Prevalence of Mismatch Repair Deficiency in Rectal Adenocarcinoma in a Prospective Screening Program

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As reported in a letter published in The New England Journal of Medicine by Papke et al, data from a prospective biopsy screening program at a large gastrointestinal pathology group indicate that approximately 3% of rectal adenocarcinomas are mismatch repair (MMR)-deficient.

Study Background

As related by the authors, a recent case series reported by Cercek et al showed that complete response was achieved with neoadjuvant monotherapy with the PD-1 inhibitor dostarlimab in 12 patients with locally advanced MMR-deficient rectal adenocarcinoma. These authors estimated that MMR deficiency was present in 5% to 10% of rectal adenocarcinomas, partly on the basis of data from tertiary referral centers. Other studies, using data from resection specimens or retrospective population database reviews, have indicated a prevalence of 2.4% to 8.4%.

As stated by the investigators, “Evidence from large-scale studies assessing MMR deficiency in rectal adenocarcinoma biopsy specimens obtained in community practice is currently lacking, and therefore the potential therapeutic effect of neoadjuvant dostarlimab therapy remains uncertain.”

Study Details

The study involved 16,083 colorectal adenocarcinoma biopsy specimens obtained at community endoscopy centers from 2010 through 2020. Overall, a total of 18 biopsy specimens (0.11%) were insufficient for MMR immunohistochemical analysis. Of the 16,083 specimens, 5,553 (34.5%) were categorized as rectal adenocarcinoma specimens; of these, material for immunohistochemical analysis was sufficient for 5,547 (99.9%).

Key Findings

In total, 147 (2.7%, 95% confidence interval [CI] = 2.2%–3.1%) of the 5,547 rectal adenocarcinomas were MMR-deficient. Among 16,065 colorectal adenocarcinomas with material sufficient for analysis, 2,150 (13.4%, 95% CI = 12.9%–13.9%) were MMR-deficient.

Among patients with rectal cancer, those aged < 50 years (33 of 784; 4.2%) were more likely (P = .003) to have MMR-deficient cancers vs those aged ≥ 50 years (114 of 4,763; 2.4%). Among the 147 patients with MMR-deficient cancers, 114 (77.6%) were aged ≥ 50 years at diagnosis, including 40 (27.2%) who were aged ≥ 70 years. MMR-deficient cancers were diagnosed at a median age of 61.5 years, compared with 63.0 years for MMR-proficient cancers.

Complete loss of MLH1 expression, commonly associated with Lynch syndrome, was found in 38.8% of MMR-deficient rectal adenocarcinomas. The remaining cases showed other patterns of MMR protein loss often associated with Lynch syndrome. No samples showed evidence of constitutional MMR deficiency—ie, germline homozygous MMR protein loss of function—however, no germline data were collected.

The investigators concluded, “Overall, we found that 2.7% of rectal adenocarcinomas were MMR-deficient. The relatively older median age at the time of presentation with MMR-deficient rectal adenocarcinoma (61.5 years) reinforces the need for universal screening. Furthermore, we found that biopsy material was sufficient for MMR immunohistochemical screening in most cases (99.9%). In light of the findings of Cercek et al, our results show the utility of a universal biopsy screening strategy and clearly delineate the target population that may benefit from this therapeutic strategy.”

Mark Redston, MD, of Brigham and Women’s Hospital, is the corresponding author for The New England Journal of Medicine article.

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