{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T23:59:33Z","timestamp":1770335973671,"version":"3.49.0"},"reference-count":36,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"9","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO Precis Oncol"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n            <jats:title>PURPOSE<\/jats:title>\n            <jats:p>Individuals with Lynch syndrome (LS) predominantly develop mismatch repair\u2013deficient\/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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS<\/jats:title>\n            <jats:p>\n              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\n              <jats:italic toggle=\"yes\">MSH2<\/jats:italic>\n              -,\n              <jats:italic toggle=\"yes\">MSH6<\/jats:italic>\n              -, and\n              <jats:italic toggle=\"yes\">PMS2<\/jats:italic>\n              -associated LS, but not\n              <jats:italic toggle=\"yes\">MLH1<\/jats:italic>\n              -associated LS.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSION<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1200\/po-25-00700","type":"journal-article","created":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:10:19Z","timestamp":1760209819000},"update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":2,"title":["Causes of Death Among Individuals With Lynch Syndrome in the Immunotherapy Era"],"prefix":"10.1200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7502-3923","authenticated-orcid":true,"given":"Asaf","family":"Maoz","sequence":"first","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA"},{"name":"Brigham and Women's Hospital, Boston, MA"},{"name":"Harvard Medical School, Boston, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7386-7121","authenticated-orcid":true,"given":"Leah","family":"Biller","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA"},{"name":"Brigham and Women's Hospital, Boston, MA"},{"name":"Harvard Medical School, Boston, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9012-6982","authenticated-orcid":true,"given":"Marios","family":"Giannakis","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA"},{"name":"Brigham and Women's Hospital, Boston, MA"},{"name":"Harvard Medical School, Boston, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5337-5231","authenticated-orcid":true,"given":"Douglas","family":"Rubinson","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA"},{"name":"Brigham and Women's Hospital, Boston, MA"},{"name":"Harvard Medical School, Boston, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3636-0353","authenticated-orcid":true,"given":"Thejus","family":"Jayakrishnan","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA"},{"name":"Brigham and Women's Hospital, Boston, MA"},{"name":"Harvard Medical School, Boston, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9800-1954","authenticated-orcid":true,"given":"Miki","family":"Horiguchi","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA"},{"name":"Harvard T.H. Chan School of Public Health, Boston, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1629-2824","authenticated-orcid":true,"given":"Chinedu","family":"Ukaegbu","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7093-5495","authenticated-orcid":true,"given":"Alyson","family":"Caruso","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5487-7471","authenticated-orcid":true,"given":"Sapna","family":"Syngal","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA"},{"name":"Brigham and Women's Hospital, Boston, MA"},{"name":"Harvard Medical School, Boston, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6184-9273","authenticated-orcid":true,"given":"Matthew B.","family":"Yurgelun","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, MA"},{"name":"Brigham and Women's Hospital, Boston, MA"},{"name":"Harvard Medical School, Boston, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"233","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hoc.2024.04.002"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10689-018-00117-1"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2009.237"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30422-9"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.02107"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2017699"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2400634"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0805-8"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)02848-4"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.11.012"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-4070"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2201445"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2404512"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.00686"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2402141"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2023.101909"},{"key":"e_1_3_5_18_2","article-title":"Prevalence and clinical implications of mismatch repair-proficient colorectal cancer in patients with lynch syndrome","author":"Ranganathan M","unstructured":"Ranganathan M, Sacca RE, Trottier M, et al: Prevalence and clinical implications of mismatch repair-proficient colorectal cancer in patients with lynch syndrome. 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