 in the Departments of Pathology and Medicine (Oncology) at the Yale University School of Medicine.

 Rimm is a professor in the Department of Pathology at Yale School of Medicine. 

"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.

Videos

David Rimm, MD, PhD, discusses how FDA-approved IHC assays may lack reproducibility in real-world settings in breast cancer.

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

David L. Rimm, MD, PhD, professor of pathology and of medicine, director of pathology tissue services, director of translational pathology, Yale Cancer Center, discusses the continued role for PD-L1 testing to predict response with checkpoint inhibitors in non&shy;—small cell lung cancer (NSCLC).

PD-L1 IHC 22C3 pharmDx is the first FDA-approved companion diagnostic test for PD-L1 testing in NSCLC. This test, used with pembrolizumab (Keytruda), is going to around for a long time, says Rim. This is because recent data demonstrated that pembrolizumab was more effective than chemotherapy in frontline metastatic NSCLC, but only for patients whose tumors have ≥50% PD-L1 expression. This means that patients will want to have this test to determine if they are a candidate for frontline pembrolizumab, says Rimm. Patients who respond to frontline pembrolizumab may not need chemotherapy for a long time, if ever, he says. This is really a breakthrough in the management of lung cancer, he says. For that reason, PD-L1 testing is not going to go away anytime soon.

The FDA approved pembrolizumab for the frontline treatment of patients with PD-L1 positive, metastatic NSCLC who do not harbor EGFR or ALK aberrations in October 2016.   

The approval was based on data from the phase III KEYNOTE-024 trial, in which single-agent pembrolizumab reduced the risk of death by 40% and improved progression-free survival (PFS) by 4.3 months compared with doublet chemotherapy for untreated patients with advanced NSCLC with PD-L1 expression on ≥50% of cells.

David L. Rimm, MD, PhD, professor of pathology and of medicine, director of pathology tissue services, director of translational pathology, Yale Cancer Center, discusses the continued role for PD-L1 testing to predict response with checkpoint inhibitors in non&shy;–small cell lung cancer (NSCLC).
 

Dr. David L. Rimm on the Continued Role for PD-L1 Testing in NSCLC

David L. Rimm, MD, PhD, professor of pathology and of medicine, director of pathology tissue services, director of translational pathology, Yale Cancer Center, discusses various options for biomarker testing in lung cancer.

Genomics testing involves an examination of the mutational or neoantigen load, explains Rimm. While this assay does select patients with a high mutational load, Rimm feels that this method is insufficiently sensitive, such that it misses those patients who may not have a high mutational load, but would still benefit from therapy.

Rimm is more optimistic about another form of biomarker testing, which involves looking at the immune cell microenvironment. In this method, one can measure the distribution and properties of T-cells determined by coexpression of other markers.

Dr. Rimm on Biomarker Testing in Lung Cancer

David L. Rimm, MD, PhD, professor of pathology and of medicine, director of pathology tissue services, director of translational pathology, Yale Cancer Center, discusses alternatives to PD-L1 testing to predict response with checkpoint inhibitors in lung cancer.

Around 10% of patients who are PD-L1 negative still show some benefit from a PD-1 inhibitor. A test is needed to identify those patients, says Rimm. There are a number of other potential approaches that are being considered, including genomic approaches, neoantigen-type approaches, and other protein or alternative microenvironment-type approaches.

Genomic and neoantigen approaches are less likely to succeed, say Rimm. A more sensitive, less specific test is preferred, because it is better to treat a few patients that may not respond than it is to be too specific and rule out those who may benefit from an immunotherapy, he says. 

One promising approach is to look at tumor-infiltrating lymphocytes or other cells within the environment of the tumor that may not actually be expressing PD-L1, but are the cells that actually kill the tumor.

David L. Rimm, MD, PhD

Articles

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

Dr. David L. Rimm on the Continued Role for PD-L1 Testing in NSCLC

Dr. Rimm on Biomarker Testing in Lung Cancer

Dr. David L. Rimm on Alternatives to PD-L1 to Predict Immunotherapy Response in Lung Cancer