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HER2 GC CRC BTC
Targeting HER2 in Gastric, Colorectal, and Biliary Tract Cancers

Released: March 05, 2026

Geoffrey Ku
Geoffrey Ku, MD
Kanwal Raghav
Kanwal Raghav, MD
Rachna Shroff
Rachna Shroff, MD, MS, FASCO
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Key Takeaways
  • HER2 testing is standard of care for the management of advanced upper GI, colorectal, and biliary tract cancers using disease-appropriate methodologies.
  • The HERIZON-GEA-01 phase III trial demonstrated clinically meaningful improvements in progression-free and overall survival, supporting zanidatamab-based combinations as a potential new first-line standard in HER2-positive locally advanced, unresectable, or metastatic GEA.
  • Optimal sequencing of HER2-targeted therapies and the role of retesting after progression remain evolving areas requiring individualized decision-making.

In this commentary, based on the live discussion from a satellite symposium at ASCO GI 2026 that focused on HER2 as a therapeutic target across GI malignancies, Geoffrey Ku, MD, Kanwal Raghav, MD, and Rachna Shroff, MD, answer audience questions and share their perspectives on how HER2 testing and targeted strategies are evolving in gastric, colorectal, and biliary tract cancers, and how these emerging data are being incorporated into real-world clinical practice.

How are you approaching HER2 testing in GI cancers in terms of who to test, when to test, and how to test?

Geoffrey Ku, MD:
It really depends on the disease site. In upper GI cancers, HER2 testing is already standard at diagnosis and directly impacts first-line treatment selection. So, in esophagogastric cancers, reflex testing upfront is well established. I would say upper GI, biliary tract cancer (BTC), and colon cancer are all settings where HER2 testing should absolutely be on your radar.

In terms of methodology, for gastric and gastroesophageal cancers, the most established approach remains immunohistochemistry (IHC) with reflex fluorescence in situ hybridization (FISH) confirmation. Next-generation sequencing (NGS) is increasingly used, but IHC and FISH still form the backbone of HER2 assessment in this setting.

Kanwal Raghav, MD:
In colorectal cancer, we are testing routinely, especially in metastatic and locally advanced disease, where it is most actionable. There is growing interest in earlier-stage testing, particularly as circulating tumor (ct) DNA–driven strategies evolve, but at this point, it does not change the standard of care outside of a clinical trial.

That said, not every GI tumor is HER2 driven. Hepatocellular carcinoma, pancreas, and neuroendocrine tumors are not scenarios where HER2 testing is typically prioritized. So HER2 testing should still be disease specific.

From a technical standpoint, in colorectal cancer it is more of an any and all approach regarding what test to use for HER2 assessment. NGS is sensitive for detecting HER2 amplification, and IHC is fast and widely available for detecting HER2 overexpression. One nuance is that amplification and overexpression exist on a continuum, so interpretation is not as binary as mutation testing. That becomes relevant when you are choosing between different HER2-directed therapies.

Rachna Shroff, MD:
In BTC, I test routinely in advanced or unresectable disease because NGS is essentially the standard of care. We are already looking for IDH1, FGFR2, and other actionable alterations, so HER2 is naturally included as part of comprehensive biomarker profiling.

In earlier-stage disease, I am more likely to test in the context of a clinical trial rather than reflexively in every patient. But in advanced BTC, it absolutely needs to be part of routine practice.

As for methodology, NGS is typically my choice because we need a full biomarker panel anyway. There is generally good concordance with IHC, and it allows us to capture multiple actionable alterations in 1 test.

What practical challenges arise with HER2 testing in GI cancers, and how do you manage cases with limited tissue?

Rachna Shroff, MD:
The biggest challenge, especially in BTCs, is tissue. Many diagnoses are made from brushings, FNAs, or very small biopsy samples, which can make comprehensive molecular testing difficult. HER2 prevalence also varies by subtype, with higher rates in gallbladder and extrahepatic cholangiocarcinoma, so the biology is not uniform across BTC.

Another layer of complexity is that defining HER2 positivity is still not completely standardized. Different trials have used different cutoffs, so translating that into real-world decision-making can sometimes feel a bit uncertain.

When tissue is limited, we often reflex to ctDNA as part of comprehensive biomarker testing. Concordance for several actionable alterations continues to improve as platforms become more sensitive, but we always recognize that we may miss certain findings.

Kanwal Raghav, MD:
I would reiterate that HER2 amplification is not binary like a mutation. It exists on a continuum, and that matters when you are selecting between therapies that rely on overexpression vs amplification. That is 1 reason tissue remains the preferred modality whenever possible.

ctDNA can certainly help, but amplification detection depends on tumor shedding, and we do not fully understand how ctDNA levels correlate with IHC expression. So, although it is a useful adjunct, I would still strongly encourage obtaining tissue whenever feasible.

Geoffrey Ku, MD:
In upper GI and colorectal cancers, tissue acquisition is usually less of a barrier. In those settings, the expectation should be comprehensive biomarker testing, including HER2, along with other relevant targets, to ensure optimal treatment selection.

What is the potential impact of HERIZON-GEA-01 on first-line treatment in HER2-positive upper GI cancers?

Geoffrey Ku, MD:
We were all genuinely excited to see the HERIZON-GEA-01 data presented at ASCO GI this year. This was a phase III study in treatment-naive patients with HER2-positive metastatic gastroesophageal adenocarcinoma, defined as IHC 3+ or IHC 2+ and FISH positive, and enrollment was irrespective of PD-L1 status. Patients were randomized to 1 of 3 arms: zanidatamab plus chemotherapy, zanidatamab plus tislelizumab plus chemotherapy, or standard trastuzumab plus chemotherapy. The dual primary endpoints were progression-free survival (PFS) and overall survival (OS), with response rate as a key secondary endpoint.

