Relying solely on Next-Generation Sequencing (NGS) is insufficient for HER2 testing in biliary tract cancers. Data shows NGS misses up to 15% of patients with HER2 overexpression detected by immunohistochemistry (IHC). Performing both tests is essential to avoid denying patients effective targeted therapies.
Related Insights
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.
ctDNA testing (liquid biopsy) is more effective than tissue biopsy for identifying ESR1 mutations. It samples DNA from all metastatic sites, capturing the disease's genetic heterogeneity and reflecting the most active resistance mechanisms, unlike a single-site needle biopsy which can miss them.
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.
An individual tumor can have hundreds of unique mutations, making it impossible to predict treatment response from a single genetic marker. This molecular chaos necessitates functional tests that measure a drug's actual effect on the patient's cells to determine the best therapy.
Experts question if HER2 status truly predicts ADC efficacy in urothelial cancer. The benefit seen across low-expression levels suggests HER2's main role may be simply to target the chemo payload to cancer cells, rather than indicating a specific biological dependency.
The panel suggests AKT inhibitor trials in prostate cancer have been disappointing due to suboptimal biomarker selection (e.g., PTEN IHC). A similar drug in breast cancer showed significant survival benefit when using a more precise NGS-based strategy, indicating a potential path forward if the right patient population is identified genetically.
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.
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.
In the rare case of a biliary tract cancer with both HER2 positivity and an FGFR2 fusion, clinicians should likely prioritize an FGFR inhibitor. FGFR2 fusions are considered more homogenous and potent early driver events compared to the often heterogeneous expression of HER2.