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Clin Cancer Res. 2019 Apr 12. doi: 10.1158/1078-0432.CCR-18-3258. [Epub ahead of print]

Mutational Diversity and Therapy Response in Breast Cancer: A Sequencing Analysis in the Neoadjuvant GeparSepto Trial.

Author information

1
German Breast Group, Neu-Isenburg, Germany. Sibylle.Loibl@gbg.de.
2
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany.
3
German Cancer Consortium (DKTK), Partner Sites Berlin and Munich, Germany.
4
Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
5
German Breast Group, Neu-Isenburg, Germany.
6
Institute of Pathology, Technical University of Munich, Munich, Germany.
7
Department of Gynecology and Obstetrics, University of Frankfurt, Frankfurt am Main, Germany.
8
Department of Obstetrics and Gynecology and Breast Cancer Center, Sana Klinikum Offenbach, Offenbach, Germany.
9
National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
10
Universitätsklinikum Erlangen, Erlangen, Germany.
11
Mammazentrum Hamburg - Brustklinik am Krankenhaus Jerusalem, Hamburg, Germany.
12
Universitätsklinikum Kiel, Kiel, Germany.
13
Helios Klinikum Berlin-Buch, Berlin, Germany.
14
Institute of Pathology, Philipps-University Marburg and University Hospital Marburg, Marburg, Germany.
#
Contributed equally

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 PIK3CA-mutated 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.

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