HER2 Positive Biliary Tract Cancer
Recent advances in targeted therapies have opened new doors for patients with HER2 positive biliary tract cancer, a rare and difficult-to-treat disease that has long been known for its poor prognosis.
Table of contents
- Understanding Biliary Tract Cancer
- The Role of HER2 in This Cancer
- How HER2 Positivity Is Detected
- HER2 Status and Patient Outcomes
- Treatment Options for HER2 Positive Disease
- Ongoing Clinical Research
Understanding Biliary Tract Cancer
Biliary tract cancer (BTC) is a group of rare cancers that develop in the bile ducts and related structures. These cancers include intrahepatic cholangiocarcinoma (cancer inside the liver), extrahepatic cholangiocarcinoma (cancer outside the liver), gallbladder cancer, and ampulla of Vater cancer. Together, these cancers represent about 3% of all digestive system cancers.[1]
Biliary tract cancers are known for being very difficult to treat, with a 5-year survival rate of only 2% and an overall survival rate of 15%.[1][8] The location where a person lives can affect their risk of developing these cancers. For example, in southeast Asian countries, cholangiocarcinoma is more common because of parasites called liver flukes that are found in that region.[1]
The Role of HER2 in This Cancer
Human epidermal growth factor receptor-2 (HER2) is a protein that plays an important role in how cells grow and survive. In some biliary tract cancers, the HER2 protein is overexpressed, meaning the cancer cells have too much of it on their surface. This overexpression can lead to uncontrolled cell growth and the spread of cancer.[1]
HER2 has been well studied in breast cancer and gastric cancer, where it has been an important target for treatment. More recently, researchers have found that HER2 is also involved in biliary tract cancers, opening up new possibilities for targeted treatment.[1]
HER2 positivity occurs in different types of biliary tract cancer at varying rates. Studies have shown that HER2 positivity is significantly more common in gallbladder cancer, where it appears in about 55% of cases, compared to intrahepatic cholangiocarcinoma (26%) or extrahepatic cholangiocarcinoma (17%).[4]
How HER2 Positivity Is Detected
To determine if a biliary tract cancer is HER2 positive, doctors use special laboratory tests. The most common method is immunohistochemistry (IHC), which looks at tissue samples under a microscope to see how much HER2 protein is present. Tumors are scored as IHC 0, 1+, 2+, or 3+, with 3+ indicating high levels of HER2 protein.[4]
When the IHC result is 2+, an additional test called in situ hybridization (ISH) may be performed to confirm whether the tumor has extra copies of the HER2 gene. A tumor is considered HER2 positive if it scores IHC 3+ or if it scores IHC 2+ and is also ISH positive.[4]
Next-generation sequencing (NGS) is another advanced technology that can identify HER2 changes, including gene amplifications (extra copies of the gene) and mutations (changes in the gene). NGS has revolutionized cancer management by providing detailed information about the genetic makeup of tumors.[1][4]
HER2 Status and Patient Outcomes
Research has shown that HER2 positivity has important effects on how patients with biliary tract cancer respond to treatment and how long they survive. A study presented at a major medical conference found that patients with HER2 positive biliary tract cancer had a trend toward shorter overall survival compared to patients with HER2 negative disease. The median overall survival was 13.7 months for HER2 positive patients versus 17.1 months for HER2 negative patients.[4]
The same study found that HER2 positive patients who received chemotherapy alone had significantly shorter time until their cancer got worse compared to HER2 negative patients. The first-line progression-free survival was 5.1 months in the HER2 positive group compared to 7.4 months in the HER2 negative group.[4]
However, the picture changes significantly when HER2 targeted therapies are used. HER2 positive patients who did not receive HER2 targeted therapy had much worse outcomes, with a median overall survival of only 8.1 months. In contrast, HER2 positive patients who did receive HER2 targeted therapy had comparable survival to HER2 negative patients, with a median overall survival of 18.2 months.[4] This finding underscores the importance of identifying HER2 positive tumors and treating them with appropriate targeted therapies.
Treatment Options for HER2 Positive Disease
For many years, chemotherapy was the main treatment for biliary tract cancer. The combination of gemcitabine with cisplatin (GEMCIS) has been the standard first-line treatment.[1] More recently, immunotherapy drugs have been added to chemotherapy, with medications like durvalumab and pembrolizumab showing benefit when combined with chemotherapy.[1]
For patients with HER2 positive biliary tract cancer, targeted therapies that specifically block the HER2 protein have become available. These medications work by attaching to the HER2 protein on cancer cells and stopping them from growing and dividing.[1]
One important HER2 targeted therapy is zanidatamab, which is a bispecific antibody. This means it can attach to two different parts of the HER2 protein at the same time, making it more effective at blocking the growth signals that cancer cells use. Zanidatamab was approved by the FDA in November 2024 for adults with HER2 positive biliary tract cancer that is advanced or cannot be removed by surgery and has already been treated with other medicines.[2][14]
The approval of zanidatamab was based on a clinical trial called HERIZON-BTC-01, which showed that the drug worked well in patients whose tumors had high levels of HER2 protein (IHC 3+). In this study, 87 patients with HER2 positive biliary tract cancer who had already tried other treatments received zanidatamab. The results showed that zanidatamab helped control the cancer and improved patient outcomes.[14]
Other HER2 targeted therapies are also being studied in biliary tract cancer, including various HER2-blocking antibodies and drug conjugates. These ongoing clinical trials are assessing the effectiveness of different HER2 targeted approaches.[1]
Ongoing Clinical Research
There is significant ongoing research to improve treatments for HER2 positive biliary tract cancer. Scientists are conducting clinical trials to test whether HER2 targeted therapies that have shown benefit in later stages of treatment can also be used earlier in the disease, either alone or in combination with chemotherapy.[11]
Researchers are also working to understand better which patients are most likely to benefit from HER2 targeted therapies. Not all HER2 alterations may respond equally to treatment, and studies are examining whether factors such as the type of HER2 change (amplification versus mutation) or the level of HER2 expression affect how well these therapies work.[1]
Clinical trials are also investigating the optimal dosing of HER2 targeted therapies. For example, a dose optimization study found that zanidatamab 20 mg per kilogram of body weight every 2 weeks is the optimal dose for patients with HER2 positive biliary tract cancer.[4]
The growing body of research emphasizes the importance of testing all biliary tract cancer patients for HER2 status at the time of diagnosis. This biomarker testing allows doctors to identify which patients might benefit from HER2 targeted therapies and to make informed treatment decisions.[1][4] These findings support the potential inclusion of HER2 targeted therapies as part of standard care for HER2 positive biliary tract cancer subgroups.[4]
