Liquid Biopsy–Guided Anti-HER2 Rechallenge in Metastatic Colorectal Cancer: JCO Precision Oncology | August 2026

Introduction:

Approximately 3–6% of metastatic colorectal cancers (mCRC) harbor HER2 amplification, particularly in RAS/BRAF wild-type tumors. HER2-targeted therapies such as trastuzumab-based combinations and trastuzumab deruxtecan have significantly improved outcomes in this molecular subgroup. However, most patients eventually develop resistance. This report highlights the emerging role of circulating tumor DNA (ctDNA) in guiding anti-HER2 rechallenge, allowing treatment decisions to be based on real-time tumor biology rather than fixed baseline molecular profiling.

Why was this study needed?

Most patients with HER2-positive mCRC eventually develop resistance to HER2-targeted therapy.

Reliable biomarkers to identify patients suitable for HER2 rechallenge are lacking.

Tumor biology evolves over time, making baseline tissue testing insufficient for treatment selection.

Liquid biopsy (ctDNA) enables noninvasive monitoring of HER2 amplification and resistance mechanisms.

Precision-guided rechallenge strategies may restore sensitivity to HER2-targeted therapy after resistant tumor clones decline.

Results:

The study demonstrated the feasibility of using serial ctDNA analysis to guide anti-HER2 rechallenge in patients with HER2-amplified metastatic colorectal cancer.

Liquid biopsy enabled real-time monitoring of HER2 amplification levels and identified dynamic changes in tumor biology during treatment.

ctDNA also detected the emergence and subsequent decline of resistance-associated MAPK pathway alterations, providing biological evidence that HER2-targeted therapy sensitivity may be restored after treatment interruption.

Carefully selected patients experienced renewed clinical benefit following HER2-targeted rechallenge, supporting the concept that resistance is often dynamic rather than permanent.

These findings parallel the established strategy of anti-EGFR rechallenge, where ctDNA is increasingly used to guide treatment sequencing.

Clinical Impact:

This study highlights the growing importance of liquid biopsy as a tool for adaptive precision oncology. Rather than considering HER2 resistance as irreversible, clinicians may be able to use serial ctDNA monitoring to determine when tumors have regained HER2 dependency and are suitable for retreatment. Although based on limited clinical experience, this approach introduces a promising strategy for extending the benefit of HER2-targeted therapies and optimizing treatment sequencing in metastatic colorectal cancer.

Bottom Line:

Liquid biopsy-guided anti-HER2 rechallenge represents a promising precision medicine strategy for HER2-amplified metastatic colorectal cancer. Serial ctDNA monitoring can identify patients who regain HER2 dependency after treatment interruption, potentially allowing effective reuse of HER2-targeted therapy and extending disease control. Larger prospective studies are needed to validate this personalized treatment approach.