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Clin Cancer Res. 2019 Apr 12. pii: clincanres.3258.2018. 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
Medicine and Research, German Breast Group Forschungs GmbH Sibylle.Loibl@gbg.de.
2
Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health.
3
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin; German Cancer Consortium (DKTK), Partner sites Berlin; Institute of Pathology, University Hospital Heidelberg, Heidelberg.
4
German Breast Group, Neu Isenburg. Germany.
5
Institute of Pathology, University Hospital Heidelberg.
6
Institute of Pathology, Charité - Universitätsmedizin Berlin.
7
Institute of General Pathology and Pathological Anatomy, Technical University Munich.
8
Institute of Pathology, Philipp University of Marburg.
9
Medicine and Research, GBG Forschungs GmbH.
10
Institute of Pathology, Charité Universtiaetsmedizin Berlin.
11
Department of Obstetrics and Gynecology, University Hospital Frankfurt.
12
Institute of Pathology, Technical University Munich.
13
Medicine and Research, German Breast group.
14
Institut of Pathology, Charité - Universitätsmedizin Berlin.
15
Department of Obstetrics and Gynecology, Sana Klinikum Offenbach.
16
Institute of Pathology, Charité Universitätsmedizin, Berlin.
17
Gynecologic oncology, National Center for Tumor Diseases, University of Heidelberg.
18
Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg.
19
Mammazentrum Hamburg - Brustklinik am Krankenhaus Jerusalem, Hamburg.
20
Institute of Pathology, Charité, Campus Mitte, Berlin.
21
Gynecology, Universitätsklinikums Schleswig-Holstein, Campus Kiel.
22
Dep. of Statistics, GBG Forschungs GmbH.
23
Helios Kliniken Berlin-Buch.
24
Charité - Universitätsmedizin Berlin.

Abstract

PURPOSE:

Next-generation-sequencing (NGS) can be used for comprehensive investigation of molecular events in breast cancer (BC). We evaluated the relevance of genomic alterations for response to neoadjuvant chemotherapy (NACT) in the GeparSepto trial.

EXPERIMENTAL DESIGN:

851 pretherapeutic 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, PTEN) and 8 genes for copy number alteration analysis (CCND1, ERBB2, FGFR1, PAK1, PIK3CA, TOP2A, TP53, 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 BC subtypes (lum/HER2neg vs HER2pos vs TNBC) was significantly linked to differences in NACT response. A significantly reduced pCR rate was observed in PIK3CA-mutated BC (PIK3CAmut: 23.0% vs wildtype (wt) 38.8%, p<0.0001) in particular in the Her2pos subcohort (multivariate OR=0.43 [0.24-0.79], p=0.006). An increased response to nab-paclitaxel was observed only in PIK3CAwt BC, 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 BC 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 BC.

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