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

Abstract

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. Eight hundred fifty-one pretherapeutic formalin-fixed paraffin-embedded (FFPE) core biopsies from GeparSepto study were sequenced. The panel included 16 genes for mutational (<i>AKT1, BRAF, CDH1, EGFR, ERBB2, ESR1, FBXW7, FGFR2, HRAS, KRAS, NRAS, SF3B1, TP53, HNF1A, PIK3CA</i>, and <i>PTEN</i>) and 8 genes for copy-number alteration analysis (<i>CCND1, ERBB2, FGFR1, PAK1, PIK3CA, TOP2A, TP53</i>, and <i>ZNF703</i>). The most common genomic alterations were mutations of <i>TP53</i> (38.4%) and <i>PIK3CA</i> (21.5%), and 8 different amplifications (<i>TOP2A</i> 34.9%; <i>ERBB2</i> 30.6%; <i>ZNF703</i> 30.1%; <i>TP53</i> 21.9%; <i>PIK3CA</i> 24.1%; <i>CCND1</i> 17.7%; <i>PAK1</i> 14.9%; <i>FGFR</i> 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 <i>PIK3CA</i>-mutated breast cancer [<i>PIK3CA</i>mut: 23.0% vs. wild-type (wt) 38.8%, <i>P</i> < 0.0001] in particular in the HER2pos subcohort [multivariate OR = 0.43 (95% CI, 0.24-0.79), <i>P</i> = 0.006]. An increased response to nab-paclitaxel was observed only in <i>PIK3CA</i>wt breast cancer, with univariate significance for the complete cohort (<i>P</i> = 0.009) and the TNBC (<i>P</i> = 0.013) and multivariate significance in the HER2pos subcohort (test for interaction <i>P</i> = 0.0074). 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. <i>PIK3CA</i> mutations could be a major mediator of therapy resistance in breast cancer.