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Investigating incidence of RAS/RAF and PIK3CA alterations in HER2-amplified colorectal cancer: a comprehensive
Svea Cheng1, Cyndi Gonzales Gomez2, Morgan Ferrell2
1University of Pittsburgh School of Medicine, Division of Hematology/Oncology, Pittsburgh, PA 15213, United States.
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.
Insights
RAS, PIK3CA, and HER2 mutations frequently co-occur with HER2 amplification in colorectal cancer, impacting treatment resistance. Understanding these alterations is crucial for effective HER2-directed therapies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Human epidermal growth factor receptor-2 (HER2) amplification is a targetable biomarker in colorectal cancer (CRC).
- Mutations in KRAS and PIK3CA, downstream of HER2, are suspected to cause resistance to HER2-targeted therapies.
- The precise frequency of these resistance mutations in HER2-amplified CRC remains largely undetermined.
Purpose of the Study:
- To determine the incidence of RAS/RAF and PIK3CA alterations in patients with HER2-amplified colorectal cancer.
- To investigate the co-occurrence of HER2 mutations with HER2 amplification.
- To analyze the clinical significance of these molecular alterations in CRC.
Main Methods:
- Utilized cBioPortal for Cancer Genomics to analyze data from 21 studies comprising CRC specimens.
- Aggregated and processed clinical, specimen, copy number alteration, and somatic mutation data.
- Generated analysis-ready data fields including demographic variables, HER2 amplification status, and mutations in KRAS, NRAS, PIK3CA, BRAF, MAPK1, MAPK3, and HER2.
Main Results:
- HER2 amplification was observed in 2.6% of 4823 CRC patients, with higher prevalence in males and Asian/Black patients.
- Among HER2-amplified CRC cases, KRAS mutations occurred in 21.8%, NRAS in 3.4%, and PIK3CA in 11.5%.
- Concurrent HER2 mutation and amplification was found in 16.1% of cases, with higher rates in colon cancer than rectal cancer. Patients with HER2-amplified CRC had significantly lower overall survival.
Conclusions:
- RAS, PIK3CA, and HER2 mutations are common in HER2-amplified CRC, particularly in colon cancer.
- These co-occurring mutations highlight significant biological heterogeneity within HER2-amplified CRC.
- Molecular profiling is essential for identifying potential resistance mechanisms prior to initiating HER2-directed therapies.
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