ERBB2 amplifications and mutations in 109 advanced breast cancer patients by next-generation sequencing.

Abstract

3565 Background: In advanced breast cancer (ABC) HER2 status is based on ASCO/CAP immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) criteria. Next generation sequencing (NGS) of tissue and blood can detect aberrations in ERBB2 such as copy number gain/amplifications (cng/amp) and mutations. Methods: We retrospectively identified patients (pts) seen at Northwestern University between 2015 and 2019 with ABC and an alteration in ERBB2 identified by tissue and/or circulating tumor DNA (ctDNA) NGS. We included pts with testing by Guardant360, TempusX, and/or FoundationOne platforms. NGS reports were evaluated for non-synonymous mutations and cng/amp. HR and HER2 status were determined based on the most recent pathologic assessment. Mutations were categorized as pathologic if they were consider oncogenic (level 1-2 evidence with direct functional data), likely oncogenic, or predicted oncogenic, based on OncoKB (Chakravarty et al., JCO PO 2017). Results: 109 cases of ABC (6 locally advanced, 103 metastatic) with ERBB2 alterations were identified. Tissue NGS was available from 43%, ctDNA from 72%, and both from 19%. The positive predictive value (PPV) of ERBB2 amp/cng by tissue NGS to predict HER2+ using the gold standard as IHC/FISH was 94% (33/35). The PPV of ERBB2 amp by ctDNA was 93% (40/43). ERBB2 mutations were detected in 52 pts. Of these, 23 pts were considered to harbor pathologic ERBB2 mutations, (19 oncogenic, 2 likely oncogenic, 1 predicted oncogenic) detected by ctDNA and tissue in 4, ctDNA in 16, and tissue in 3 pts. The most frequently detected mutations were V777L and S310. Four pts had co-mutations of ERBB2 V777L and S310F. Disease subtype among those with ERBB2 pathologic mutations was HR+ HER2- in 57%, HER2+ in 26%, and triple negative in 17%. In all patients with serial ctDNA analysis and pathologic ERBB2 mutations, the mutation was detected on the first analysis. Pathologic ERBB2 mutation represented the mutant with the highest mutant allele frequency (MAF) in 30% and top 3 highest MAF in an additional 35%. PIK3CA was co-mutated in 48%. Conclusions: The PPV of ERBB2 amp/cng by tissue and ctDNA NGS was high, and has potential utility for cancers where HER2 IHC/FISH is not standardly assessed or cases where biopsy is challenging. ERBB2 pathologic mutations were found in all breast cancer subtypes. When present, they were identified on the initial ctDNA analysis and often represented a significant clone, supporting its role as a ‘driver mutation’.