The frequency of second primary malignancies and colonic polyps in Lynch syndrome with MSI tumors following immune checkpoint blockade.

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10505 Background: Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair genes and is characterized by microsatellite instability (MSI) status of associated tumors. MSI sensitizes tumors to immune checkpoint inhibition (ICI). The incidence of second primary malignancies and colonic polyps in LS patients with MSI tumors following ICI has not been evaluated. Methods: The Memorial Sloan Kettering LS database was queried for all patients with cancer who received ≥1 cycle of ICI using an IRB approved protocol. LS was confirmed by presence of a germline pathogenic/likely pathogenic alteration in a DNA mismatch repair gene ( MLH1, MSH2, MSH6, PMS2, EPCAM). Tumor and matched normal DNA sequencing was performed via MSK-IMPACT, an IRB approved protocol (NCT01775072). MSI status was assessed using MSIsensor. Results: At our center, 131 patients with LS received ICI mostly (73.3%) in the context of metastatic cancer. While 108 patients received ICI for an MSI tumor, 23 LS patients received ICI for a MSS (Microsatellite Stable) tumor (4 hepatobiliary, 3 colorectal, 3 CNS, 2 endometrial, 2 gastroesophageal, 2 renal, 2 sarcoma, 5 other). Five patients (3.8%) developed ≥1 second primary malignancy while on or following ICI comprised of an MSI small bowel adenocarcinoma, MSI upper tract urothelial cancer, 2 MSS prostate cancers, MSS HCC and MSI sebaceous neoplasm; 1 patient developed both MSS prostate cancer and MSI urothelial cancer on ICI. All five patients’ primary malignancy was MSI. Only a minority of patients underwent surveillance colonoscopies post completion of ICI (31.3%, (41/131)). Of these 41, nine (22%, (9/41)) were identified to have polyps including 8 tubular adenomas and 1 tubulo-villous adenoma. Median time to development of a polyp was 22 months (95% CI 16.82-27.18) from last colonoscopy and 13 months (95% CI 4-25 months) from last ICI. Notably amongst the 23 LS patients whose tumors were MSS, 14 had progression on ICI. Conclusions: Herein, we demonstrate that in LS-patients in receipt of ICI for cancer treatment, the risk of a second primary cancer and polyps remain high following treatment with ICI. Biological mechanisms underlying immune escape warrant further investigation. Surveillance strategies should be continued for LS patients post ICI.