Abstract LB-027: Mutational diversity and therapy response in breast cancer-a sequencing analysis in the neoadjuvant GeparSepto trial
Authors: Loibl Sibylle , Treue Denise , Budczies Jan , Weber Karsten , Stenzinger Albrecht , Schmitt Wolfgang D. , Weichert Wilko , Jank Paul , Furlanetto Jenny , Klauschen Frederick , Karn Thomas , Pfarr Nicole , Minckwitz Gunter von , Lehmann Annika , Jackisch Christian , Sers Christine , Schneeweiss Andreas , Fasching Peter A. , Schem Christian , Hummel Michael , Mackelenbergh Marion van , Nekljudova Valentina , Untch Michael , Denkert Carsten 
Published: August 2018

Abstract
Background: Targeted next-generation sequencing (NGS) enables investigation of key molecular events in breast cancer (BC) and driver genes. In this study we evaluated the relevance of mutations in 15 cancer genes and copy number amplifications in 8 cancer genes for response to neoadjuvant therapy in the GeparSepto cohort. The pCR rate was significantly higher in patients treated with nab-paclitaxel (nP) instead of paclitaxel (P).
Methods: A total of 851 pretherapeutic formalin-fixed paraffin embedded (FFPE) core biopsies including luminal/HER2- (n=397), HER2+ (n=295) and TNBC (n=159) tumors from the neoadjuvant GeparSepto trial were analysed by targeted NGS. We used a panel of 21 genes including 15 genes selected for mutation analysis (AKT1, ATM, CCND1, CDH1, EGFR, ERBB2, FBXW7, FGFR2, HRAS, KRAS, NRAS, PIK3CA, PTEN, SF3B1, TP53) and 8 genes selected for amplifications (CCND1, ERBB2, FGFR1, PAK1, PIK3CA, TOP2A, TP53, ZNF703).
Results: The most prevalent mutations were in TP53 (38.4%), ATM (27.7%) and PIK3CA (21.5%) genes; the amplification frequencies were TOP2a (34.9%), ERBB2 (30.6%), ZNF703 (30.1%), PIK3CA (24.1%), TP53 (21.9%), CCND1 (17.7%), PAK1 (14.9%) and FGFR1 (12.6%). Amplification of ERBB2 was observed in 84.7% of HER2+ BC, but only in 1.5% of luminal/HER2- BC and 2.5% of TNBC (p&lt;0.0005). In univariate analysis of the complete cohort, the two most important mutations (TP53 and PIK3CA) and 7 of 8 amplifications (CCND1, ERBB2, FGFR1, PAK1, TOP2A, TP53 and ZNF703) were significantly associated with the pCR rate. PIK3CA mutations overall predicted significantly lower pCR rate (23.0% mutant [mt] vs 38.3% wild-type [wt] group, OR 0.47 [0.32-0.69], p&lt;0.0005). An increased pCR rate was only observed in the PIK3CA wt group treated with nP compared to P (43.5% vs 33.6%, OR 1.52 [1.11-2.08], p=0.009). Within the PIK3CA wt HER2+ group there was a significant interaction of the PIK3CA mutations with the response to taxane therapy in favour for nP (71.7% vs 60.7%, OR 1.64 [0.95-2.83], p=0.079; test for interaction p=0.039). Overall in the HER2+ cohort tumors with an additional ERBB2 amplification had a higher pCR rate than those without (65.6% vs 44.4%, OR 2.38 [1.25-4.53], p=0.008). An opposite effect was observed for PAK1 amplifications (47.2% vs 64.5%, OR 0.49 [0.24-1.00], p=0.048).
Conclusion: NGS sequencing of FFPE samples from clinical trials is feasible, detects mutations and copy number alterations, and reveals high molecular heterogeneity indifferent BC types. Our results points to PIK3CA as a major mechanism of therapy resistance in BC, which might also be relevant for response to nP vs standard P. In general, NGS holds promise to identify markers of therapy resistance as a basis for individualized and new molecular-targeted BC therapies.
Citation Format: Sibylle Loibl, Denise Treue, Jan Budczies, Karsten Weber, Albrecht Stenzinger, Wolfgang D. Schmitt, Wilko Weichert, Paul Jank, Jenny Furlanetto, Frederick Klauschen, Thomas Karn, Nicole Pfarr, Gunter von Minckwitz, Annika Lehmann, Christian Jackisch, Christine Sers, Andreas Schneeweiss, Peter A. Fasching, Christian Schem, Michael Hummel, Marion van Mackelenbergh, Valentina Nekljudova, Michael Untch, Carsten Denkert. Mutational diversity and therapy response in breast cancer-a sequencing analysis in the neoadjuvant GeparSepto trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-027.