When a colorectal tumor loses HER2 protein expression (IHC 0) but retains HER2 gene amplification via NGS, the decision to continue HER2-targeted therapy is guided by the amplification copy number. A low copy number argues against continuing the targeted regimen.

In the increasingly common scenario of gastric cancer with multiple biomarkers (HER2, PD-L1, Claudin), experts recommend a clear hierarchy. Based on data maturity, HER2-targeted therapy is the first choice, followed by PD-L1 immunotherapy, with Claudin-targeted therapy third.

For RAS wild-type metastatic colorectal cancer, oncologists may prefer starting with a trastuzumab/tucatinib regimen over TDXD. This sequencing strategy preserves TDXD as a later option, as there is currently no data supporting tucatinib's efficacy after a patient has progressed on TDXD.

A subtle finding in the DESTINY-Breast11 trial, where TDXD alone underperformed TDXD followed by THP, suggests that taxane-based chemotherapy might remain effective even after a patient's HER2-positive cancer becomes resistant to the antibody-drug conjugate TDXD.

In the rare scenario of colorectal cancer with both HER2 amplification and a KRAS G12C mutation, US-based experts might prioritize KRAS-directed therapy. This preference is driven by durable data for KRAS inhibitors, even though choosing between targets is difficult without direct comparative studies.

To mitigate long-term toxicity from TDXD, oncologists are proposing an "induction/maintenance" approach. Patients receive TDXD for an initial period to achieve maximal response, then switch to a less toxic maintenance regimen for a "chemotherapy holiday," improving quality of life.

In HER2-positive colorectal cancer, the choice of targeted therapy depends on RAS mutation status. The tucatinib/trastuzumab combination is effective only in RAS wild-type patients. In contrast, the antibody-drug conjugate trastuzumab deruxtecan (TDXD) shows efficacy regardless of whether a RAS mutation is present.

HER2 amplification is a primary resistance mechanism to anti-EGFR therapies in colorectal cancer. Therefore, oncologists should avoid using drugs like panitumumab or cetuximab in HER2-positive patients, even if they are RAS wild-type, as these patients experience rapid progression on such regimens.

In the DESTINY-CRC02 trial, the lower 5.4 mg/kg dose of trastuzumab deruxtecan (TDXD) resulted in a higher response rate in colorectal cancer compared to the 6.4 mg/kg dose used in gastric cancer. This counter-intuitive finding suggests better tolerability led to longer treatment duration and superior outcomes.