HER2 testing in biliary tract cancer (IHC, ISH and NGS)
Bile duct and gallbladder tumours are scored for HER2 with the stomach cancer rules, not the breast ones, and a strong stain (3+) is enough for zanidatamab. A borderline stain (2+) needs a gene-copy test, and a sequencing panel can find both the amplification and the rarer point mutations that a stain misses.
Overview
Scoring. Biliary series and trials score HER2 immunohistochemistry (IHC) by the gastro-oesophageal adenocarcinoma guideline, which accepts incomplete basolateral membrane staining; HERIZON-BTC-01 enrolled patients with ERBB2 amplification confirmed by in situ hybridisation (ISH) at a central laboratory and analysed IHC 2+ or 3+ as HER2-positive, and the FDA label for zanidatamab requires IHC 3+ on an FDA-authorised test, the Ventana PATHWAY 4B5 antibody (Harding 2023; label quoted on the HER2 IHC 3+ readout page). In 140 resected biliary cancers scored this way, IHC was 0 in 72.9%, 1+ in 12.1%, 2+ in 8.6% and 3+ in 6.4%; every 3+ tumour was amplified on chromogenic ISH, some 2+ and rarely 1+ tumours were also amplified, and the mean ERBB2 to CEP17 ratio was 6.2 in 3+ tumours against 3.9 in amplified 2+ or 1+ tumours (Angerilli 2026). Heterogeneity. HER2 staining involved less than half the tumour cells in many cases (Angerilli 2026) and was heterogeneous in 83% of HER2-positive biliary cancers, with loss of expression in deeper, dedifferentiated invasive areas, so small biopsies can under-call it and larger tissue should be tested where possible (Hiraoka 2020). Amplification versus mutation. ERBB2 alterations in gallbladder cancer split into amplification (8%), kinase or extracellular domain mutations such as S310F/Y (4%), both (1.5%) and fusion (0.4%) (Mondaca 2024; Suryavanshi 2025); IHC and ISH see the amplified tumours, whereas mutations are found only by sequencing and are covered by the separate HER2 mutation readout. Panels and turnaround. Comprehensive genomic profiling panels (FoundationOne CDx, MSK-IMPACT, Tempus xT, TruSight Oncology Comprehensive, Caris) report ERBB2 copy number and mutations alongside MSI, TMB, BRAF, NTRK and FGFR2, which is why guidelines ask for panel testing at diagnosis of advanced biliary cancer; in the NHS the Genomic Test Directory route is cited on the cancer page. Turnaround is faster for IHC (days) than for panel sequencing (typically two to four weeks), so IHC with reflex ISH remains the quickest route to a HER2 answer while the panel runs. Plasma. ctDNA panels detected ERBB2 amplification among the therapeutically relevant alterations in 124 biliary patients (Mody 2019), and 37 Indian cfDNA samples mirrored tissue findings qualitatively though 13 had no variant detected (Suryavanshi 2025).
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · A growth-signal receptor. Some cancers make far too much of it, and drugs that block it or use it as a docking site have transformed those cancers.
Showing the target this term concerns: HER2.
The glossary entry explains the word; the readout page carries the scoring rule, the thresholds approvals use, the companion diagnostics and the tests.
A direct check of the HERIZON-BTC-01 testing algorithm in routine pathology: IHC 3+ can stand alone, 2+ needs ISH, and the low-level amplification in weakly stained tumours is the group where HER2 drugs are least likely to help.
HER2 is as frequent in India as in the West, so HER2 testing pays off in the highest-incidence population, while tumour-agnostic immunotherapy markers will rarely apply. The paper also shows plasma testing is feasible where tissue is scarce.
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.
One cancer page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
The highest gallbladder HER2 rate in the literature comes from whole resected tumours scored generously; biopsy-based trial screening finds fewer. Heterogeneity is the practical warning for pathologists and for why HER2-directed drugs do not work in every positive tumour.
Biliary tumours are often diagnosed on tiny biopsies or brushings, so a blood-based panel that detects HER2 amplification and other targets in half of patients is a practical route to testing, with tissue confirmation where the blood is uninformative.
The largest Chilean HER2 series and the reason HER2 rates in the highest-incidence country are quoted at around 13%; scoring by breast rather than gastric rules explains part of the gap to the Japanese 31%.
Similar pages
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