How to validate pan-HER2 immunohistochemistry

Xuchen Zhang, MD, PhD
Emily Meserve, MD, MPH

January 2026—Based on the results of Destiny-PanTumor02,¹ targeted HER2-based therapies are now available as treatment options agnostic of tumor type. As oncologists seek to offer these targeted therapies to the patients likely to benefit, many laboratories have had to determine how best to expand the use of existing HER2 assays. At the same time, other laboratories may now see testing volumes increasing to justify new validation.

The 2024 “Principles of Analytic Validation of Immunohistochemical Assays: Guideline Update” recommends validation based on an assay-scoring system combination.² Destiny-PanTumor02 used scoring criteria based on HER2 assessment in gastric/gastroesophageal adenocarcinomas (GEA).³ Therefore, laboratories that wish to perform HER2 immunohistochemistry under the pantumor indication, to be able to perform HER2 IHC on any tumor type on which a request for this testing is received, must consider:

• The details of any current HER2 IHC assays performed in their laboratories, including assay conditions and scoring systems.
• Whether the test is being performed as FDA approved, is modified in any way, or is being performed as a laboratory-developed test (LDT).

With these details in mind, the goal of any additional validation work is to demonstrate that the assay-scoring system combination performs acceptably before deploying the test clinically in additional tumor types. Based on current recommendations, it is not necessary to perform separate validations for each type of tumor tested.

Given the natural history of how HER2 IHC testing has developed in the United States, many laboratories are likely to have an existing HER2 IHC assay validated on breast cases and using breast scoring criteria.⁴ If this is an unmodified FDA-approved assay, then a minimum of 20 positive and 20 negative breast tumors are included in the validation documentation.

If the laboratory subsequently expanded the use of this test to gastric/GEA tumors using the 2016 gastric scoring criteria,³ then an additional minimum of 20 positive and 20 negative gastric/GEA tumors should be added to the validation documentation.

At this time, for a laboratory in this situation to expand the use of its HER2 IHC assay to all other tumor types, additional validation work is not required, so long as the scoring criteria remain the 2016 gastric/GEA criteria. However, if among the pantumor scenarios other scoring systems are required (e.g. endometrial serous tumors), an additional 20 positive and 20 negative cases of tumor types on which the additional scoring systems are used would need to be added to the validation documentation to achieve 20 positive and 20 negative cases for each additional assay-scoring system combination.