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HER2 Testing and Treatment FAQ
Expert Insights Into Testing and Treatment for HER2-Expressing Solid Tumors

Released: May 14, 2025

Expiration: May 14, 2026

James M. Cleary
James M. Cleary, MD, PhD
Yin (Rex) Hung
Yin (Rex) Hung, MD, PhD
Lei Zhao
Lei Zhao, MD, PhD
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Key Takeaways
  • Best practices in HER2 testing across solid cancers continue to evolve; heterogeneity with HER2 testing results remains a challenge.
  • In advanced HER2-positive gastric cancer, first-line pembrolizumab plus trastuzumab plus chemotherapy is now standard of care, although trastuzumab deruxtecan is indicated for locally advanced or metastatic HER2-positive gastric of GEJ adenocarcinoma after a prior trastuzumab-based regimen.
  • Zanidatamab was recently approved for previously treated, unresectable or metastatic HER2-positive BTC based on the HERIZON-BTC-01 trial.

Introduction
Leading medical oncology and pathology faculty, James M. Cleary, MD, PhD; Yin (Rex) Hung, MD, PhD, and Lei Zhao, MD, PhD, met at a recent live symposium to discuss key questions regarding diagnosis and management of HER2-expressing solid tumors.

Do you suggest HER2 tests for all colorectal cancers (CRCs), similar to how microsatellite instability testing is recommended for all CRCs?

Lei Zhao, MD, PhD:
In my practice, we do not perform HER2 testing routinely for all colon cancer biopsies. The rationale from pathologists is that we assume HER2-targeted therapies are reserved for patients with late-stage metastatic or advanced disease who have limited options.

It is difficult to determine which HER2 test is best for patients with CRC. I think pathologists should think more about how to integrate HER2 biomarker testing into routine practice.

James M. Cleary, MD, PhD:
As Dr Zhao mentioned, we do not do HER2 testing for all CRCs in our clinic. For patients with stages I-III CRC, HER2 testing results are not going to affect management, so we do not do HER2 testing there; however, as oncologists, it is very important to know the HER2 status. My practice is to use NGS to determine a tumor’s HER2 status. We typically do not test with HER2 immunohistochemistry (IHC) because we can get all the information we need from NGS.

Are there efforts to provide HER2 testing guidelines for lung cancer, CRC, or biliary tract cancers (BTCs)? Or are the guidelines for HER2 testing for breast and gastric cancer sufficient?

Yin (Rex) Hung, MD, PhD:
It took approximately a decade to harmonize all the scoring systems, tumor proportion score, combined positive score, immune cells, and different antibodies for PD-L1 immunostaining. Regarding HER2 testing, I think we are still in our early development of scoring system unification. Maybe we will harmonize HER2 testing 10 years from now. We should keep in mind, though, that the presence of HER2 IHC3-positive is an indication for HER2-targeted therapy across all solid cancers.

I have received requests to score HER2 in thymic cancer, sarcomas, and other cancers. How do we score HER2 in these cancers? Breast or gastric biopsy/resection HER2 testing guidelines?

My practice uses the gastric biopsy/resection HER2 testing guidelines for lung and other types of rare cancers. We still do not know the best guidelines to use for the future, as data are still pending. Perhaps in the future, we will be able to harmonize the HER2 testing scoring system.

Do you prioritize testing a metastatic site biopsy rather than localized biopsy or resection specimens?

James M. Cleary, MD, PhD:
As an oncologist, I find that heterogeneity with HER2 results is a challenge. My personal preference is to use cell-free DNA testing. The advantage of cell-free DNA is that you are really getting a sense of what all the tumors in the body are doing. Regarding whether to use the metastatic biopsy or initial resection specimen, we do not have enough evidence. I think either is fine.

Yin (Rex) Hung, MD, PhD:
Using PD-L1 testing as an analogy in non-small-cell lung cancer, it is known that if you were to test the metastatic site as compared with the primary, you see statistically high PD-L1 in the metastatic site. Therefore, there is intratumoral heterogeneity as well as tumor evolution over time.

What is the optimal treatment for advanced HER2-positive gastric cancers? 

James M. Cleary, MD, PhD:
The randomized phase III KEYNOTE-811 trial included patients with locally advanced or metastatic HER2-positive gastric gastroesophageal junction (GEJ) adenocarcinoma treatment. They received first-line pembrolizumab or placebo both in combination with standard chemotherapy (fluoropyrimidine and platinum-based therapy) plus trastuzumab, and the addition of pembrolizumab improved objective response rate from 60% to 73%. Median overall survival in the PD-L1 population was 20 months in the pembrolizumab arm and 15.7 months in the placebo arm. Because of this trial, chemotherapy plus trastuzumab plus pembrolizumab has become the standard of care for all patients with advanced HER2-amplified gastric/GEJ cancer with PD-L1 combined positive score ≥1.

The randomized phase II DESTINY-Gastric-01 trial shows a later-line therapy where trastuzumab deruxtecan (T-DXd) was compared with chemotherapy in patients with advanced HER2-plus gastric/GEJ cancer that had progressed after ≥2 previous therapies, including trastuzumab. Median progression-free survival in patients who received chemotherapy was 3.5 months, although patients who received T-DXd had a median progression-free survival of 5.6 months. T-DXd has now received FDA approval for patients with locally advanced or metastatic HER2-plus gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen.

Can you describe HER2-targted therapy for advanced BTC?

James M. Cleary, MD, PhD:
Recently, the bispecific HER2-directed antibody zanidatamab received accelerated FDA approval for treating previously treated, unresectable or metastatic HER2-plus BTC. This approval was supported by the single-arm phase IIb HERIZON-BTC-01 trial, where patients with advanced HER2-amplified BTC previously treated with ≥1 gemcitabine-containing systemic chemotherapy regimen received zanidatamab. This study revealed a response rate of approximately 40% with zanidatamab, which was significant considering that second-line cytotoxic chemotherapy usually has a response rate of approximately% for BTCs. These data support the use of zanidatamab in this space.

T-DXd can also be considered for advanced HER2-plus BTCs, as this agent received accelerated FDA approval for patients with unresectable/metastatic HER2-positive (IHC 3-plus) solid tumors who received prior systemic treatment and have no satisfactory alternative treatment options. 

As an oncologist thinking about HER2 and CRC testing, I use NGS for patients with BTC. In the HERIZON-BTC-01 pivotal trial with zanidatamab, investigators also performed HER2 IHC.

Your Thoughts
How do you test for HER2 overexpression in nonbreast or gastric solid tumors? At what disease stage do you test for HER2 amplification or mutation? Add to the conversation by contributing a comment below.

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