Causes of Death Among Individuals With Lynch Syndrome in the Immunotherapy Era

PURPOSE Individuals with Lynch syndrome (LS) predominantly develop mismatch repair–deficient/microsatellite-unstable (MMR-D/MSI-H) cancer, for which immunotherapy can yield long-term disease control, even in the metastatic setting, leading to tissue-agnostic US Food and Drug Administration approval for pembrolizumab for any advanced MMR-D/MSI-H cancer in May 2017. The primary aim of this study was to assess the causes of death in individuals with LS in the era of immunotherapy. METHODS We performed a retrospective cohort study of individuals with LS seen at a single academic cancer center for oncology-/genetics-related care, who died between May 30, 2017, and December 20, 2024. An expert panel adjudicated the cause of death after a detailed review of the electronic medical record (EMR). Data regarding personal cancer history, germline and somatic testing, and treatment were obtained from the EMR. RESULTS Fifty-four individuals with LS were known to have died since May 2017 (52% female; median age at death 64 years; IQR, 51-75), of whom 44 were determined to have died of cancer and/or cancer treatment toxicities/complications. Of these, 19 of 44 (43%) died of MMR-proficient/MS-stable cancer (five because of pancreatic cancer, four because of colorectal cancer), 20 of 44 (46%) died of MMR-D/MSI-H cancer (six because of colorectal cancer, four because of pancreatic cancer), and 5 of 44 (11%) died of cancer with unknown/indeterminate MMR/MSI status. Among those who died with MMR-D/MSI-H cancer, 14 of 20 (70%) had disease progression on immunotherapy, 2 of 20 (10%) died of immunotherapy toxicity, and 3 of 20 (15%) died of other treatment complications. Deaths from MMR-proficient/MS-stable cancer were seen among patients with MSH2 -, MSH6 -, and PMS2 -associated LS, but not MLH1 -associated LS. CONCLUSION In this single-center analysis, MMR-proficient/MS-stable cancers were a frequent cause of death among individuals with LS. MMR-D/MSI-H cancers resistant to immunotherapy and treatment-associated deaths were other significant contributors to mortality. Larger, multicenter studies are warranted to validate these findings.