Marayam; Nouri, Mohammad; Fattahi, Amir; Dittrich, Ralf (International Journal of Fertility & Sterility, 2022)
Background: Growth hormone (GH) is a potential treatment in the assisted reproductive technology (ART) to improve endometrial receptivity and thickness. In the current study, we investigated the effect of the intrauterine administration of GH on the endometrial thickness (EMT) and ART outcomes in the patients with refractory thin endometrium. Materials and Methods: In this clinical trial study, women with a refractory thin endometrium and a history of one or more frozen embryo transfer (FET) cancellation who were referred to the infertility center of the Tabriz AlZahra hospital (Tabriz, Iran) and Milad Infertility Clinic (Tabriz, Iran) received intrauterine injections of GH every other day from day 14 of the menstrual cycle until the EMT reached ≥7 mm in addition to the routine endometrium preparation protocol. EMT was evaluated during the treatment and in the cases with EMT ≥7 mm, biochemical/ clinical pregnancy was evaluated after embryo transfer. Results: Thirty-one women aged 35.29 ± 6.21 years were included in this study. The mean amount of EMT was significantly increased following the GH treatment (7.03 ± 1.23 mm) vs. before treatment (5.14 ± 1.1 mm, P<0.001). The EMT reached ≥7 mm in the 65% patients (20/31). Also, the embryo transfer resulted in pregnancy in the patients, biochemical pregnancy: 9/20 (45%) and clinical pregnancy: 7/20 (35%). There was a positive correlation between EMT on the day 13 of cycle (before the treatment) and the maximum EMT (r=0.577 and P=0.001). The EMT was statistically different on the embryo transfer day between clinically pregnant and non-pregnant women (7.18 ± 0.56 vs. 6.21 ± 0.72 mm, P=0.007). Conclusion: The intrauterine administration of GH could be an appropriate therapeutic strategy for patients with refractory thin endometrium. This treatment could significantly increase the EMT as well as implantation and pregnancy rates in these patients (registration number: IRCT20210220050429N1).
CRIS-Team Scopus Importer:2022-11-04
Keywords: Assisted Reproductive Technology; Growth Hormone; Implantation; Pregnancy

GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer - Pharoah, Paul D. P.; Tsai, Ya-Yu; Ramus, Susan J.; Phelan, Catherine M.; Goode, Ellen L.; Lawrenson, Kate; Buckley, Melissa; Fridley, Brooke L.; Tyrer, Jonathan P.; Shen, Howard; Weber, Rachel; Karevan, Rod; et al. (Nature Genetics, 2013)
Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10-9) and 10p12 (rs1243180, P = 1.8 × 10-8) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
CRIS-Team Scopus Importer:2021-07-19

Gynecologic oncologists' attitudes and practices relating to integrative medicine: results of a nationwide AGO survey - Klein, Evelyn; Beckmann, Matthias; Bader, Werner; Brucker, Cosima; Dobos, Gustav; Fischer, Dorothea; Hanf, Volker; Hasenburg, Annette; Jud, Sebastian; Kalder, Matthias; Kiechle, Marion; Kuemmel, Sherko; et al. (Archives of Gynecology and Obstetrics, 2017)
PURPOSE: The growing popularity and acceptance of integrative medicine is evident both among patients and among the oncologists treating them. As little data are available regarding health-care professionals' knowledge, attitudes, and practices relating to the topic, a nationwide online survey was designed. METHODS: Over a period of 11 weeks (from July 15 to September 30, 2014) a self-administered, 17-item online survey was sent to all 676 members of the Research Group on Gynecological Oncology (Arbeitsgemeinschaft Gynäkologische Onkologie) in the German Cancer Society. The questionnaire items addressed the use of integrative therapy methods, fields of indications for them, advice services provided, level of specific qualifications, and other topics. RESULTS: Of the 104 respondents (15.4%) using integrative medicine, 93% reported that integrative therapy was offered to breast cancer patients. The second most frequent type of tumor in connection with which integrative therapy methods were recommended was ovarian cancer, at 80% of the participants using integrative medicine. Exercise, nutritional therapy, dietary supplements, herbal medicines, and acupuncture were the methods the patients were most commonly advised to use. CONCLUSION: There is considerable interest in integrative medicine among gynecological oncologists, but integrative therapy approaches are at present poorly implemented in routine clinical work. Furthermore there is a lack of specific training. Whether future efforts should focus on extending counseling services on integrative medicine approaches in gynecologic oncology or not, have to be discussed. Evidence-based training on integrative medicine should be implemented in order to safely guide patients in their wish to do something by themselves.
EVALuna2:36130

