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. 2025 May 1;31(9):1746-1753.
doi: 10.1158/1078-0432.CCR-24-1210.

Prevalence of Mismatch Repair Deficiency in Primary Prostate Cancer in a Large Prospective Cohort

Ciara S McNevin  1   2 , Anna Keogh  3 , Mutaz Mohammed Nur  3 , Brianán McGovern  3 , Julie McFadden  3 , Anne-Marie Baird  4 , Karen Cadoo  2 , Sarah Mc Carron  5 , Cathal O'Brien  5 , Martin P Barr  4 , Steven G Gray  4 , Orla Sheils  4 , Lesley A Sutton  5 , Sinead Flanagan  1   6 , Lorelei A Mucci  6 , Konrad H Stopsack  6   7   8 , Stephen P Finn  1
Affiliations

Prevalence of Mismatch Repair Deficiency in Primary Prostate Cancer in a Large Prospective Cohort

Ciara S McNevin et al. Clin Cancer Res. .

Abstract

Purpose: Mismatch repair (MMR) deficiency and microsatellite instability are predictive biomarkers for immunotherapy response. The best approach to identify patients with such tumors is unclear in prostate cancer.

Experimental design: This study included 1,016 men diagnosed with primary prostate cancer during prospective follow-up of the Health Professionals Follow-up Study and Physicians' Health Study. The highest-grade/index lesions from radical prostatectomy (95%) or transurethral resections of the prostate were mounted on tissue microarrays. Scoring of immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6, and PMS2 required a nontumor internal positive control for designating deficiency. Validation was done on full sections and with PCR-based quantification of microsatellite repeats.

Results: Tumor stage was predominantly pathologically localized with a full distribution of Gleason scores. MMR tumor scoring could be performed with available internal positive control tissue in 75% to 90% of cases, depending on the MMR protein. Of the 903 tumors evaluable for MSH2 protein loss, 4 tumors had loss of MSH2 (prevalence, 0.4%; 95% confidence interval, 0.2%-1.1%), and 3 of 708 evaluable tumors had concomitant loss of MSH6 (prevalence, 0.4%; 95% confidence interval, 0.1%-1.2%). No tumor had loss of MLH1 or PMS2. The four MMR-deficient cases had higher Gleason scores, and three had non-zero microsatellite repeats.

Conclusions: In this nationwide prospective study, MMR deficiency was rare in primary, surgically treated prostate cancer. The low prevalence and the need for an internal positive control for this assay are feasibility concerns for unselected routine immunohistochemistry-based screening for MMR deficiency on limited tissue specimens, such as prostate biopsies.

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Conflict of interest statement

Conflicts of interest:

St James’s Hospital received gift of Idylla Biocartis assay from Biocartis, Mechelen, Belgium. C. S. McNevin reports grants from Wellcome Trust during the conduct of the study; other support from AstraZeneca, other support from Takeda Pharmaceutical Company, and other support from MSK Pharma, outside this study. A. Baird reports personal fees from Roche, personal fees from AstraZeneca, personal fees from J&J, and personal fees from Medscape outside the submitted work; and Steering Committee Member (unpaid) for Roche, and being the current President of Lung Cancer Europe, which has received funding to undertake unrestricted educational activities from: Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Lilly, Merck, MSD, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, Janssen, Novocure, ThermoFisher, and Pierre Fabre. K. Cadoo has the following disclosures: consulting fee from Nextcure, GSK Ireland, invited speaker for GSK Ireland, MJH Life Sciences, Astra Zeneca, and MSD Ireland, payment for expert testimony from St Vincents Health, support to attend meeting from Roche Ireland, MSD Ireland, and Pfizer, participation in advisory board by Merck, Astra Zeneca, Eisai, and GSK Ireland. S. G. Gray received grants from Portage Biotech outside this study. L. A. Mucci is on the Scientific Advisory Board and holds equity in Convergent Therapeutics, unrelated to the study, and has received research funding (to Harvard University) from AstraZeneca. S. P. Finn has the following disclosures: Amgen, Advisory Board; Astra Zeneca, Invited Speaker; Illumina, Advisory Board; Pfizer, Advisory Board; Roche, Advisory Board; Takeda, Invited speaker; Revolution Medicines, Stocks/Shares (all unrelated to the study). No disclosures were reported by the other authors.

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