HER2 Alterations Signal Poorer Outcomes in Untreated RAS/BRAF Wild-Type Metastatic Colorectal Cancer
Key Clinical Summary:
- In an analysis of 1604 patients with pMMR/MSS RAS/BRAF wild-type metastatic colorectal cancer (mCRC), HER2-positive tumors represented 5% and were associated with significantly shorter PFS and OS.
- HER2 amplification/overexpression and HER2 mutations did not predict differential benefit from bevacizumab or anti-EGFR therapy.
- HER2-mutant tumors (2%) also demonstrated inferior OS compared with HER2 wild-type cancers.
A pooled analysis of 8 major randomized clinical trials (TRIBE2, TRIPLETE, VALENTINO, ATEZOTRIBE, PANDA, PANAMA, PARADIGM, and CALGB/SWOG80405) provides the largest dataset to date evaluating the prognostic and predictive role of HER2 alterations in untreated metastatic colorectal cancer. Investigators assessed outcomes based on HER2 amplification/overexpression and mutation status in patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS) RAS/BRAF wild-type disease, focusing on response to biologic therapies including anti-EGFR agents and bevacizumab.
Among 1604 eligible patients, 81 (5%) had HER2-positive tumors. These patients experienced significantly shorter survival outcomes than those with HER2-negative disease. Median progression-free survival (PFS) was 9.8 months for HER2-positive tumors versus 12.2 months for HER2-negative cancers (HR, 1.31; P = .02). Median overall survival (OS) was similarly reduced at 28 months compared with 34.9 months (HR, 1.37; P = .01). These results remained significant after multivariable adjustment (PadjPFS = .02; PadjOS = .048).
Objective response rates (ORR) were comparable between HER2-positive and HER2-negative groups (75% vs 72%; OR, 1.21; P = .47). Importantly, no interaction emerged between HER2 status and the efficacy of anti-EGFR or bevacizumab therapy for PFS (Pint = .76), OS (Pint = .76), or ORR (Pint = .64).
In the subgroup of left-sided HER2-positive tumors, outcomes remained similar regardless of whether chemotherapy was paired with bevacizumab or anti-EGFR therapy. PFS was 9.8 versus 9.3 months (HR, 0.73; P = .29), OS was 29.8 versus 28 months (HR, 1.29; P = .40), and ORR was 59% versus 79% (OR, 0.39; P = .10).
HER2 mutations, detected in 2% of HER2-negative tumors, also conferred worse survival. Median OS was 23.7 months in HER2-mutant cancers versus 34.4 months in HER2 wild-type tumors (HR, 1.56; P = .04). As with amplified/overexpressed HER2, mutational status did not alter benefit from biologics (all interaction P values >.80).
These findings reinforce HER2 alterations, both amplification and mutation, as negative prognostic markers in pMMR/MSS RAS/BRAF wild-type mCRC. Although HER2-positive and HER2-mutant tumors do not appear to derive reduced benefit from current frontline biologics, their shortened PFS and OS highlight the need for early molecular characterization and closer clinical monitoring.
In conclusion, HER2 amplification and mutation independently predict poorer survival in untreated pMMR/MSS RAS/BRAF wild-type mCRC but do not guide selection between bevacizumab and anti-EGFR therapies. As targeted strategies advance, these findings help refine prognostic assessment and highlight opportunities for therapeutic innovation.
Source:
Germani MM, Borelli B, Hashimoto T, et al. Impact of Human Epidermal Growth Factor Receptor 2 in Patients With Metastatic Colorectal Cancer Treated With Chemotherapy Plus Bevacizumab or Anti-EGFRs: Exploratory Analysis of Eight Randomized Trials. J Clin Oncol. 2025 Oct 10;43(29):3184-3197. doi:10.1200/JCO-25-01003
