Ghassan K. Abou-Alfa

For gallbladder cancer the points that matter are that HER2 can disappear under HER2-directed pressure, that SMAD4 co-mutation predicts a worse response, and that sequencing at progression, not just at diagnosis, may be needed to guide the next line.

The cleanest split of HER2 alterations in gallbladder cancer into amplification and mutation, which matters because IHC and ISH only see the amplified tumours. It also shows the high-incidence Chilean population has not been sequenced at scale.

The reference Western cohort for gallbladder cancer frequencies, deposited on cBioPortal as gbc_mskcc_2022, where the per-gene sample counts on OnCo were read. It supports panel testing at diagnosis: one patient in three has a targetable finding.

A positive randomised phase 2 that the German NALIRICC trial failed to reproduce; guidelines list the regimen as an option, and the disagreement is a reminder that single-country phase 2 results in biliary cancer need replication.

The first prospective evidence that HER2 blockade works in biliary cancer, which led to HERIZON-BTC-01 and the HER2 antibody-drug conjugate studies; the definition of HER2-positive here (amplification or overexpression) is looser than the later IHC 3+ label.

Regional biology is real but partial: exposures and age differ, some genes differ, and SMAD4 loss emerges as the shared bad-prognosis marker. It is the paper behind the MSK 2018 gallbladder study on cBioPortal (gbc_msk_2018).