Gynecologists’ attitudes toward and use of complementary and integrative medicine approaches: results of a national survey in Germany - Grimm, Donata; Voiss, Petra; Paepke, Daniela; Dietmaier, Johanna; Cramer, Holger; Kümmel, Sherko; Beckmann, Matthias; Woelber, Linn; Schmalfeldt, Barbara; Freitag, Ulrich; Kalder, Matthias; Wallwiener, Markus; et al. (Archives of Gynecology and Obstetrics, 2020)
Purpose: Despite patients’ widespread use and acceptance of complementary and integrative medicine (IM), few data are available regarding health-care professionals’ current implementation of it in clinical routine. A national survey was conducted to assess gynecologists’ attitudes to and implementation of complementary and integrative treatment approaches. Methods: The Working Group on Integrative Medicine of the German Society of Gynecological Oncology conducted an online survey in collaboration with the German Society of Gynecology and Obstetrics (DGGG) in July 2019. A 29-item survey was sent to all DGGG members by email. Results: Questionnaires from 180 gynecologists were analyzed, of whom 61 were working office-based in private practice and 95 were employed in hospitals. Seventy percent stated that IM concepts are implemented in their routine clinical work. Most physicians reported using IM methods in gynecological oncology. The main indications for IM therapies were fatigue (n = 98), nausea and vomiting (n = 89), climacteric symptoms (n = 87), and sleep disturbances (n = 86). The most commonly recommended methods were exercise therapy (n = 86), mistletoe therapy (n = 78), and phytotherapy (n = 74). Gynecologists offering IM were more often female (P = 0.001), more often had qualifications in anthroposophic medicine (P = 0.005) or naturopathy (P = 0.019), and were more often based in large cities (P = 0.016). Conclusions: There is strong interest in IM among gynecologists. The availability of evidence-based training in IM is increasing. Integrative therapy approaches are being implemented in clinical routine more and more, and integrative counseling services are present all over Germany. Efforts should focus on extending evidence-based knowledge of IM in both gynecology and gynecological oncology.
CRIS-Team Scopus Importer:2020-11-27
Keywords: Attitude; Breast cancer; Complementary and alternative medicine; Gynecologic oncology; Integrative medicine; Supportive care

Gynecologists ' attitude towards their use of complementary and integrative medicine approaches: results of a nationwide AGO IMed survey - Grimm, D.; Paepke, D.; Voiss, P.; Cramer, H.; Kuemmel, S.; Beckmann, Matthias; Kalder, M.; Woelber, L.; Kiechle, M.; Schmalfeldt, B.; Hasenburg, A.; Hack, Carolin (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

Health outcomes in offspring born to survivors of childhood cancers following assisted reproductive technologies - Sommerhäuser, Greta; Borgmann-Staudt, Anja; Astrahantseff, Kathy; Baust, Katja; Calaminus, Gabriele; Dittrich, Ralf; Fernández-González, Marta J.; Hölling, Heike; König, Charlotte J.; Schilling, Ralph; Schuster, Theresa; Lotz, Laura; et al. (Journal of Cancer Survivorship, 2020)
Purpose: An increasing number of childhood cancer survivors are using assisted reproductive technologies (ART) to overcome treatment-related fertility impairment. We report perinatal and health outcomes of offspring born to survivors following ART. Methods: The FeCt Multicenter Offspring Study surveyed the health of offspring of childhood cancer survivors. Health outcomes in offspring born to survivors following ART (n = 57, 4.6%) or after spontaneous conception (n = 1182) were assessed in the German cohort (n = 1239) using bivariate analysis. Findings were put into the context of the general German population by health outcome assessment in 1:1 matched-pair analysis (n = 2478). Results: Nearly twice the survivors used ART compared with numbers reported for the German general population (4.6% vs. 2.6%). Successful pregnancies were achieved after a median of two cycles, mainly using non-cryopreserved oocytes/sperm. Multiple sibling births (p < 0.001, 28.1% vs. 3.0%) and low birth weight (p = 0.008; OR = 2.659, 95% CI = 1.258–5.621) occurred significantly more often in offspring born to survivors who utilized ART than spontaneously conceived children, whereas similar percentages were born preterm or too small for their gestational age. ART did not increase the prevalence of childhood cancer or congenital malformations in offspring born to survivors. Conclusion: ART use by childhood cancer survivors was successful with both fresh and cryopreserved oocytes/sperm, and did not influence perinatal health or health outcomes when known confounders were taken into account. Implications for Cancer Survivors: Oncofertility is an important component of patient care. Our study implicates that the utilization of ART by adult survivors of childhood cancer does not put offspring at additional risk for adverse perinatal or health outcomes.
CRIS-Team Scopus Importer:2020-09-04
Keywords: Assisted reproductive technologies; Childhood cancer survivor; Infertility; Offspring; Pediatric cancer

