Work

Occurrence of dMMR/MSI-H tumor during follow-up in Lynch syndrome patients treated with immune checkpoint inhibitors for metastatic digestive cancer between 2015 and 2024: a retrospective analysis of a monocentric prospective cohort study

Year: 2025

Type: article

Abstract: BACKGROUND: Immune checkpoint inhibitors (ICIs) represent a paradigm shift and a therapeutic revolution in the management of mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC), and therefore for patients with Lynch syndrome (LS). The risk of developing metachronous cancers and colorectal polyps in a population of LS patients treated with ICI(s) is not well understood. MATERIALS AND METHODS: In a single-center cohort study, we retrospectively reviewed 93 LS patients from the prospective 'ImmunoMSI' cohort, who were diagnosed with dMMR/MSI-H gastrointestinal cancer and were treated with ICIs for index metastatic gastrointestinal cancer between February 2015 and April 2024. The primary and secondary outcomes were the cumulative risks of metachronous dMMR/MSI-H cancer(s) and de novo colorectal preneoplastic polyps, respectively. RESULTS: The median age at diagnosis was 62 years (range 26-77 years). Most patients carried a germline pathogenic variant in the MSH2/EPCAM (47%) or MLH1 (30%) genes. The majority presented CRC as their index cancer (83%), followed by cancers of the small intestine (6%), stomach (4%), and pancreas (4%). During or after treatment with ICI(s), 8 out of 93 patients (8%) developed a total of 9 dMMR/MSI-H cancers, including urothelial (n = 4), colorectal (n = 3), pancreatic (n = 1), and skin cancer (n = 1). All patients who developed metachronous cancers had either a complete or partial response to ICI(s) treatment for their index cancer. During a median follow-up of 47.8 months, 44 patients had colonoscopies, and 17 (39%) developed de novo preneoplastic polyps. CONCLUSIONS: Our results show that patients with LS treated with ICIs for dMMR/MSI-H metastatic digestive cancers are at risk of developing metachronous dMMR/MSI-H cancers and preneoplastic colorectal polyps. This underlines the importance of dedicated long-term follow-up in this population, even after successful ICI treatment for their first digestive cancer.

Source: ESMO Open

DOI: 10.1016/j.esmoop.2025.105559