Abstract S3-6: Profiling of triple-negative breast cancers after neoadjuvant chemotherapy identifies targetable molecular alterations in the treatment-refractory residual disease
Authors: JM Balko, K Wang, ME Sanders, MG Kuba, JA Pinto, F Doimi, H Gomez, G Palmer, MT Cronin, VA Miller, R Yelensky, PJ Stephens, CL Areaga
Journal: Cancer Research (2012)

Abstract Background: Neoadjuvant chemotherapy (NAC) is increasingly used in patients with triple-negative breast cancer (TNBC). NAC can induce a pathologic complete response (pCR) in ∼30% of patients which portends a favorable prognosis. In contrast, patients with residual disease (RD) in the breast at surgical resection exhibit worse outcomes. Objective: We hypothesized that profiling residual TNBCs after NAC would identify molecularly targetable lesions in the chemotherapy-resistant component of the tumor and that the persistent tumor cells would mirror micro-metastases which ultimately recur in such patients. Methods: We utilized targeted next generation sequencing (NGS) for 182 oncogenes and tumor suppressors in a CLIA certified lab (Foundation Medicine, Cambridge, MA) and gene expression profiling (NanoString) of the RD after NAC in 102 patients with TNBC. The RD was stained for Ki67, which has been reported to predict outcome after NAC in unselected breast cancers. Results: Thirteen tumors were not evaluable due to low tumor cellularity. Of 89 evaluable post-NAC tumors, 57 (64%) were basal-like; 19% HER2-enriched; 6% luminal A; 6% luminal B and 5% normal-like. Mean depth of coverage was 635 (range: 135–1207). Of 81 tumors evaluated by NGS, 72/81 (89%) demonstrated mutations in TP53, 22 were MCL1-amplified (27%), and 17 were MYC-amplified (21%). Alterations in the PI3K/mTOR pathway (AKT1-3, PIK3CA, PIK3R1, RAPTOR, PTEN, and TSC1) were identified in 27 tumors (33%). Cell cycle genes were altered in 25 tumors (31%), including amplifications of CDK2, CDK4, and CDK6, CCND1-3, and CCNE1 as well as RB loss. Alterations in the DNA repair pathway (BRCA1/2, ATM; 16 tumors; 20%) and the Ras/MAPK pathway (KRAS, RAF1, NF1; 10 tumors; 12%) were also common. Sporadic growth factor receptor amplifications occurred in EGFR, KIT, PDGFRA, PDGFRB, MET, FGFR1, FGFR2, and IGF1R. NGS identified 7 patients with ERBB2 gene amplification in the RD which was confirmed by FISH in both the pre- and post-treatment tissue, suggesting NGS could assist in the identification of ERBB2-overexpressing tumors misclassified at the time of diagnosis. In general, the gene amplifications identified by NGS corresponded to enhanced gene expression levels. Amplifications of MYC were independently associated with poor recurrence-free survival (RFS) and overall survival (OS). An interaction effect on survival was observed between MEK activation (assayed by a gene expression signature) and MYC amplification, suggesting cooperation between these pathways. Alterations in DNA repair also identified a subgroup with poor RFS and OS. In contrast, high post-NAC Ki67 score did not predict poor RFS or OS in this predominantly TNBC cohort. Conclusions: The diversity of lesions in residual TNBCs after NAC underscores the need for powerful and broad molecular approaches to identify actionable molecular alterations and, in turn, better inform personalized therapy of this aggressive disease. Incorporation of this platform into clinical studies and eventually standards of care should aid in the prioritization of patients with RD after NAC into rational adjuvant studies. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S3-6.