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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.

Figures

Figure 1.
Figure 1.
Representative images of immunohistochemical staining for MMR proteins. Columns are tumors (patients) 1 through 7, rows are MMR proteins PMS2 (first row, A), MLH1 (second row, B), MSH2 (third row, C), and MSH6 (fourth row, D). Tumors 1–4 were scored dMMR based on absent MSH6 nuclear staining in tumor cells despite intact nuclear staining in other cells of the same case. Tumors 1–3 also demonstrate dMMR by loss of MSH2. Tumor 4 had faint positive control staining for MSH6 and is unevaluable for MSH2. Tumors 5–7 are MMR-intact. Photomicrographs were taken at 40X optical magnification. The scale bar is 50 μm. Arrows point to tumor epithelial cells, unless tumor predominates in the image.
Figure 2.
Figure 2.
Validation of MMR immunohistochemistry using an orthogonal, clinical-grade assay on full sections, and evaluation of the extent of intratumoral heterogeneity in MMR protein loss. Arrows denote tumor epithelial cells, unless tumor predominates in the image; arrowheads denote internal positive controls in non-tumor cells. Images were taken at 20X or 40X optimal magnification, and scale bars represent 50 μm. The first two rows show full sections corresponding to the tissue microarrays spots in Figure 1 for dMMR cases (A, tumor 1 in Figure 1; B, tumor 2; C, tumor 3; D, tumor 4) as well as MMR-intact cases (E, tumor 5; F, tumor 6; G, tumor 7; H, additional full section of an MMR-intact tumor as per tissue microarray). Note the absence of nuclear staining in dMMR cases in A (tumor 1) and D (tumor 4) with some cytoplasmatic staining. The third and fourth rows show biopsy (I–L) and corresponding prostatectomy full sections (M–P) for one of four hospital-based cases, all MMR-intact, stained for PMS2 (I/M), MLH1 (J/N), MSH2 (K/O), and MSH6 (L/P). The fifth row shows full sections of a hospital-based case with known MSH2/MSH6 dMMR (Q, PMS2; R, MLH1; S, MSH2; T, MSH6). Scoring results for all comparisons to full sections are in Supplementary Table 1.
See this image and copyright information in PMC

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