Key Biomarkers Beyond MSI-H in Metastatic Colorectal Cancer

In this segment, the panel transitions to a focused discussion of critical biomarkers in mCRC beyond MSI-H/dMMR, emphasizing how rapidly the biomarker landscape has expanded heading into 2026. Faculty underscore that comprehensive molecular testing is no longer optional, as multiple actionable alterations now meaningfully influence treatment selection and outcomes.

KRAS G12C is highlighted as one of the earliest newly actionable targets in CRC, with FDA-approved therapies now available in later-line settings. Panelists note that variant allele frequency matters when interpreting results and that not all KRAS G12C-positive tumors will derive equal benefit, reinforcing the importance of careful patient selection.

HER2 amplification emerges as another major biomarker, supported by multiple FDA-approved regimens based on data from studies such as MOUNTAINEER and DESTINY-CRC. The panel stresses the importance of accurate HER2 testing, including IHC scoring and reflex testing for equivocal (2+) cases, as HER2-directed therapy is often preferred in the second-line setting when available. Faculty express enthusiasm for ongoing trials such as MOUNTAINEER-03, which may move HER2-targeted approaches into the frontline setting.

The discussion then turns to BRAF V600E–mutated CRC, described as one of the most practice-changing areas in recent years. Panelists reference data from the BREAKWATER trial demonstrating dramatic improvements in response rates and overall survival when BRAF- and EGFR-targeted therapy is combined with chemotherapy in the first-line setting. These results represent a major departure from historical outcomes seen with second-line approaches such as BEACON, reinforcing the importance of early biomarker identification.

Overall, the panel emphasizes that early, comprehensive molecular profiling enables timely initiation of targeted therapies, prevents missed opportunities, and is increasingly central to optimizing survival outcomes in mCRC.