Mismatch repair deficient rectal cancer is resistant to induction combination chemotherapy

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Background: Although most rectal cancers are responsive to combination induction chemotherapy, the sensitivity of mismatch repair deficient (MMR-D) rectal cancers to chemotherapy remains uncertain. Methods: MMR-D rectal tumor cases were retrospectively reviewed with tabulation of baseline characteristics, treatment modalities and clinical outcomes. Prevalence of germline mutations in the MMR genes, diagnostic of Lynch syndrome (LS), was compared to LS-associated colon cancer patients. We also assessed somatic mutational status for a subset of these patients. Results: Twenty of the 49 patients received induction chemotherapy with 5FU and oxaliplatin, 15 received standard neoadjuvant chemoradiation, and 14 proceeded directly to surgery. Of the 15 patients treated with induction chemoradiation, 93% (n = 14) experienced radiographic response and tumor downstaging; and none of these patients showed evidence of disease progression. In contrast, of the 18 patients treated with induction chemotherapy alone, only 61% (n = 11) experienced tumor response and 28% (n = 5) of patients demonstrated progressive disease while on therapy. The majority of these cases, 82% (41/50) harbored germline mutations in the MMR genes and the observed prevalence of germline MSH2 and MSH6 mutations was significantly higher in the rectal (n = 41) versus colon (n = 244) cancer patients (rectal vs colon: MSH2: 57% vs 37%; MSH6: 20% vs 11%; p-value <0.0005). Conclusions: Patients with MMR-D rectal tumors appear to have a high chance of disease progression on induction chemotherapy. As opposed to LS-associated colon cancers, LS-associated rectal cancers are more likely to harbor MSH2 or MSH6 germline mutations. Upfront testing for MMR status and initial treatment with chemoradiation in MMR-D rectal tumors should be undertaken until better therapies are available. Legal entity responsible for the study: Andrea Cercek. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

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