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. 2025 Jul 4;30(7):oyaf158.
doi: 10.1093/oncolo/oyaf158.

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

Svea Cheng  1 , Cyndi Gonzales Gomez  2 , Morgan Ferrell  2 , Richard Giza  2 , Masood Pasha Syed  2 , Tara Magge  3 , Vikram Gorantla  3 , Ronan W Hsieh  4 , Riyue Bao  2   3 , Aatur Singhi  5 , Anwaar Saeed  6 , Ibrahim Halil Sahin  6
Affiliations

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

Svea Cheng et al. Oncologist. .

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Keywords: BRAF; HER2 amplification; HER2-directed therapy; KRAS; PIK3CA; colorectal cancer; human epidermal growth factor receptor-2; resistance mechanisms.

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Conflict of interest statement

I.H.S. received Advisory Board fees in Seattle Genetics, Pfizer, Amgen, GSK, and Lumanity and Speaker for Pfizer and Amgen; M.M. had speaker role for Daiichi Sankyo and AstraZeneca; A.D.S received Honorarium from Foundation One; A.S. received research grants (to institution) from Merck, AstraZeneca, Bristol Myers Squibb, Exelixis, Clovis, Biontech, Astellas, Dragonfly therapeutics, Innovent biologics, KAHR medical, Amgen, Celgene, Actuate therapeutics, Incyte corporation, Seagen, Daiichi Sankyo, and Advisory board fees from Bristol Myers Squibb, AstraZeneca, Exelixis, Pfizer, and Daiichi Sankyo.

Figures

Figure 1.
Figure 1.
Incidence of HER2 amplification by gender, race, and gender location. HER2, human epidermal growth factor receptor-2.
Figure 2.
Figure 2.
Incidence of concurrent RAS/RAF, PIK3CA, MAPK, and ERBB2 mutations in HER2-amplified CRC. CRC, colorectal cancer; HER2, human epidermal growth factor receptor-2.
See this image and copyright information in PMC

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