HER2+ BTC has its own playbook—and so should your treatment for it

Biliary tract cancers (BTCs) are notorious for being difficult to treat and their poor prognosis — they represent 3% of all cancers and have a 5-year survival rate of 2%.^[]

Although it sometimes feels like we have little to offer BTC patients, state-of-the-art genomic technologies, such as next-generation sequencing (NGS), have transformed cancer management and uncovered the genomic landscape of biliary tract cancers, moving us a step in the right direction^[].

Once the domain of breast and gastric cancer, an emerging body of research implicates human epidermal growth factor receptor-2 (HER2) in the pathology of BTC, offering unique new treatment paths to explore.^[]HER2 expression and amplification makes BTC cancers unique — and thus impacts treatment.

Location matters for HER2

“HER2 biliary cancer can be differently expressed as to where the cancer starts within the bile duct,” says Shubham Pant, MD, professor in Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, in an interview with MDLinx.

Biliary tract cancers exhibit heterogeneous anatomy, with varying pathogenesis and genomic drivers. The burden of somatic mutations differs between intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer.

Although reports vary, the incidence of HER2 overexpression in biliary tract cancer is approximately 20% to 30% in gallbladder cancer; 10% to 16% in extrahepatic cholangiocarcinoma; and 5% in intrahepatic cholangiocarcinoma^[].

Impact on prognosis

HER2 expression seems to affect prognosis, according to the research.

“Because biliary tract cancer is relatively rare, we do not have a lot of data, but it seems like that the patient with HER2 amplified or HER2 expressed biliary tract cancer maybe seem to do worse or have a more aggressive disease than the ones who don't, but this is still under study,” says Dr. Pant.

Dr. Pant points to a retrospective study presented at the 2025 ASCO Gastrointestinal Cancers Symposium in which researchers evaluated the prognostic implications of HER2-targeted therapies in 389 patients with advanced biliary tract cancer from the Yonsei Cancer Center (YCC) and the University of Texas MD Anderson Cancer Center between 2009 and 2023^[].

Patients were classified as HER2-positive by immunohistochemistry (IHC 3+ or 2+/ISH+) or by next-generation sequencing (NGS, ERBB2 amplification). Primary outcomes included overall survival (OS) and palliative first-line progression-free survival (PFS).

Of the 310 BTC patients from YCC with available HER2 IHC results, 25.2% were HER2-positive and 74.8% were HER2-negative. The investigators found that HER2 positivity was significantly more prevalent in gallbladder cancer (55.1%) versus in intrahepatic or extrahepatic cholangiocarcinoma (22.8%, p<0.001).

Opening opportunities to improve survival

When it came to survival, 310 patients were eligible, comprising 239 from YCC who were HER2-positive and negative, and 71 from MD Anderson who were all HER2-positive. Regardless of exposure to HER2-targeted therapy, there was a trend toward shorter OS in HER2-positive patients versus HER2-negative patients, with a median OS of 13.7 vs. 17.1 months, respectively (p=0.084, HR=1.246, 95% CI=0.97–1.60).

In HER2-positive patients, a total of 56.8% were administered HER2-targeted therapy in the second-line setting.

A history of surgical treatment, radiation therapy, HER2 positivity, and HER2-targeted therapy were independent prognostic factors for OS on multivariable analysis.

“HER2 positivity is associated with a poorer prognosis in advanced BTC. However, HER2-targeted therapies improve outcomes, suggesting their potential inclusion in standard care for HER2-positive subgroups. Discrepancies between IHC and NGS in HER2 assessment emphasize the need for optimized testing guidelines in BTC,” the authors concluded.^[]