Dr Rimm on How FDA-Approved IHC Tests Pose Reproducibility Challenges in Breast Cancer

"Recently, there have been a number of immunohistochemistry tests approved that are not possible for the pathologist to [replicate] in clinical practice."

David Rimm, MD, PhD, professor of pathology and medicine at Yale School of Medicine, discusses the limitations associated with recently FDA-approved immunohistochemistry (IHC) assays and their impact on diagnostic accuracy and treatment selection in breast cancer.

Several IHC-based companion diagnostics have received regulatory approval for use in selecting patients for targeted therapies. However, many of these assays were validated under highly controlled laboratory conditions, which may not be reproducible in standard clinical pathology settings, Rimm explains. As a result, pathologists are increasingly placed in a challenging position with the expectation to perform and interpret complex IHC tests that may not yield consistent results outside of the original validation environment.

Although the oncology community relies on these assays to guide certain treatment decisions, such as immune checkpoint inhibitors or other targeted agents, pathologists often face technical or interpretive limitations that hinder reliable test execution, Rimm notes. These challenges are compounded by a desire to remain aligned with clinical colleagues and avoid denying patients access to therapies approved based on these diagnostics.

Evidence from multiple studies, including work from Rimm’s laboratory, has indicated substantial inter-observer variability in IHC scoring, particularly for assays measuring low-expression biomarkers. In these cases, the results may vary significantly between readers, leading to concerns about diagnostic reproducibility and potential misclassification of patients, he states. Despite these concerns, pathologists often proceed with testing due to the regulatory approval status and associated clinical expectations.

Rimm emphasizes that this situation reflects a broader misalignment between regulatory standards and clinical practicality. Companion diagnostics approved by the FDA are often assumed to be broadly deployable, yet pathologists may lack access to identical instrumentation, antibodies, or interpretive frameworks used during initial validation, which compromises test performance in the real-world setting.

To address these challenges, Rimm advocates for enhanced transparency about assay limitations, increased collaboration between diagnostic developers and pathologists, and the development of more objective, quantitative alternatives to traditional IHC, such as digital image analysis or multiplexed biomarker platforms.