Investigating incidence of RAS/RAF and PIK3CA alterations in HER2-amplified colorectal cancer: a comprehensive analysis.

Amplification of human epidermal growth factor receptor-2 (HER2) can be targeted with HER2-directed combination therapies for patients with colorectal cancer (CRC). Evolving data from clinical trials suggest mutations in KRAS and PIK3CA, downstream effectors of HER2, may confer resistance to HER2 blockade. However, the true incidence of these alterations in HER2-amplified CRC is largely unknown. In this large cohort study, we investigated the incidence of RAS/RAF and PIK3CA alterations among patients with HER2-amplified CRC. Twenty-one studies containing CRC specimens as of April 2023 were sampled using cBioPortal for Cancer Genomics. Clinical, specimen, copy number alteration, and somatic mutation data were aggregated and processed to generate ~30 analysis-ready fields encompassing demographic variables, HER2 amplification, and KRAS/NRAS/PIK3CA/BRAF/MAPK1/MAPK3/HER2 mutations. Among 4823 patients with CRC, the incidence of HER2 amplification was 2.6% (87/4823), with a higher incidence in male, Asian, and Black patients. Among patients with HER2-amplified CRC, the incidence of KRAS, NRAS, and PIK3CA mutations was 21.8% (19/87) (27.9% [17/61] in colon cancer, 7.7% [2/26] in rectal cancer), 3.4% (3/87)(3.3% [2/61] in colon cancer, 3.8% [1/26] in rectal cancer), and 11.5% (10/87) (13.1% [8/61] in colon cancer, 7.7% [2/26] in rectal cancer), respectively. No BRAF, MAPK1, or MAPK3 mutations were identified. Notably, concurrent HER2 mutation and amplification occurred at an incidence of 16.1% (14/87) (16.4% [10/61] in colon cancer, 15.4% [4/26] in rectal cancer). Median overall survival for all stage patients was significantly lower in patients with HER2-amplified CRC (37.2 months) than in patients with CRC without HER2 amplification (74.9 months) (P = .038). RAS, PIK3CA, and HER2 mutations can commonly co-occur with HER2 amplification, with higher rates in colon cancer than rectal cancer. These findings underscore biological heterogeneity and the importance of molecular profiling in identifying potential resistance before initiation of HER2-directed therapy.