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In 140 resected bile duct and gallbladder cancers scored by the rules used in the zanidatamab trial, about one in ten was HER2-positive; every strongly stained tumour had extra gene copies, some weakly stained ones did too, and staining was often patchy.
HER2 status was evaluated in 140 consecutive surgically resected biliary tract cancers collected between 2020 and 2025 (87 extrahepatic cholangiocarcinomas and 53 gallbladder carcinomas) using immunohistochemistry and dual chromogenic in situ hybridisation. HER2 expression was scored by gastric cancer criteria and positivity was defined by HERIZON-BTC-01 criteria; selected cases were also analysed with a combined IHC-DISH approach.
HER2 expression was 0 in 72.9%, 1+ in 12.1%, 2+ in 8.6% and 3+ in 6.4% of cases. HER2 positivity was 9.2% in extrahepatic cholangiocarcinoma and 9.4% in gallbladder carcinoma. ERBB2 amplification was consistently identified in all IHC 3+ tumours and in a subset of IHC 2+ and, rarely, 1+ cases; the mean ERBB2/CEP17 ratio was 6.2 in 3+ tumours versus 3.9 in amplified 2+ or 1+ tumours (P = 0.001). Combined analysis confirmed that overexpression and amplification sat in the same tumour cells, and HER2 expression frequently showed intratumoral heterogeneity, often involving less than 50% of tumour cells.
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.
Shares Reflex HER2 testing of every advanced gallbladder and extrahepatic biliary cancer, HERIZON-BTC-01, HER2 IHC 2+ (equivocal, reflex to ISH), HER2 testing in biliary tract cancer (IHC, ISH and NGS).
Shares Reflex HER2 testing of every advanced gallbladder and extrahepatic biliary cancer, HER2-positive (IHC 3+ or ISH-amplified), FISH / ISH (in situ hybridisation), Extrahepatic cholangiocarcinoma (perihilar and distal).
Shares HER2 testing in biliary tract cancer (IHC, ISH and NGS), HER2 IHC 3+ (HER2-positive by immunohistochemistry), FISH / ISH (in situ hybridisation), Immunohistochemistry (IHC).
Shares Reflex HER2 testing of every advanced gallbladder and extrahepatic biliary cancer, HERIZON-BTC-01, Zanidatamab, Extrahepatic cholangiocarcinoma (perihilar and distal).
Shares HER2 testing in biliary tract cancer (IHC, ISH and NGS), HER2 ISH amplified (ERBB2 gene amplification), Zanidatamab, HER2.
Shares HER2 IHC 2+ (equivocal, reflex to ISH), HER2 testing in biliary tract cancer (IHC, ISH and NGS), HER2 ISH amplified (ERBB2 gene amplification), HER2-positive (IHC 3+ or ISH-amplified).
Shares HER2 testing in biliary tract cancer (IHC, ISH and NGS), Immunohistochemistry (IHC), HER2, Gallbladder cancer.
Shares HER2 ISH amplified (ERBB2 gene amplification), HER2 IHC 3+ (HER2-positive by immunohistochemistry), FISH / ISH (in situ hybridisation), Immunohistochemistry (IHC).