HER2 Alterations May Influence Response to Cetuximab in Metastatic Colorectal Cancer
Clinical Summary:
- Design/Population: This exploratory analysis of the CAPRI2-GOIM study evaluated the prognostic and predictive significance of HER2 alterations in patients with RAS/BRAF wild-type, microsatellite-stable metastatic colorectal cancer treated with first-line FOLFIRI plus cetuximab. HER2 alterations were identified using tissue or liquid biopsy genomic profiling.
- Key Outcomes: HER2 alterations were associated with shorter progression-free and overall survival. Exploratory analyses suggested that HER2 mutations were associated with limited benefit from cetuximab-based therapy, whereas some patients with HER2 amplification continued to derive clinical benefit.
- Clinical Relevance: These findings suggest that HER2 mutations may represent a biomarker of resistance to anti-EGFR therapy, while HER2 amplification may have greater prognostic than predictive significance in metastatic colorectal cancer.
Davide Ciardiello, MD, European Institute of Oncology, Milan, Italy, discusses an exploratory analysis of the CAPRI2-GOIM study evaluating HER2 alterations as potential biomarkers in patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC) treated with FOLFIRI plus cetuximab.
The analysis suggests that not all HER2 alterations have the same clinical implications, with HER2 mutations appearing to confer resistance to anti-EGFR therapy while HER2 amplification may retain sensitivity in selected patients. These findings support more refined molecular stratification to optimize frontline treatment selection in mCRC.
Transcript:
Hi, I am Davide Ciardiello, a medical oncologist in the division of gastrointestinal and neuroendocrine tumors at the European Institute of Oncology in Milan. Today, we will discuss the findings from an exploratory analysis of the CAPRI 2-GOIM study investigating the role of HER2 as a potential biomarker in patients treated with FOLFIRI plus cetuximab.
Metastatic colorectal cancer is one of the most common causes of cancer-related death, especially in young adults, and optimization of frontline treatment has a crucial impact on the entire therapeutic program. In this regard, better molecular stratification has a key role in defining the optimal frontline strategy.
For patients with RAS/BRAF wild-type, microsatellite-stable tumors, the combination of chemotherapy plus anti-EGFR treatment represents a standard of care. In this scenario, the role of HER2 as a prognostic or predictive biomarker is still debated. To date, there are different trials investigating anti-HER2 strategies as frontline treatment in metastatic colorectal cancer in patients with HER2-overexpressed or HER2-amplified tumors, such as the MOUNTAINEER-03 and CHIMERA trials. However, in clinical practice, the role of HER2 alterations is still debated.
In our study, we observed that around 6% of patients with RAS/BRAF wild-type tumors had HER2 alterations, either HER2 amplification or HER2 mutation, detected by FoundationOne Liquid or FoundationOne tissue analysis. We investigated the potential role of HER2 as a biomarker in patients treated with FOLFIRI plus cetuximab in the CAPRI 2-GOIM trial.
Interestingly, we observed that the presence of HER2 alterations was correlated with shorter median progression-free survival and overall survival compared with patients without these alterations. Of note, within the limitations of the small number of cases, we also investigated the potential differences between HER2 amplification and HER2 mutation. Most patients with HER2 mutations showed limited benefit from anti-EGFR therapy, whereas some patients with HER2 amplification still benefited from this treatment.
Within the limitations of an exploratory analysis in a small subgroup of patients, these findings highlight the role of HER2 as a potential biomarker to assess when defining the best first-line treatment. In particular, the presence of HER2 mutation should be considered a potential biomarker of resistance to anti-EGFR therapy, whereas HER2 amplification should be taken into account but should mainly be considered a prognostic biomarker rather than a predictive biomarker.
Source:
Ciardiello D, Bielo LB, Napolitano S, et al. HER-2 gene alterations as biomarker in patients with metastatic colorectal cancer treated with FOLFIRI + cetuximab: Findings from the CAPRI-2 GOIM study. ESMO Gastrointest Oncol. Published online: January 19, 2026. doi: 10.1016/j.esmogo.2025.100295
