Characterization and clinical outcomes of mismatch repair deficient (dMMR) small bowel adenocarcinoma (SBA).

Abstract

1511 Background: SBA is a rare cancer known to be associated with Lynch syndrome (LS). The prevalence, tumor characteristics, and clinical course of SBAs in the setting of LS is not well understood. We sought to characterize SBA according to mismatch repair and germline mutation status, comparing clinical outcomes. Methods: A retrospective review of SBAs at a single institution identified 74 SBAs that were assessed for dMMR either via immunohistochemical staining (IHC) or microsatellite instability status (MSI) using NGS. Germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM) and when available, clinical records were reviewed. Results: Of 74 individuals with SBA, 28.4% (21/74) of tumors exhibited dMMR and/or high-frequency MSI (MSI-H). The overall prevalence of LS in SBA was 9.5% (7/74), with all LS patients having dMMR/MSI-H tumors. 33.3% (7/21) of dMMR/MSI-H SBA patients had LS. The distribution of germline mutations among LS patients was 57.1% (4/7) in MLH1, 28.6% (2/7) in MSH2, and 14.3% (1/7) in PMS2. One patient with an dMMR/MSI-H tumor was found to have a high-penetrance APC mutation, diagnostic of familial adenomatous polyposis (FAP). In the 38 patients with available clinical follow-up, median age of onset was similar in the dMMR/MSI-H vs the pMMR/MSS group (62 vs 57, p = 0.8). The prevalence of synchronous/metachronous cancers was 5.9% (1/17) in the pMMR/MSS group and 38% (8/21) in the dMMR/MSI-H group (p = 0.02), with 62.5% (5/8) of these in LS (p = 0.001; synchronous/metachronous in LS (5/7) vs. non-LS (4/31)). In the pMMR/MSS group, 58.8% (10/17) of patients presented with metastatic disease at diagnosis, compared to 19% (4/21) in the dMMR/MSI-H group (p = 0.01). In dMMR/MSI-H SBA patients with early-stage disease, 11.8% (2/17) recurred, compared to 71.4% (5/7) in the pMMR/MSS group (p = 0.009). Conclusions: This preliminary evaluation suggests that SBA exhibiting dMMR/MSI-H status is more closely associated with early-stage disease and lower recurrence rates, similar to prior observations in colon cancer. LS was found in 9.5% of all SBA and in 33.3% of dMMR/MSI-H tumors, suggesting that germline assessment for LS in SBA is warranted.