May 2019: Mutational landscape and therapy response in GeparSepto trial

Translational studies investigating mutational landscape of breast cancer after neoadjuvant chemotherapy (NACT) in large clinical trial cohorts are limited. In this study a total of 851 pretherapeutic formalin-fixed paraffin-embedded (FFPE) samples from the neoadjuvant GeparSepto trial were sequenced by targeted NGS. A breast cancer-specific hotspot panel of 24 genes including 16 genes for mutation (AKT1, BRAF, CDH1, EGFR, ERBB2, ESR1, FBXW7, FGFR2, HRAS, KRAS, NRAS, SF3B1, TP53, HNF1A, PIK3CA, PTEN) and 8 genes for copy-number alterations (CAN) (CCND1, ERBB2, FGFR1, PAK1, PIK3CA, TOP2A, TP53, ZNF703) was used to investigate the prevalence of alterations in different breast cancer subgroups as well as the role for response to NACT. Three genes, PIK3CA, TP53 and ERBB2 were analyzed for both mutations and CNAs. 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%). The genetic heterogeneity in different breast cancer subtypes [lum/HER2-negative vs. HER2-positive vs. triple-negative breast cancer (TNBC)] was significantly linked to differences in NACT response. PIK3CA-mutated tumors showed a significantly reduced pathological complete response (pCR) rate compared with wild-type tumors (23.0% vs. 38.8%; p<0.001), in particular in the HER2-positive subcohort (multivariate OR=0.43 [95%CI 0.24–0.79]; p=0.006). This study is the first comprehensive FFPE-based NGS analysis of different breast cancer subtypes after NACT and provided evidence for using NGS to dissect molecular heterogeneity in clinical trial samples. Furthermore, the findings pointed to PIK3CA mutations as a therapy resistance parameter in the HER2-positive breast cancer.

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 PA, Schem C, Hummel M, van Mackelenbergh M, Nekljudova V, Untch M, Denkert C. Mutational Diversity and Therapy Response in Breast Cancer: A Sequencing Analysis in the Neoadjuvant GeparSepto Trial. Clin Cancer Res. 2019 Apr 12. [Epub ahead of print]

Link in PubMed