Characterization and Clinical Outcomes of DNA Mismatch Repair–deficient Small Bowel Adenocarcinoma

Abstract

Background: The prevalence and clinical characteristics of small bowel adenocarcinomas (SBAs) in the setting of LS have not been well-studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes. Methods: A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via immunohistochemical (IHC) staining. Germline DNA was analyzed for mutations in known cancer-predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, EPCAM). Clinical variables were correlated with MMR/MSI status. Results: 26% (26/100; 95% CI: 18.4-35.4) of SBAs exhibited MMR deficiency (MMR-D). LS prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-LS MMR-D vs MMR-proficient (MMR-P) SBAs (65 vs 61, p= 0.75), but significantly younger in LS (47.5 vs 61; p=0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P vs 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in LS (p=0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared to 23.1% (6/26) in the MMR-D group (p=0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared to 18.2% (2/11) in the MMR-D group (p=0.0002). Conclusions: When compared to MMR-P SBA, MMR-D SBA is associated with earlier-stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline LS testing in MMR-D SBA is warranted.