The first formal comparison was trastuzumab plus chemotherapy vs the triplet regimen of zanidatamab, tislelizumab, and chemotherapy. That result was striking. Median PFS improved from 8.1 months to 12.4 months, correlating to a 37% reduction in the risk of disease progression or death. At 18 months, the PFS rate was 43.9% in the triplet arm. OS was also significantly improved, with a median OS of 26.4 months vs 19.2 months, correlating to a 28% reduction in the risk of disease progression or death. That translates to a 2-year OS rate of 54.3% and a 30-month rate of 43.8%, which is quite impressive in this disease.

The next comparison looked at trastuzumab plus chemotherapy vs zanidatamab plus chemotherapy. PFS was again statistically significant, with the same median PFS of 12.4 months vs 8.1 months. If you look at the 18-month PFS rate, it was slightly lower at 38%, which raises the possibility that the immunotherapy-containing arm may be contributing to a longer tail on the curve. For OS, zanidatamab plus chemotherapy was numerically better at 24.4 months vs 19.2 months, with a hazard ratio of 0.80, but the P value narrowly missed statistical significance at 0.0564.

It is important to remember that this was the first of several planned interim analyses. Another analysis is expected later this year. Given the strong trend in OS, there is optimism that with additional events, the zanidatamab plus chemotherapy arm may ultimately achieve statistical significance as well.

Rachna Shroff, MD:
These data are potentially practice changing for HER2-positive advanced upper GI malignancies. A median OS of over 2 years is very exciting, especially after a long period without major advances in the first-line setting.

Kanwal Raghav, MD:
From a clinical perspective, the survival benefit really stands out. If a regimen is offering a clear survival advantage, many of us will naturally gravitate toward that approach, assuming the patient can tolerate it.

In HERIZON-GEA-01, how are you interpreting the added value of tislelizumab in the triplet regimen?

Kanwal Raghav, MD:
The study was not stratified by PD-L1 status, and of interest, both PD-L1–positive and PD-L1–negative tumors appeared to benefit from the triplet approach. At this point, I tend to favor the regimen that delivers the greatest survival advantage, unless there is a clear contraindication to immunotherapy.

Rachna Shroff, MD:
I agree. Based on the way the trial was designed and the magnitude of benefit seen, the 3-drug combination is very compelling. Although we still need additional data to fully understand the incremental contribution of immunotherapy, in the absence of a reason to avoid it, the triplet regimen is a reasonable approach in eligible patients.

How do you approach treatment sequencing in HER2-positive BTCs?

Rachna Shroff, MD:
Honestly, nobody truly knows the optimal sequence yet. T-DXd was available earlier, so many healthcare professionals (HCPs) used it first. Now that zanidatamab is available, the decision is often individualized based on toxicity profiles, patient comorbidities, and preferences.

For example, zanidatamab is commonly associated with diarrhea, which is usually grade 1 or 2 but can occasionally be grade 3, as well as infusion-related reactions that are typically mild and manageable with appropriate premedication and monitoring. In contrast, T-DXd requires careful monitoring for interstitial lung disease and pneumonitis, which, although uncommon, can be serious and require early recognition and multidisciplinary management. Because of these differences, HCPs often consider baseline pulmonary risk, gastrointestinal comorbidities, and overall patient tolerance when deciding which agent to use first.

I have seen durable responses with zanidatamab in practice, but cross-sequencing data are still limited. These are very real-world decisions right now.

Geoffrey Ku, MD:
And I think that reflects where the field is. We are making evidence-informed decisions in the absence of head-to-head data.

Should HCPs retest HER2 after progression on anti-HER2 therapy?

Kanwal Raghav, MD:
There is some evidence that HER2 loss can occur after exposure to HER2-targeted therapies, potentially as a resistance mechanism. However, it is not entirely clear whether this is therapy driven or related to a longer disease course and treatment pressure.

Rachna Shroff, MD:
Sequential tissue testing is often challenging, especially in biliary cancers, so we frequently rely on ctDNA. That said, the safest approach is to reassess biomarkers when possible before initiating another HER2-directed therapy.

Geoffrey Ku, MD:
Clinically, the key takeaway is simple. If you are planning another HER2-targeted treatment, it is reasonable to retest when feasible, because biomarker evolution can influence response and treatment selection.

Looking ahead: What is the broader takeaway for HER2 targeting in GI cancers?

Geoffrey Ku, MD:
Across gastric, colorectal, and biliary tract cancers, HER2 is clearly becoming a more relevant and actionable target. Testing is expanding, treatment options are increasing, and newer agents are moving earlier in the disease course. At the same time, questions around sequencing, resistance, and optimal patient selection remain. For now, the practical approach is consistent biomarker testing, thoughtful interpretation of HER2 status, and individualized treatment decisions grounded in both emerging data and real-world patient factors.

Your Thoughts
In your practice, what are your biggest challenges with HER2 testing across GI malignancies? If approved, will you adopt the HERIZON-GEA-01 results into your first-line treatment decisions for HER2-positive gastroesophageal adenocarcinoma? Share your perspectives below.

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If approved, how likely are you to incorporate the HERIZON-GEA-01 regimen into your practice for patients with newly diagnosed advanced gastroesophageal adenocarcinoma?

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