Use of the FoundationOne next-generation sequencing (NGS) assay to detect actionable alterations leading to clinical benefit of targeted therapies for relapsed and refractory breast cancer.

Abstract

1009 Background: Genomically-informed cancer therapy linking therapeutics targeting the molecular alterations driving the malignancy has the potential to transform the care of patients with metastatic breast cancer (MBC). Methods: DNA was isolated from 4 FFPE sections cut at 10 microns from 177 consecutive MBC that had relapsed after surgery, conventional hormonal/chemo and anti-HER2 targeted therapies received by our CLIA lab (Foundation Medicine). DNA sequencing was performed for 3,320 exons of 182 cancer-related genes to average depth of 1017X. Actionable Genomic alterations (GA) were defined as those linked to targeted anti-cancer therapies approved or being evaluated in active registered clinical trials. Results: Genomic profiles were generated from 169/177 (95%) BCs identifying 565 GA, averaging 3.34 GAs per tumor (range 0 to 10). 152 (90%) tumors harbored an actionable alteration mean 1.88 per tumor (range 0 to 6). In 124 (73%) tumors, ≥1.0 actionable GA was detected that would be missed by current “hotspot assays”. Notable GA involved PIK3CA (37%), ERBB2 (14%), FGFR1/2 (14%), PTEN (10%), MDM2 (7%), CCND1/CCNE1/CDK4 (7%), BRCA1 and BRCA2 (6% each) and ESR1 and EGFR (3% each). Of 23 ERBB2 GA, 74% were amplifications and 26% were mutation/gene fusion. The frequency of ERBB2 mutation/fusion was significantly enriched in CDH1 mutated ILC (~9% of total BC) with a frequency of 19.0% (4/21) compared to other histological types of BCs 1.4% (2/148) [p=0.002]. Significant clinical efficacy included patients with HER2 IHC/FISH negative tumors featuring HER2 and EGFR activating mutations benefitting from lapatinib/trastuzumab and erlotinib respectively. Conclusions: Comprehensive genomic profiling with a NGS assay identified actionable GAs in the majority of MBC patients including ERBB2 and EGFR mutations that initiated use of targeted therapies resulting in significant clinical benefit. These data provide a framework for the GAs expected in advanced BC and should facilitate the implementation of molecularly targeted trials supporting the efforts for a modern approach to precision medicine for the disease.