Health-related Quality of Life in Metastatic and Adjuvant Breast Cancer Patients - Wallwiener, M.; Simoes, E.; Sokolov, A. N.; Brucker, S. Y.; Fasching, Peter; Graf, J. (Geburtshilfe und Frauenheilkunde, 2016)
Introduction: When cancer patients have advanced disease and a primary cure is no longer possible, the focus is on maintaining the patient's quality of life. Recent therapeutic advances in breast cancer treatment mean that even patients with metastatic disease can remain stable for long periods of time. The aim of this study was to look at the health-related quality of life (HRQL) of these patients and compare it with data for the general population and to show the differences in outcomes for different survey instruments used to measure quality of life.Material and Methods:A total of 96 breast cancer patients with metastatic disesae or receiving adjuvant therapy were questioned about their quality of life. Patients were investigated using the established survey instruments EORTC QLQ-C30, EORTC QLQ-BR23, EQ-5D-5L and EQ VAS. All patients filled out questionnaires. Statistical analysis was done using MS Excel and SPSS.Results:Although the questionnaires were completed at the same time, the different questionnaires showed significant differences with regard to the level of stress experienced by the patient. When the EQ VAS questionnaire was used, the patient's current state of health was assessed as significantly better than with the EORTC QLQ-C30. Overall, all aspects of patients' quality of life were found to be in need of optimization and HRQL of patients was significantly poorer in all areas compared to the reference population.Conclusion:To improve the quality of life of patients with metastatic disease, it is necessary to continuously monitor the success of therapy. The choice of survey tools is highly relevant as assessments differ considerably depending on the choice of questionnaire.
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Health utilities in gynecological oncology and mastology in Germany - Hildebrandt, Thomas; Thiel, Falk; Fasching, Peter; Graf, Christiane; Bani, Mayada; Löhberg, Christian; Schrauder, Michael G.; Jud, Sebastian; Hack, Carolin; Beckmann, Matthias; Lux, Michael P. (Anticancer Research, 2014)
Cost increases in the healthcare system are leading to a need to distribute financial resources in accordance with the value of each service performed. Health-economic decision-making models can support these decisions. Due to the previous unavailability of health utilities in Germany (scored states of health as a basis for calculating quality-adjusted life-years, QALYs) for women undergoing treatment, international data are often used for such models. However, these may widely deviate from the values for a woman actually living in Germany. It is, therefore, necessary to collect and analyze health utilities in Germany.In a questionnaire survey, health utilities were collected, along with data for a healthy control group, for 580 female patients receiving treatment in the fields of mastology and gynecological oncology using a German version of the EuroQol questionnaire (EQ-5D) and a visual analogue scale (VAS). Data were also collected for the patients' medical history, tumor disease, and treatment.Significant differences with regard to quality of life were measured in relation to the individual tumor entities and in comparison to the controls. Apart from the healthy control group, patients with breast or cervical carcinoma had the best quality of life. In patients with recurrent and metastatic disease, those with breast carcinoma experienced the greatest impairment of their quality of life. According to current treatment, the most important impairment of life quality occurred in patients under radiotherapy and after surgical treatment. There are significant differences from the health utilities recorded for other countries - for example, the state of health declines much more markedly in patients with metastatic disease among American women with breast carcinoma than among German women, in whom recurrent disease and a first diagnosis of metastasis were comparable. Overall, the VAS was able to distinguish more adequately than the EQ-5D questionnaire between the different situations and impairments resulting from diagnosis and therapy.Health utilities are now, for the first time, available for further health-economics analyses in the field of gynecological oncology and mastology for women living in Germany. Important differences in these utilities from those of other countries are evident.
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Heart Rate Measurement Accuracy of Fitbit Charge 4 and Samsung Galaxy Watch Active2: Device Evaluation Study - Nissen, Michael; Slim, Syrine; Jäger, Katharina; Flaucher, Madeleine; Hübner, Hanna; Danzberger, Nina; Fasching, Peter; Beckmann, Matthias; Gradl, Stefan; Eskofier, Björn (JMIR Formative Research, 2022)
Background: Fitness trackers and smart watches are frequently used to collect data in longitudinal medical studies. They allow continuous recording in real-life settings, potentially revealing previously uncaptured variabilities of biophysiological parameters and diseases. Adequate device accuracy is a prerequisite for meaningful research. Objective: This study aims to assess the heart rate recording accuracy in two previously unvalidated devices: Fitbit Charge 4 and Samsung Galaxy Watch Active2. Methods: Participants performed a study protocol comprising 5 resting and sedentary, 2 low-intensity, and 3 high-intensity exercise phases, lasting an average of 19 minutes 27 seconds. Participants wore two wearables simultaneously during all activities: Fitbit Charge 4 and Samsung Galaxy Watch Active2. Reference heart rate data were recorded using a medically certified Holter electrocardiogram. The data of the reference and evaluated devices were synchronized and compared at 1-second intervals. The mean, mean absolute error, mean absolute percentage error, Lin concordance correlation coefficient, Pearson correlation coefficient, and Bland-Altman plots were analyzed. Results: A total of 23 healthy adults (mean age 24.2, SD 4.6 years) participated in our study. Overall, and across all activities, the Fitbit Charge 4 slightly underestimated the heart rate, whereas the Samsung Galaxy Watch Active2 overestimated it (−1.66 beats per minute [bpm]/3.84 bpm). The Fitbit Charge 4 achieved a lower mean absolute error during resting and sedentary activities (seated rest: 7.8 vs 9.4; typing: 8.1 vs 11.6; laying down [left]: 7.2 vs 9.4; laying down [back]: 6.0 vs 8.6; and walking slowly: 6.8 vs 7.7 bpm), whereas the Samsung Galaxy Watch Active2 performed better during and after low- and high-intensity activities (standing up: 12.3 vs 9.0; walking fast: 6.1 vs 5.8; stairs: 8.8 vs 6.9; squats: 15.7 vs 6.1; resting: 9.6 vs 5.6 bpm). Conclusions: Device accuracy varied with activity. Overall, both devices achieved a mean absolute percentage error of just <10%. Thus, they were considered to produce valid results based on the limits established by previous work in the field. Neither device reached sufficient accuracy during seated rest or keyboard typing. Thus, both devices may be eligible for use in respective studies; however, researchers should consider their individual study requirement
Keywords: wearable validation; heart rate validation; Fitbit Charge 4; Samsung Galaxy Watch Active2; heart rate accuracy; fitness tracker accuracy; wearable accuracy; wearable (21); Fitbit (10); heart rate (14); fitness tracker (3); fitness (2); cardiovascular (8)

Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization - Zhang, Ben; Shu, Xiao-Ou; Delahanty, Ryan J.; Zeng, Chenjie; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Wen, Wanqing; Long, Jirong; Li, Chun; Dunning, Alison M.; et al. (Journal of the National Cancer Institute, 2015)
Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear.We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control patients, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control patients.The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5×10(-8).Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.
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HELLP Syndrome or Acute Fatty Liver of Pregnancy: A Differential Diagnostic Challenge - Rath, Werner; Tsikouras, Panagiotis; Stelzl, Patrick (Geburtshilfe und Frauenheilkunde, 2020)
HELLP syndrome and the less common acute fatty liver of pregnancy (AFL) are unpredictable, life-threatening complications of pregnancy. The similarities in their clinical and laboratory presentations are often challenging for the obstetrician when making a differential diagnosis. Both diseases are characterised by microvesicular steatosis of varying degrees of severity. A specific risk profile does not exist for either of the entities. Genetic defects in mitochondrial fatty acid oxidation and multiple pregnancy are considered to be common predisposing factors. The diagnosis of AFL is based on a combination of clinical symptoms and laboratory findings. The Swansea criteria have been proposed as a diagnostic tool for orientation. HELLP syndrome is a laboratory diagnosis based on the triad of haemolysis, elevated aminotransferase levels and a platelet count < 100 G/l. Generalised malaise, nausea, vomiting and abdominal pain are common symptoms of both diseases, making early diagnosis difficult. Clinical differences include a lack of polydipsia/polyuria in HELLP syndrome, while jaundice is more common and more pronounced in AFL, there is a lower incidence of hypertension and proteinuria, and patients with AFL may develop encephalopathy with rapid progression to acute liver failure. In contrast, neurological symptoms such as severe headache and visual disturbances are more prominent in patients with HELLP syndrome. In terms of laboratory findings, AFL can be differentiated from HELLP syndrome by the presence of leucocytosis, hypoglycaemia, more pronounced hyperbilirubinemia, an initial lack of haemolysis and thrombocytopenia < 100 G/l, as well as lower antithrombin levels < 65% and prolonged prothrombin times. While HELLP syndrome has a fluctuating clinical course with rapid exacerbation within hours or transient remissions, AFL rapidly progresses to acute liver failure if the infant is not delivered immediately. The only causal treatment for both diseases is immediate delivery. Expectant management between 24 + 0 and 33 + 6 weeks of gestation is recommended for HELLP syndrome, but only in cases where the mother can be stabilised and there is no evidence of foetal compromise. The maternal mortality rate for HELLP syndrome in developed countries is approximately 1%, while the rate for AFL is 1.8-18%. Perinatal mortality rates are 7-20% and 15-20%, respectively. While data on the long-term impact of AFL on the health of mother and child is still insufficient, HELLP syndrome is associated with an increased risk of developing cardiovascular, metabolic and neurological diseases in later life.
CRIS-Team Scopus Importer:2020-06-16
Keywords: acute fatty liver of pregnancy; differential diagnosis; HELLP syndrome; Swansea criteria; treatment and prognosis

HER2 and TOP2A amplification in a hospital-based cohort of breast cancer patients: associations with patient and tumor characteristics - Fasching, Peter A.; Weihbrecht, Sebastian; Haeberle, Lothar; Gasparyan, Armen; Villalobos, Ivonne E.; Ma, Yanling; Ekici, Arif Bülent; Wachter, David; Hartmann, Arndt; Beckmann, Matthias; Slamon, Dennis J.; Press, Michael F. (Breast Cancer Research and Treatment, 2014)
Gene amplification is an important factor for altered gene expression in breast cancers. TOP2A-amplification often occurs concomitantly with HER2 amplification, and it has been suggested to be predictive for the response to anthracycline chemotherapy. This study assessed the correlation between HER2 status and TOP2A co-amplification, the possible association of TOP2A single-nucleotide polymorphisms with the frequency of this co-amplification as well as confirmation of association with outcome. HER2 and TOP2A amplification were analyzed in a tissue microarray from a clinical cohort study. Additionally, a common genetic variant (rs13695) in the TOP2A gene was genotyped in germline DNA. HER2 gene amplification was compared with HER2-IHC findings assessed during clinical routine work, and the association between all the biomarkers analyzed and the clinical outcome was determined. As an exploratory aim, rs13695 genotypes were compared with TOP2A amplification status. HER2 amplification was seen in 101 of 628 (16.1 %) and TOP2A amplification in 32 (5.1 %) cancers. No TOP2A amplification occurred without HER2 co-amplification. HER2 amplification was found in 8, 13.6, and 55.1 % of patients with HER2-IHC 0/1+, 2+, and 3+ tumors, respectively. HER2-IHC was not associated with an effect on the prognosis, but HER2-FISH was. There was an association between the rs13695 genotype and TOP2A amplification status (P = 0.03). Although there was a significant correlation between HER2 status determined by IHC and HER2 by FISH, only HER2 gene amplification status by FISH was correlated with outcome indicating greater utility for FISH in routine clinical settings.
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Heregulin (HRG) assessment for clinical trial eligibility testing in a molecular registry (PRAEGNANT) in Germany - Hübner, Hanna; Kurbacher, Christian M.; Kuesters, Geoffrey; Hartkopf, Andreas D.; Lux, Michael P.; Huober, Jens; Volz, Bernhard; Taran, Florin Andrei; Overkamp, Friedrich; Tesch, Hans; Häberle, Lothar; Lüftner, Diana; et al. (BMC Cancer, 2020)
Background: Eligibility criteria are a critical part of clinical trials, as they define the patient population under investigation. Besides certain patient characteristics, clinical trials often include biomarker testing for eligibility. However, patient-identification mostly relies on the trial site itself and is often a time-consuming procedure, which could result in missing out on potentially eligible patients. Pre-selection of those patients using a registry could facilitate the process of eligibility testing and increase the number of identified patients. One aim with the PRAEGNANT registry (NCT02338167) is to identify patients for therapies based on clinical and molecular data. Here, we report eligibility testing for the SHERBOC trial using the German PRAEGNANT registry. Methods: Heregulin (HRG) has been reported to identify patients with better responses to therapy with the anti-HER3 monoclonal antibody seribantumab (MM-121). The SHERBOC trial investigated adding seribantumab (MM-121) to standard therapy in patients with advanced HER2-negative, hormone receptor–positive (HR-positive) breast cancer and HRG overexpression. The PRAEGNANT registry was used for identification and tumor testing, helping to link potential HRG positive patients to the trial. Patients enrolled in PRAEGNANT have invasive and metastatic or locally advanced, inoperable breast cancer. Patients eligible for SHERBOC were identified by using the registry. Study aims were to describe the HRG positivity rate, screening procedures, and patient characteristics associated with inclusion and exclusion criteria. Results: Among 2769 unselected advanced breast cancer patients, 650 were HER2-negative, HR-positive and currently receiving first- or second-line treatment, thus potentially eligible for SHERBOC at the end of current treatment; 125 patients also met further clinical eligibility criteria (e.g. menopausal status, ECOG). In the first/second treatment lines, patients selected for SHERBOC based on further eligibility criteria had a more favorable prognosis than those not selected. HRG status was tested in 38 patients, 14 of whom (36.8%) proved to be HRG-positive. Conclusion: Using a real-world breast cancer registry allowed identification of potentially eligible patients for SHERBOC focusing on patients with HER3 overexpressing, HR-positive, HER2-negative metastatic breast cancer. This approach may provide insights into differences between patients eligible or non-eligible for clinical trials. Trial registration: Clinicaltrials, NCT02338167, Registered 14 January 2015 - retrospectively registered.
CRIS-Team Scopus Importer:2020-11-20
Keywords: Advanced breast cancer; Antihormone therapy; Heregulin; Metastatic; MM-121; Seribantumab

