PD-L1 is often assessed in archived primary tumor material (PRIM) rather than pretreatment metastatic biopsies (MET). In mUC, significant genetic heterogeneity has been previously demonstrated between primary and metastatic tumors suggesting that immunophenotypes could also be divergent. A recent study by Erlmeier et al. analyzed matched primary and metastatic samples to determine how immunophenotypes were correlated with treatment response in patients with mUC.
The study cohort consisted of 154 mUC patients treated with first-line platinum-based chemotherapy and a second-line immune checkpoint inhibitor. The investigators evaluated PD-L1 expression, stromal tumor infiltration lymphocytes (sTILs), and immune cell populations. MET samples had lower sTIL and immune cells, particularly in hepatic, osseous, and peritoneal/pleural metastases. Matched PRIM and MET samples exhibited a cumulative discordance rate of 30% for the immune cell score and 25% for the combined positivity score representing PD-L1 expression. Notably, only the PD-L1 immune cell status of MET samples correlated with overall survival. Hierarchical clustering of immune cell populations led to two distinct clusters representing inflamed or uninflamed tumors. Patient-matched samples exhibited a discordance rate of 36% in immunophenotypes, with the inflamed cluster showing a higher degree of heterogeneity.
Subsequent analyses focused on MET samples, in which researchers clustered immune cell populations to yield three distinct immune phenotypes: evasion, inflamed-cytotoxic, and inflamed-suppressed. Different types of metastases exhibited varying distributions of these phenotypes, and survival rates were significantly different across the clusters. The disease control rate (DCR) – defined as patients with stable disease, partial remission, or complete remission – with first-line chemotherapy was highest for the inflamed-cytotoxic phenotype. This also applied to second-line immune checkpoint inhibitor therapy. Finally, since MHC-I loss in metastasis is associated with resistance to chemotherapy and immune checkpoint inhibitors, the researchers investigated changes in its expression in metastasis. Overall, there was a 70% loss rate in MHC-1 expression in MET tumors, with different rates of loss across the different immune phenotypes. Higher MHC-1 expression was associated with higher DCR after both first-line chemotherapy and second-line immune checkpoint inhibitor therapy.
This study underscores the importance of using patient samples, including metastatic biopsies that are representative of disease progression, rather than relying on archived primary tumor samples. Ignoring genetic and immunotypic biomarker heterogeneity between primary and metastatic tumors can lead to poor selection of patients likely to respond to a specific treatment. However, since obtaining metastatic or on-treatment biopsies may not be feasible in all cases, alternative liquid biopsy methods will need to be developed to provide a real-time picture of cancer evolution to guide precision treatments.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
References:
- Faltas BM, Prandi D, Tagawa ST, Molina AM, Nanus DM, Sternberg C, Rosenberg J, Mosquera JM, Robinson B, Elemento O, Sboner A, Beltran H, Demichelis F, Rubin MA. Clonal evolution of chemotherapy-resistant urothelial carcinoma.
- Nat Genet. 2016 Dec;48(12):1490-1499. doi: 10.1038/ng.3692. Epub 2016 Oct 17.
- Erlmeier F, Klümper N, Landgraf L, et al. Spatial Immunephenotypes of Distant Metastases but not Matched Primary Urothelial Carcinomas Predict Response to Immune Checkpoint Inhibition. Eur Urol. 2023;83(2):133-142. doi:10.1016/j.eururo.2022.10.020