Reconstructing tumor history in breast cancer: signatures of mutational processes and response to neoadjuvant chemotherapy☆

Denkert C, Untch M, Benz S, Schneeweiss A, Weber KE, Schmatloch S, Jackisch C, Sinn HP, Golovato J, Karn T, Marmé F, Link T, Budczies J, Nekljudova V, Schmitt WD, Stickeler E, Müller V, Jank P, Parulkar R, Heinmöller E, Sanborn JZ, Schem C, Sinn BV, Soon-Shiong P, van Mackelenbergh M, Fasching P, Rabizadeh S, Loibl S (2021)

Publication Type: Journal article

Publication year: 2021

Journal

DOI: 10.1016/j.annonc.2020.12.016

Abstract

Background: Different endogenous and exogenous mutational processes act over the evolutionary history of a malignant tumor, driven by abnormal DNA editing, mutagens or age-related DNA alterations, among others, to generate the specific mutational landscape of each individual tumor. The signatures of these mutational processes can be identified in large genomic datasets. We investigated the hypothesis that genomic patterns of mutational signatures are associated with the clinical behavior of breast cancer, in particular chemotherapy response and survival, with a particular focus on therapy-resistant disease. Patients and methods: Whole exome sequencing was carried out in 405 pretherapeutic samples from the prospective neoadjuvant multicenter GeparSepto study. We analyzed 11 mutational signatures including biological processes such as APOBEC-mutagenesis, homologous recombination deficiency (HRD), mismatch repair deficiency and also age-related or tobacco-induced alterations. Results: Different subgroups of breast carcinomas were defined mainly by differences in HRD-related and APOBEC-related mutational signatures and significant differences between hormone-receptor (HR)-negative and HR-positive tumors as well as correlations with age, Ki-67 and immunological parameters were observed. We could identify mutational processes that were linked to increased pathological complete response rates to neoadjuvant chemotherapy with high significance. In univariate analyses for HR-positive tumors signatures, S3 (HRD, P < 0.001) and S13 (APOBEC, P = 0.001) as well as exonic mutation rate (P = 0.002) were significantly correlated with increased pathological complete response rates. The signatures S3 (HRD, P = 0.006) and S4 (tobacco, P = 0.011) were prognostic for reduced disease-free survival of patients with chemotherapy-resistant tumors. Conclusion: The results of this investigation suggest that the clinical behavior of a tumor, in particular, response to neoadjuvant chemotherapy and disease-free survival of therapy-resistant tumors, could be predicted by the composition of mutational signatures as an indicator of the individual genomic history of a tumor. After additional validations, mutational signatures might be used to identify tumors with an increased response rate to neoadjuvant chemotherapy and to define therapy-resistant subgroups for future therapeutic interventions.

Authors with CRIS profile

Involved external institutions

Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) NantOmics United States (USA) (US) Krankenhaus Jerusalem Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) GBG Forschungs GmbH (German Breast Group) Germany (DE) Philipps-Universität Marburg Germany (DE) Institut für Pathologie Nordhessen Germany (DE) Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen Germany (DE) Goethe-Universität Frankfurt am Main Germany (DE) HELIOS Kliniken Germany (DE) Universitätsklinikum Mannheim Germany (DE) Sana Kliniken AG Germany (DE) Technische Universität Dresden Germany (DE) Universitätsklinikum Heidelberg Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE)

How to cite

APA:

Denkert, C., Untch, M., Benz, S., Schneeweiss, A., Weber, K.E., Schmatloch, S.,... Loibl, S. (2021). Reconstructing tumor history in breast cancer: signatures of mutational processes and response to neoadjuvant chemotherapy☆. Annals of Oncology. https://doi.org/10.1016/j.annonc.2020.12.016

MLA:

Denkert, C., et al. "Reconstructing tumor history in breast cancer: signatures of mutational processes and response to neoadjuvant chemotherapy☆." Annals of Oncology (2021).

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