ASCO 2018: Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade

Chicago, IL (UroToday.com)   In 2017, based on the data from 149 patients enrolled across 5 single-arm clinical trials, the US FDA granted its first tissue site agnostic drug approval - the use of pembrolizumab for patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment. 

In prostate cancer, MSI-H and dMMR have been reported anywhere from 1% in primary tumors to up to 12% in metastatic tumors1. In case series of 10 ductal prostatic carcinomas, an aggressive histopathologic variant of prostate cancer, four (40%) patients’ tumors had an MMR gene alteration2. Small studies have had mixed success with the use of pembrolizumab3. This abstract adds to the literature on MSI-H/dMMR status in prostate cancer by testing an innovative computational method to determine MSI status. 

In this study, 839 patients with prostate cancer underwent next generation sequencing of tumor as well as matched normal tissue for characterization of somatic mutations, copy number alterations and germline mutations. The investigators utilized MSIsensor, a C++ program which calculates the length distribution of microsatellites per site in paired samples of tumor tissue and normal tissue4. Tumor mutational burden and immunohistochemical staining for mismatch repair proteins were also analyzed in selected cases. 

The investigators found that 20 out of 839 patients (2.4%) had MSI-H/dMMR tumor using the MSIsensor. These findings were confirmed using immunohistochemical and mutational signature analysis. 13 of these patients consented to germline analysis, and 3/13 had a germline MMR gene mutation. 10 MSI-H patients received a PD1 or PD/1 checkpoint inhibitor and 5 of the 10 have had a PSA decline of >60%. Of those 5, 2 had a radiographic PR and a PSA decline of >80%. These early results suggest that patients with MSI-H/dMMR prostate cancer may respond to checkpoint inhibition and that MSI frequently develops as a somatic event in many of these patients as only small fraction of the patients had a germline MMR gene mutation. Given these responses, it may be reasonable to look for MSI/MMR status in patients with metastatic prostate cancer.   

Presented By: Wassim Abida, MD, PhD. Memorial Sloan Kettering Cancer Center

Written by: Jason Zhu, MD Fellow, Division of Hematology and Oncology Duke University Medical Center, Twitter: @TheRealdJasonZhu at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA 

References: 
1. Hempelmann JA, Lockwood CM, Konnick EQ, et al. Microsatellite instability in prostate cancer by PCR or next-generation sequencing. Journal for ImmunoTherapy of Cancer 2018;6:29. 
2. Schweizer MT, Cheng HH, Tretiakova MS, et al. Mismatch repair deficiency may be common in ductal adenocarcinoma of the prostate. Oncotarget 2016;7:82504-10. 
3. Graff JN, Alumkal JJ, Drake CG, et al. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget 2016;7:52810-7. 
4. Niu B, Ye K, Zhang Q, et al. MSIsensor: microsatellite instability detection using paired tumor-normal sequence data. Bioinformatics 2014;30:1015-6.