High impact of sleeping problems on quality of life in transgender individuals: A cross-sectional multicenter study - Auer, Matthias K.; Liedl, Anita; Fuss, Johannes; Nieder, Timo; Briken, Peer; Stalla, Guenter K.; Hildebrandt, Thomas; Biedermann, Sarah V.; Sievers, Caroline (PLoS ONE, 2017)
INTRODUCTION: Studies in the general population suggest that determinants of QoL are often sex-dependent. Sex-dependent analyses of QoL in transgender populations have not been performed so far. AIM: To identify sex-specific and potentially modifiable determinants of QoL in transgender patients. METHODS: In this cross-sectional multicentre study including 82 transwomen (TW) and 72 transmen (TM) at different treatment stages, we investigated potential determinants for QoL focusing on the impact of mood (BDI, STAI-X), sleep quality (PSQI), chronic pain (GPQ), body image (FBeK) and social support (SSS). MAIN OUTCOME MEASURE: Health-related quality of life measured with the Short Form (36) Health Survey (SF-36). RESULTS: The age-adjusted SF-36 total score and its subscales did not significantly differ between TM and TW. Using a multivariate regression analysis approach, we identified common but also sex-dependent determinants for QoL (Adjusted R2 = 0.228; 0.650 respectively). Accounting for general characteristics such as age, BMI and treatment status, sleep quality according to the PSQI was an independent and strong determinant of QoL in both sexes (β = -0.451, p = 0.003 TM; β = -0.320; p = 0.0029 TW). Chronic pain was a significant independent predictor of QoL in TM (β = -0.298; p = 0.042) but not in TW. In contrast, anxiety (β = -0.451; p< 0.001) being unemployed (β = -0.206; p = 0.020) and insecurity about the own appearance (FBeK) (β = -0.261; p = 0.01) were independent predictors of QoL in TW. The rate of those reporting high sleep disturbances (PSQI ≥5) was high with 79.2% in TW and 81.2% in TM. Accordingly, age-adjusted QoL was also significantly lower in those reporting poor sleep in both sexes. CONCLUSIONS: Sleep strongly affected QoL in both genders, while other factors, like pain and body image, seem to be gender specific in transgender individuals.
EVALuna2:36176

High Ki-67 as a biomarker for identifying patients with high risk early breast cancer treated in monarchE - Harbeck, Nadia; Johnston, Stephen; Fasching, Peter; Martin, Miguel; Toi, Masakazu; Rastogi, Priya; Song, Chuangui; Molthrop, David; Vuky, Jacqueline; Yamashita, Toshinari; Jaliffe, Georgina Garnica; Gumus, Mahmut; et al. (CANCER RESEARCH, 2021)
CRIS-Team WoS Importer:2021-03-26

History of Comorbidities and Survival of Ovarian Cancer Patients, Results from the Ovarian Cancer Association Consortium - Minlikeeva, Albina N.; Freudenheim, Jo L.; Eng, Kevin H.; Cannioto, Rikki A.; Friel, Grace; Szender, J. Brian; Segal, Brahm; Odunsi, Kunle; Mayor, Paul; Diergaarde, Brenda; Zsiros, Emese; Kelemen, Linda E.; et al. (Cancer Epidemiology Biomarkers & Prevention, 2017)
Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients.Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes.Results: None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced).Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival.Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(9); 1470-3. ©2017 AACR.
EVALuna2:36128

