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HER2 in GI and Lung Cancers
HER2 in Focus: Experts Address Questions on Biomarker Testing in GI and Lung Cancer

Released: May 18, 2026

Jonathan E. Dowell
Jonathan E. Dowell, MD
Rondell P. Graham
Rondell P. Graham, MBBS
Geoffrey Ku
Geoffrey Ku, MD
Alexander Craig Mackinnon, Jr.
Alexander Craig Mackinnon, Jr., MD, PhD, MSHA
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Key Takeaways
  • HER2 IHC scoring criteria vary by tumor type; guidelines for gastric/GEJ tumors are commonly used for other gastrointestinal tumors.
  • ctDNA testing occurs more commonly in lung cancer due to limited tissue sampling vs other cancers, where it is primarily an ancillary test.
  • Next-generation sequencing and immunohistochemistry results for HER2 can be discordant.

In this commentary, Jonathan E. Dowell, MD; Rondell P. Graham, MBBS; Geoffrey Ku, MD; and Alexander Craig Mackinnon, Jr., MD, PhD, MSHA, address key questions posed by healthcare professionals (HCPs) during a recent satellite symposium titled, “Identify and Inform: Best Practices to Optimize Proficiency in the Assessment of HER2-Altered Solid Tumors” presented in conjunction with USCAP 2026.

What is the role of circulating tumor (ct)DNA biomarker testing to inform targeted therapy in advanced GI and lung cancer?
Geoffrey Ku, MD: Focusing on advanced GI cancers, the gold standard in biomarker testing remains next-generation sequencing (NGS) with tumor tissue. ctDNA can be used as an adjunct in a number of ways. In rare instances, if you do not have access to a biopsy or surgical specimen, then ctDNA would be the fallback option. ctDNA can also be used in other specific scenarios. With ctDNA, we may be able to observe an increase in variant allele frequency and ultimately the emergence of a possible resistance mechanism. This use of ctDNA remains experimental in the sense that unless there is a clearly well-defined mechanism of resistance coupled with therapies to overcome that resistance, we may not have anything to do with these ctDNA data.

Jonathan E. Dowell, MD: With NSCLC, we frequently deal with small biopsies. In my practice and many of my colleagues’ practices, we send ctDNA for molecular testing along with tissue. We send it simultaneously, hoping that we will get a result from one, realizing the limitations of ctDNA. As these assays improve, we may be able to use ctDNA to monitor response and then use it to trigger a change in therapy. At least in lung cancer, this is not yet a validated strategy, but it may be useful in the future.

Can you see a HER2 mutation with NGS in conjunction with a negative HER2 stain by immunohistochemistry (IHC)? How do you interpret that result?
Alexander Craig Mackinnon, Jr., MD, PhD, MSHA: Yes, there can be discordance between NGS mutation status and IHC staining.

Jonathan E. Dowell, MD: In NSCLC, HER2 mutation status and protein expression by IHC are not tightly correlated, but trastuzumab deruxtecan has accelerated approvals for either HER2 IHC 3+ tumors or HER2 mutation–positive disease after prior therapy.

What are recent practice-changing data in HER2-targeted therapy for advanced GI and lung cancers?
Geoffrey Ku, MD: In the phase III HERIZON-GEA-01 trial, patients with previously untreated HER2-positive advanced gastroesophageal adenocarcinoma were randomized to zanidatamab (a bispecific HER2-directed antibody) plus chemotherapy, zanidatamab plus tislelizumab plus chemotherapy, or trastuzumab plus chemotherapy. Data recently presented at ASCO GI 2026 showed that zanidatamab plus chemotherapy and zanidatamab plus tislelizumab plus chemotherapy significantly improved outcomes vs trastuzumab plus chemotherapy (median overall survival of 24.4, 26.4, and 19.2 months, respectively, with P = .0564 with zanidatamab plus chemotherapy vs control and P = .0043 with zanidatamab/tislelizumab plus chemotherapy). These zanidatamab-containing regimens are being evaluated by the FDA.

Jonathan E. Dowell, MD: In non-small-cell lung cancer (NSCLC), in the phase Ib Beamion LUNG-1 study, patients with previously untreated advanced or metastatic HER2-mutant nonsquamous NSCLC were treated with zongertinib, an oral HER2-selective tyrosine kinase inhibitor. Zongertinib was associated with a 77% overall response rate, with these data supporting the accelerated FDA approval of zongertinib for patients with unresectable or metastatic NSCLC whose tumors have HER2 tyrosine kinase domain–activating mutations. In the phase I/II SOHO-01 trial, patients with advanced HER2-mutant NSCLC—including treatment-naive patients, previously treated patients naive to HER2-targeted therapy, and patients previously treated with HER2-directed antibody–drug conjugates—received sevabertinib, an oral HER2-selective tyrosine kinase inhibitor. This agent produced durable responses in both treatment-naive and previously treated patients, including those exposed to HER2 antibody–drug conjugates, leading to accelerated FDA approval for patients with locally advanced or metastatic nonsquamous NSCLC whose tumors have HER2 tyrosine kinase domain–activating mutations, and who have received a prior systemic therapy.

Do you suggest HER2 testing for all colon cancers, the same as microsatellite instability/mismatch repair testing?
Rondell P. Graham, MBBS: We perform HER2 and mismatch repair testing on all colon cancers.

Geoffrey Ku, MD: Everyone with colon cancer gets NGS, so hopefully, that will detect a HER2 amplification if it is a HER2-positive tumor, but also recognizing that HER2 positivity is much more common in the left side of the colon than the right side.

Do you score HER2-low in lung or GI cancers, and would this finding be actionable at this time?
Jonathan E. Dowell, MD: In lung, we do not have data yet for HER2-low tumors, so I do not use that clinically.

Geoffrey Ku, MD: In GI tumors, we have seen some data in colon and biliary tract cancer that, with a score of less than IHC 3+, there is not typically a great response. In gastric cancers, I would say that there is currently interest in looking at HER2-low disease, in other words, IHC 1+ or IHC2 + and FISH-negative cancer. The only data that HER2-low status might be actionable come from an initial study with trastuzumab deruxtecan. There was limited activity with this drug in patients whose tumors were IHC 1+/FISH-negative or IHC 2+/FISH-negative. It remains an area of investigation, but we do not appear to see the same level of activity in GI cancers as has been observed in HER2-low breast cancer.

Do you prioritize testing metastatic site biopsy rather than localized biopsy or resection specimens?
Alexander Craig Mackinnon, Jr., MD, PhD, MSHA: I was taught that metastatic tissue is probably the best to test, because it might have the most current mutation profile or represent the most aggressive clone. But metastatic sites are sometimes the least likely to be biopsied. It is a paradox in that sense.

Jonathan E. Dowell, MD: You end up balancing the risk of a biopsy vs the availability of tissue from a prior specimen. If it is an old surgical specimen that I am not sure is going to be successful in testing, then I will perform a new biopsy and attempt to test that sample. The reality is that in lung cancer, we deal with the tissue that we have, whether it is the metastatic site or the primary site; we will use what is adequate, acknowledging that there could be heterogeneity in the molecular results between the metastatic site and the primary site.

Geoffrey Ku, MD: HER2 heterogeneity is well established. This can be an argument for ctDNA testing, where it is a summation of all the alterations. Sometimes you detect an alteration that you do not find in the primary biopsy.

Your Thoughts
Does your institution reflexively test lung cancer samples for HER2 alterations and overexpression? What questions do you have about applying HER2 testing to solid tumor types without specific guidelines?

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For which of the following advanced solid cancers do you routinely request HER2 testing? Please select all that apply.

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