Metastatic Urothelial Carcinoma Shows Low Co-Expression of PD-L1, HER2, and c-MET

Human epidermal growth factor receptor 2 (HER2) and c-MET signal activation have been involved in the pathogenesis of urothelial carcinoma (UC) subsets, with anti-programmed death-ligand 1 (PD-L1) agents commonly used for the disease. Novel therapeutic combinations that target both immune checkpoints and c-MET or HER2 pathways are currently being investigated in metastatic urothelial carcinoma (mUC), but co-expression of these molecular targets has not been characterized in mUC, and the rate of PD-L1 co-expression with c-MET and HER2 may be low.

A research team sought to define the tumor protein co-expression of PD-L1, c-MET, and HER2 in a cohort of patients with mUC. They shared their findings at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium.

A total of 143 patients with mUC were identified from an institutional database. Formalin-fixed paraffin-embedded tumor samples taken from metastatic sites and available paired primary tumors underwent immunohistochemical staining for PD-L1 (SP-142), c-MET, and HER2 expression.

High expression was defined by: PD-L1, ≥5% of infiltrated immune cells; c-MET, ≥50% of tumor cells; HER2, score=3+ (complete membrane staining that is intense and >10% of tumor cells). Simple and weighted Cohen’s kappa statistics (κ) were used to determine the agreement in expression and co-expression between paired primary and metastatic samples.

The study analyzed 143 patients with mUC. Of those patients, 79 had available paired primary tumors. In primary tumors (n=79), a high expression of PD-L1, c-MET, and HER2 was seen in 15.2%, 34.2%, and 12.7% of patients, respectively. In metastatic samples (n=143), a high expression of PD-L1, c-MET, and HER2 was detected in 9.8%, 41.3%, and 9.8% of patients, respectively.

Expression agreement rates among primary and metastatic specimens (n=79) were: PD-L1, 79.7% (κ=.09, slight agreement); c-MET, 69.6% (κ=.35, fair agreement); HER2, 84.8% (κ=.17, slight agreement). Rates were driven by high prevalence of low expression.

High PD-L1/c-MET co-expression was observed in 5.1% (n=4) of primary and 4.9% (n=7) of metastatic specimens. High co-expression of PD-L1/HER2 occurred in 3.8% (n=3) of primary samples and did not occur in any metastatic samples. The overall co-expression agreement rate between paired primary and metastatic samples was 55.7% (κ=.22, fair agreement) for PD-L1/c-MET and 67.1% (κ=.06, slight agreement) for PD-L1/HER2. However, agreement rates for high co-expression between primary and metastatic samples were significantly low (2.5% for PD-L1/c-MET and 0% for PD-L1/HER2).

Among the patients with mUC in the study, tumor co-expression of high c-MET or HER2 and PD-1 was low, and agreement of high co-expression in primary and metastatic sites was rare. Investigational strategies to combine immune checkpoint inhibitors with either c-MET- or HER2-targeted agents for mUC may result in limited synergistic activity.