HLA-G and HLA-F protein isoform expression in breast cancer patients receiving neoadjuvant treatment - Würfel, Franziska; Hübner, Hanna; Häberle, Lothar; Gaß, Paul; Hein, Alexander; Jud, Sebastian; Hack, Carolin; Wunderle, Marius; Schulz-Wendtland, Rüdiger; Erber, Ramona; Hartmann, Arndt; Ekici, Arif Bülent; et al. (Scientific Reports, 2020)
The immunosuppressive human leukocyte antigens HLA-G and HLA-F are expressed on trophoblast and malignant cells. Four membrane-bound and three soluble HLA-G protein isoforms have been described, which have different immunosuppressive potentials. HLA-F has three transcript variants, resulting in three different protein isoforms. The aim of this study was to evaluate the prognostic and predictive value of HLA-G and HLA-F protein isoform expression patterns in patients with breast cancer. Core biopsies were taken at diagnosis in patients with HER2+ (n = 28), luminal B-like (n = 49) and triple-negative (n = 38) breast cancers who received neoadjuvant chemotherapy. Expression levels of HLA-F and -G were correlated with the pathological complete response (pCR). Protein expression was determined by Western blot analysis, using two antibodies for each HLA, specific for different isoforms. The protein expression of HLA isoforms did not significantly differ between breast cancer subtypes. However, some initial indications were found for an association between the soluble HLA-G6 protein isoform and pCR in HER2+ breast cancer. The study provides preliminary evidence for the evaluation of HLA-G isoform expression, in particular HLA-G6, as a possible new marker for pCR in HER2+ breast cancer.
CRIS-Team Scopus Importer:2020-10-02

HLA-G expression associates with immune evasion muscle-invasive urothelial cancer and drives prognostic relevance - Branz, Annalena; Matek, Christian; Lange, Fabienne; Bahlinger, Veronika; Klümper, Niklas; Hölzel, Michael; Strissel, Pamela; Strick, Reiner; Sikic, Danijel; Wach, Sven; Taubert, Helge; Wullich, Bernd; et al. (Frontiers in Immunology, 2024)
Introduction: Urothelial bladder cancer is frequent and exhibits diverse prognoses influenced by molecular subtypes, urothelial subtype histology, and immune microenvironments. HLA-G, known for immune regulation, displays significant membranous expression in tumor tissues. Methods: We studied the protein expression of Human Leucocyte Antigen G (HLA-G) in 241 Muscle-Invasive Bladder Cancer (MIBC) patients, elucidating its potential clinical and biological significance. Protein expression levels were evaluated and correlated with molecular subtypes, histological characteristics, immune microenvironment markers, and survival outcomes. Results: High HLA-G expression associates with poor overall survival (OS) and diseasespecific survival (DSS), independent of clinicopathological parameters. HLA-G expression varies among molecular subtypes and Urothelial Subtype Histology, e.g., elevated expression levels in basal/squamous MIBC and those with sarcomatoid differentiation. Notably, HLA-G is increased in MIBC with an immune evasive microenvironment (high PD-L1 tumor cell expression, NK cell depletion, granzyme B (GZMB)/CD8 ratio reduction, MHC class I (MHCI) expression reduction) that are characterized by immunosuppressive features and poor prognosis. Furthermore, HLA-G correlates with elevated levels of other immune checkpoint proteins (TIGIT, LAG3, CTLA-4), indicating its role in immune evasion. Discussion: Our findings underscore HLA-G’s role as a potential prognostic marker and interesting immunotherapeutic target in MIBC. Its impact on immune evasion mechanisms and broad expression, coupled with associations withpoor survival and distinct tumor phenotypes, positions HLA-G as a promising protein for further exploration in developing targeted immunotherapies for MIBC patients.
CRIS-Team Scopus Importer:2024-11-15
Keywords: HLA-G; immune checkpoints; immune evasion; immune microenvironment; urothelial cancer

HLA-J, a Non-Pseudogene as a New Prognostic Marker for Therapy Response and Survival in Breast Cancer - Würfel, Franziska M.; Wirtz, Ralph M.; Winterhalter, Christoph; Taffurelli, Mario; Santini, Donatella; Mandrioli, Anna; Veltrup, Elke; Rübner, Matthias; Fasching, Peter; Würfel, Wolfgang; Zamagni, Claudio (Geburtshilfe und Frauenheilkunde, 2020)
The human leukocyte antigen (HLA) genes are cell-surface proteins, essential for immune cell interaction. HLA-G is known for their high immunosuppressive effect and its potential as predictive marker in breast cancer. However, nothing is known about the HLA-J and its immunosuppressive, prognostic and predictive features, as it is assumed to be a pseudogene by in silico sequence interpretation. HLA-J, ESR1, ERBB2, KRT5 and KRT20 mRNA expression were analysed in 29 fresh frozen breast cancer biopsies and their corresponding resectates obtained from patients treated with neoadjuvant chemotherapy (NACT). mRNA was analysed with gene specific TaqMan-based Primer/Probe sets and normalized to Calmodulin 2. All breast cancer samples did express HLA-J and frequently increased HLA-J mRNA levels after NACT. HLA-J mRNA was significantly associated with overexpression of the ESR1 mRNA status (Spearman ρ 0,5679; p = 0.0090) and KRT5 mRNA (Spearman ρ 0,6121; p = 0.0041) in breast cancer core biopsies and dominated in luminal B subtype. Kaplan Meier analysis revealed that an increase of HLA-J mRNA expression after NACT had worse progression free survival (p = 0,0096), indicating a counterreaction of tumor tissues presumably to prevent elimination by enhanced immune infiltration induced by NACT. This counterreaction is associated with worse prognosis. To our knowledge this is the first study identifying HLA-J as a new predictive marker in breast cancer being involved in immune evasion mechanisms.
CRIS-Team Scopus Importer:2020-11-20
Keywords: breast cancer subtypes; HLA-J; MHC1; RT-qPCR

