Abstract 360: The dilemma of the current diagnostic tests for MSI in prostate cancer

Abstract Background: Understanding the relationship between tumor genomics and the immune response in cancer has gotten more attention with the advance of immunotherapy. Microsatellite instability (MSI) is a molecular marker that provides prognostic and predictive information in many types of tumors including prostate cancer (PC). In PC, MSI-H and dMMR have been reported anywhere from 1% in primary tumors to up to 12% in metastasis. Reliable testing strategies for MSI/MMR status are critical for clinical management of patients with PC. MSI detection methods include PCR based molecular tests, NGS-based MSI detection or immunohistochemical staining (IHC). We observe technical difficulties in our daily practice with current molecular diagnostic tests. Design: We examined MMR protein expression (MSH2, MSH6, MLH1, PMS2) and PD-L1 by IHC in 30 PC. Results: Among 30 PC tested, 1 tumor (3%) was completely negative for MLH1 and PMS2 and 1 tumor (3%) revealed loss of PMS2 by IHC even though gene panel did not reveal any mutation in PMS2. The PD-L1 IHC was 44% positive, but the single MMR negative biopsy was PD-L1 negative. PD-L1 expression in PC samples did not show correlation with defective MMR expression. Conclusion: In our study, controversial results were obtained. Based on our experience; even though many exons of MMR genes are covered with these panels, there are some exons do not get enough coverage to be analyzed. This low coverage problem creates false negative results. There are also pseudogene pairs of these genes, especially PMS2. For some specific regions, even though there is enough coverage it is impossible to know if the pathogenic variant is on the PMS2 or the pseudogene without additional test. This result suffers from false positive results without a confirmatory test. It is also known that 5% to 11% of MSI-H cases demonstrate intact MMR staining and localization (proficient MMR, pMMR) due to retained antigenicity and nonfunctional protein. So far, in regular practice we use MMR analyzing strategies which set up for colon cancer where the tumor is uniform. PC is more complex; most of the time more than one clone is involving.We believe MSI detection for PC requires improvement the technics of detection, robust set up of testing strategy with high sensitivity and specificity, analyzing strategy and training of pathologists. Due to technical difficulties of the detection, we believe that the prevalence of MSI-high/dMMR PC might be higher than reported in the literature so far. Citation Format: Esra Dikoglu, Xu Naizhen, Luke P. O'Connor, Peter Pinto, Maria J. Merino. The dilemma of the current diagnostic tests for MSI in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 360.