DNA Mismatch Repair Deficiency in Rectal Cancer: Benchmarking Its Impact on Prognosis, Neoadjuvant Response Prediction, and Clinical Cancer Genetics

Abstract

Purpose: DNA mismatch repair deficiency (dMMR) hallmarks consensus molecular subtype 1 of colorectal cancer. It is being routinely tested, but little is known about dMMR rectal cancers. The efficacy of novel treatment strategies cannot be established without benchmarking the outcomes of dMMR rectal cancer with current therapy. We aimed to delineate the impact of dMMR on prognosis, the predicted response to fluoropyrimidine-based neoadjuvant therapy, and implications of germline alterations in the MMR genes in rectal cancer.

Methods: Between 1992 and 2012, 62 patients with dMMR rectal cancers underwent multimodality therapy. Oncologic treatment and outcomes as well as clinical genetics work-up were examined. Overall and rectal cancer-specific survival were calculated by the Kaplan-Meier method.

Results: The median age at diagnosis was 41 years. MMR deficiency was most commonly due to alterations in MSH2 (53%) or MSH6 (23%). After a median follow-up of 6.8 years, the 5-year rectal cancer-specific survival was 100% for stage I and II, 85.1% for stage III, and 60.0% for stage IV disease. Fluoropyrimidine-based neoadjuvant chemoradiation was associated with a complete pathologic response rate of 27.6%. The extent of surgical resection was influenced by synchronous colonic disease at presentation, tumor height, clinical stage, and pelvic radiation. An informed decision for a limited resection focusing on proctectomy did not compromise overall survival. Five of the 11 (45.5%) deaths during follow-up were due to extracolorectal malignancies.

Conclusion: dMMR rectal cancer had excellent prognosis and pathologic response with current multimodality therapy including an individualized surgical treatment plan. Identification of a dMMR rectal cancer should trigger germline testing, followed by lifelong surveillance for both colorectal and extracolorectal malignancies. We herein provide genotype-specific outcome benchmarks for comparison with novel interventions.

Fig 1.

A standardized algorithm for testing colorectal cancer for DNA mismatch repair (MMR) status at University of Texas MD Anderson Cancer Center was used in identifying our study cohort of 62 patients with MMR-deficiency rectal cancers. All clinical testing has been updated to the current standard of care. IHC, immunohistochemistry; MSI, microsatellite instability.

Fig 2.

(A) Overall survival, (B) rectal cancer–specific survival, and (C) stage-stratified rectal cancer–specific survival.

Fig A1.

The length of follow-up for 62 patients with mismatch repair–deficient rectal cancer. The follow-up was > 5 years in the majority of the patients, with a median follow-up of 7.0 years (interquartile ratio, 5.0 to 11.1 years) among 51 alive patients (gold bars), and 3.5 years (interquartile ratio, 1.9 to 12.4 years) among 11 deceased patients (blue bars).