Hormonal markers as noninvasive predictors of sperm retrieval in non-obstructive azoospermia - Zarezadeh, Reza; Fattahi, Amir; Nikanfar, Saba; Oghbaei, Hajar; Ahmadi, Yadollah; Rastgar Rezaei, Yeganeh; Nouri, Mohammad; Dittrich, Ralf (Journal of Assisted Reproduction and Genetics, 2021)
Non-obstructive azoospermia (NOA) is one of the leading causes of male factor infertility, which results from impaired spermatogenesis. Currently, the sole feasible therapeutic option for men with NOA to father their biologic children is sperm retrieval by testicular sperm extraction (TESE) approaches followed by an intracytoplasmic sperm injection program. Nevertheless, the rate of sperm retrieval from NOA men following TESE has remained as low as 50%, leading to a significant number of unsuccessful TESE operations. Given that TESE is associated with multiple side effects, the prediction of TESE outcome preoperatively can abolish unnecessary operations and thereby prevent NOA patients from sustaining adverse side effects. As the process of spermatogenesis is under the regulation of hormones, the hormonal profile of serum and/or seminal plasma may contain useful information about spermatogenesis status and can potentially predict the chance of sperm retrieval from NOA patients. A large body of literature is available on the predictive capability of different serum and seminal plasma hormones such as FSH, LH, testosterone, inhibin B, AMH, estradiol, prolactin, and leptin in a stand-alone basis or combinational fashion with respect to the TESE outcome. The present review aimed to evaluate the potential of these hormonal markers as noninvasive predictors of sperm retrieval in men with NOA.
CRIS-Team Scopus Importer:2021-04-19
Keywords: Azoospermia; Biomarkers; Hormones; Sperm retrieval; Spermatozoa

Hormone replacement therapy and prognosis in ovarian cancer patients - Hein, Alexander; Thiel, Falk; Bayer, Christian M.; Fasching, Peter; Häberle, Lothar; Lux, Michael P.; Renner, Stefan; Jud, Sebastian; Schrauder, Michael G.; Müller, Andreas; Wachter, David; Strehl, Johanna; et al. (European Journal of Cancer Prevention, 2013)
Estrogen exposure has at least a moderate effect on the risk for ovarian cancer, and antiestrogen therapy may be helpful in treating the disease. It is known from breast cancer that previous hormone replacement therapy (HRT) may influence the molecular profile and prognostic behavior of these tumors. The aim of this study was therefore to investigate the influence of previous HRT on the prognosis in a cohort of patients with invasive epithelial ovarian cancer. Among 547 patients who were treated for ovarian malignancies at a single institution from 1995 to 2008, a total of 244 postmenopausal patients with epithelial cancer and under the age of 75 were identified for whom information about HRT before the onset of the disease was available. HRT was correlated with tumor and patient characteristics. Analyses of overall survival and progression-free survival were carried out using Cox proportional hazards models. Age, tumor stage, and resection status correlated significantly with HRT in the univariate analysis. Patients with previous HRT were more likely to have a lower stage, to be younger, and to have optimal debulking. With regard to survival, HRT had a positive effect on overall survival, specifically in the subgroup of patients with optimal debulking. No correlation was seen in relation to progression-free survival. Sex hormone exposure through HRT may influence the behavior of ovarian cancers after the onset of the disease. This study supports the hypothesis that ovarian cancer is a hormonally influenced tumor. © 2012 Lippincott Williams & Wilkins.
CRIS-Team Scopus Importer:2021-07-19
Keywords: estrogen; hormone replacement therapy; ovarian cancer; pathogenesis; prognosis

Hormone Therapy and its Effect on the Prognosis in Breast Cancer Patients - Rauh, C.; Schuetz, F.; Rack, B.; Stickeler, E.; Klar, M.; Orlowska-Volk, M.; Windfuhr-Blum, M.; Heil, J.; Rom, J.; Sohn, C.; Andergassen, U.; Jueckstock, J.; et al. (Geburtshilfe und Frauenheilkunde, 2015)
Introduction: Use of hormone therapy (HT) has declined dramatically in recent years. Some studies have reported that HT use before a diagnosis of breast cancer (BC) may be a prognostic factor in postmenopausal patients. This study aimed to examine the prognostic relevance of HT use before BC diagnosis. Methods: Four BC cohort studies in Germany were pooled, and 4492 postmenopausal patients with HT use data were identified. Patient data and tumor characteristics were compared between users and nonusers, along with overall survival (OS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS). Cox proportional hazards models were stratified by study center and adjusted for age at diagnosis, tumor stage, grading, nodal status, and hormone receptors. Results: Women with HT use before the diagnosis of BC were more likely to have a lower tumor stage, to be estrogen receptor-negative, and to have a lower grading. With regard to prognosis there were effects seen for OS, DMFS and LRFS, specifically in the subgroup of women with a positive hormone receptor. In these subgroups, BC patients had a better prognosis with previous HT use. Conclusions: HT use before a diagnosis of BC is associated with a more favorable prognosis in women with a positive hormone receptor status. It may be recommended that the prognostic factor HT should be documented and analyzed as a confounder for prognosis in studies of postmenopausal hormone-responsive breast cancers.
EVALuna2:6745

HPV16-L1-specific antibody response is associated with clinical remission of high-risk HPV-positive early dysplastic lesions - Mehlhorn, Grit; Hautmann, Simone K.; Koch, Martin; Strehl, Johanna D.; Hartmann, Arndt; Hilfrich, Ralf; Beckmann, Matthias; Griesser, Henrik (Anticancer Research, 2014)
The present study was aimed at clarifying if use of a rapid human papillomavirus type 16 L1-specific antibody test could be used to improve clinical management of high-risk HPV-positive low-grade squamous intraepithelial lesion (LSIL)/high-grade squamous intraepithelial lesion (HSIL).The study was nested within a prospective study of 801 patients with early dysplastic high-risk HPV-positive lesions to examine the prognostic significance of HPV-L1 protein detection. Serum samples of 87 patients were tested with a rapid HPV16-L1-specific antibody test. The results were correlated with the clinical outcome during 66 months of follow-up.A combined analysis of the 22 antibody-positive women showed that 17 were also L1 protein-positive, and 5 were L1 capsid protein-negative. An HPV-specific immune competence strongly correlates with clinical remission of low-grade squamous intraepithelial lesion (76.6%). For L1 antigen and HPV16-L1 antibody double-positive women, the risk of progression to cervical intraepithelial neoplasia grade 3 was low (5.8%).The rapid anti-HPV16-L1 test could be a promising tool to improve risk assessment and appropriate clinical management of high-risk HPV-positive early dysplastic lesions.
EVALuna2:6623

