While Trastuzumab deruxtecan (TDXD) is effective in HER2-low breast cancer, there is no evidence that it benefits patients with HER2-low or HER2-intermediate (IHC 2+/FISH negative) gastric cancer. Its use should be strictly limited to truly HER2-positive cases in this disease.

The HER2CLIMB-02 trial found that adding tucatinib to TDM-1 offered only a modest 2-month PFS benefit. This came at the cost of substantially increased toxicity, including transaminitis and diarrhea, suggesting the two agents are better used sequentially for most patients.

For HER2+ biliary tract cancer patients with hyperbilirubinemia where stenting isn't possible, zanidatumab is a preferable option over TDXD. Zanidatumab lacks significant hepatotoxicity, whereas TDXD's irinotecan-like payload poses a risk in patients with moderate hepatic impairment.

NGS testing is revealing that acquired HER2 kinase domain mutations, not amplifications, are an emerging resistance mechanism in ER+ lobular breast cancer. This creates a targetable population for HER2 TKIs like neratinib or tucatinib, offering a new line of targeted therapy.

The same cancer-driving mutation behaves differently depending on the cell's internal "wiring." For example, a drug targeting a mutation works in melanoma but induces resistance in colorectal cancer due to a bypass pathway. This cellular context is why genetic data alone is insufficient.

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.

Contrary to concerns about cross-resistance between HER2 antibody-drug conjugates (ADCs), retrospective data shows TDM-1 remains effective after progression on TDXD. This suggests the different cytotoxic payloads are key, allowing for effective sequencing and challenging the assumption that progression on one ADC class member precludes using another.

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.

Due to selective pressure from first-line treatment, 30-40% of HER2-positive gastroesophageal cancers lose HER2 expression by the time of progression. It is crucial to re-test these patients, either via tissue biopsy or ctDNA, to confirm continued HER2 positivity before initiating second-line HER2-targeted therapy like TDXD.