Mutational diversity and therapy response in breast cancer: A sequencing analysis in the neoadjuvant geparsepto trial

Loibl S, Treue D, Budczies J, Weber K, Stenzinger A, Schmitt WD, Weichert W, Jank P, Furlanetto J, Klauschen F, Karn T, Pfarr N, Von Minckwitz G, Möbs M, Jackisch C, Sers C, Schneeweiss A, Fasching P, Schem C, Hummel M, Van Mackelenbergh M, Nekljudova V, Untch M, Denkert C (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Clinical Cancer Research American Association for Cancer Research

Book Volume: 25

Pages Range: 3986-3995

Journal Issue: 13

DOI: 10.1158/1078-0432.CCR-18-3258

Abstract

Purpose: Next-generation sequencing (NGS) can be used for comprehensive investigation of molecular events in breast cancer. We evaluated the relevance of genomic alterations for response to neoadjuvant chemotherapy (NACT) in the GeparSepto trial. Experimental Design: Eight hundred fifty-one pretherapeutic formalin-fixed paraffin-embedded (FFPE) core biopsies from GeparSepto study were sequenced. The panel included 16 genes for mutational (AKT1, BRAF, CDH1, EGFR, ERBB2, ESR1, FBXW7, FGFR2, HRAS, KRAS, NRAS, SF3B1, TP53, HNF1A, PIK3CA, and PTEN) and 8 genes for copy-number alteration analysis (CCND1, ERBB2, FGFR1, PAK1, PIK3CA, TOP2A, TP53, and ZNF703). Results: The most common genomic alterations were mutations of TP53 (38.4%) and PIK3CA (21.5%), and 8 different amplifications (TOP2A 34.9%; ERBB2 30.6%; ZNF703 30.1%; TP53 21.9%; PIK3CA 24.1%; CCND1 17.7%; PAK1 14.9%; FGFR 12.6%). All other alterations had a prevalence of less than 5%. The genetic heterogeneity in different breast cancer subtypes [lum/HER2neg vs. HER2pos vs. triple-negative breast cancer (TNBC)] was significantly linked to differences in NACT response. A significantly reduced pathologic complete response rate was observed in PIK3CAmutated breast cancer [PIK3CAmut: 23.0% vs. wild-type (wt) 38.8%, P < 0.0001] in particular in the HER2pos subcohort [multivariate OR = 0.43 (95% CI, 0.24-0.79), P = 0.006]. An increased response to nab-paclitaxel was observed only in PIK3CAwt breast cancer, with univariate significance for the complete cohort (P = 0.009) and the TNBC (P = 0.013) and multivariate significance in the HER2pos subcohort (test for interaction P = 0.0074). Conclusions: High genetic heterogeneity was observed in different breast cancer subtypes. Our study shows that FFPE-based NGS can be used to identify markers of therapy resistance in clinical study cohorts. PIK3CA mutations could be a major mediator of therapy resistance in breast cancer.

Authors with CRIS profile

Peter Fasching Professur für Translationale Frauenheilkunde und Geburtshilfe

Involved external institutions

Deutsches Konsortium für Translationale Krebsforschung (DKTK) DE Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) DE Germany (DE) Charité - Universitätsmedizin Berlin DE Germany (DE) HELIOS Kliniken DE Germany (DE) GBG Forschungs GmbH (German Breast Group) DE Germany (DE) Sana-Krankenhaus Hürth DE Germany (DE) Krankenhaus Jerusalem DE Germany (DE) Universitätsklinikum Heidelberg DE Germany (DE) Goethe-Universität Frankfurt am Main DE Germany (DE) Technische Universität München (TUM) DE Germany (DE)

How to cite

APA:

Loibl, S., Treue, D., Budczies, J., Weber, K., Stenzinger, A., Schmitt, W.D.,... Denkert, C. (2019). Mutational diversity and therapy response in breast cancer: A sequencing analysis in the neoadjuvant geparsepto trial. Clinical Cancer Research, 25(13), 3986-3995. https://dx.doi.org/10.1158/1078-0432.CCR-18-3258

MLA:

Loibl, Sibylle, et al. "Mutational diversity and therapy response in breast cancer: A sequencing analysis in the neoadjuvant geparsepto trial." Clinical Cancer Research 25.13 (2019): 3986-3995.

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