HRQoL with neoadjuvant pembrolizumab plus chemotherapy vs placebo plus chemotherapy, followed by adjuvant pembrolizumab vs placebo for early-stage TNBC: Results from KEYNOTE-522 - Dent, R. A.; Cortes, J.; Pusztai, L.; Mcarthur, H. L.; Kuemmel, S.; Bergh, J.; Denkert, C.; Park, Y. H.; Hui, R.; Harbeck, N.; Takahashi, M.; Untch, M.; et al. (ANNALS OF ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-12-23

Human endogenous retroviruses differentially regulate immune checkpoints and modulation of immune responses in serous ovarian carcinoma - Strissel, Pamela; Chiappinelli, Katherine B.; Strehl, Johanna; Wuefel, Franziska M. B.; Beckmann, Matthias; Baylin, Stephen B.; Strick, Reiner (2017)
EVALuna2:34862

Human leucocyte antigen class i in hormone receptor-positive, HER2-negative breast cancer: Association with response and survival after neoadjuvant chemotherapy - Sinn, Bruno Valentin; Weber, Karsten E.; Schmitt, Wolfgang Daniel; Fasching, Peter; Symmans, William Fraser; Blohmer, Jens Uwe; Karn, Thomas; Taube, Eliane Tabea; Klauschen, Frederick; Marmé, Frederik; Schem, Christian; Stickeler, Elmar; et al. (BREAST CANCER RES, 2019)
Background: Clinical application of cancer immunotherapy requires a better understanding of tumor immunogenicity and the tumor microenvironment. HLA class I molecules present antigens to CD8+ cytotoxic cells. Their loss or downregulation is frequently found in tumors resulting in reduced T cell responses and worse prognosis. Methods: We evaluated HLA class I heavy chain expression by immunohistochemistry in 863 biopsies (GeparTrio trial). Patients received neoadjuvant chemotherapy and adjuvant endocrine treatment if tumors were hormone receptor-positive (HR+). In parallel, the expression of HLA-A was analyzed using a microarray cohort of 320 breast cancer patients from the MD Anderson Cancer Center. We evaluated its association with clinical outcome, tumor-infiltrating lymphocytes (TILs), and immune cell metagenes. Results: In HR+/HER2- breast cancer, HLA class I heavy chain expression was associated with increased TILs and better response to chemotherapy (7% vs. 14% pCR rate, P = 0.029), but worse disease-free survival (hazard ratio (HR) 1.6 (1.1-2.4); P = 0.024). The effect was significant in a multivariate model adjusted for clinical and pathological variables (HR 1.7 (1.1-2.6); P = 0.016) and was confirmed by analysis of HLA-A in a microarray cohort. HLA-A was correlated to most immune cell metagenes. There was no association with response or survival in triple-negative or HER2+ disease. Conclusions: The study confirms the negative prognostic role of lymphocytes in HR+ breast cancer and points at a complex interaction between chemotherapy, endocrine treatment, and tumor immunogenicity. The results point at a subtype-specific and potentially treatment-specific role of tumor-immunological processes in breast cancer with different implications in triple-negative and hormone receptor-positive disease.
CRIS-Team Scopus Importer:2019-12-24
Keywords: Breast cancer; HLA; Tumor-infiltrating lymphocytes

Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment - Heidkamp, Gordon Frederik; Sander, Jil; Lehmann, Christian; Heger, Lukas; Eissing, Nathalie; Baranska, Anna; Lühr, Jennifer; Hoffmann, Alana; Reimer, Katharina; Lux, Anja; Söder, Stephan; Hartmann, Arndt; et al. (Science immunology, 2016)
In mice, conventional and plasmacytoid dendritic cells (DCs) derive from separate hematopoietic precursors before they migrate to peripheral tissues. Moreover, two classes of conventional DCs (cDC1 and cDC2 DCs) and one class of plasmacytoid DCs (pDCs) have been shown to be transcriptionally and functionally distinct entities. In humans, these three DC subtypes can be identified using the cell surface markers CD1c (cDC2), CD141 (cDC1), and CD303 (pDCs), albeit it remains elusive whether DC functionality is mainly determined by ontogeny or the tissue microenvironment. By phenotypic and transcriptional profiling of these three DC subtypes in different human tissues derived from a large number of human individuals, we demonstrate that DC subpopulations in organs of the lymphohematopoietic system (spleen, thymus, and blood) are strongly defined by ontogeny rather than by signals from the microenvironment. In contrast, DC subsets derived from human lung or skin differed substantially, strongly arguing that DCs react toward modulatory signals from tissue microenvironments. Collectively, the data obtained in this study may serve as a major resource to guide further studies into human DC biology during homeostasis and inflammatio
EVALuna2:6852

Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment - Heidkamp, Gordon Frederik; Sander, J.; Lehmann, C. H. K.; Heger, Lukas; Eissing, N.; Baranska, A.; Lühr, Jennifer; Hoffmann, Alana; Reimer, Katharina; Lux, Anja; Söder, Stephan; Hartmann, Arndt; et al. (2017)
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