{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T10:56:01Z","timestamp":1793357761729,"version":"4.5.0"},"reference-count":36,"publisher":"BMJ","issue":"11","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"unspecified","delay-in-days":17,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"publisher","award":["RP240392"],"award-info":[{"award-number":["RP240392"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"publisher","award":["RR180035"],"award-info":[{"award-number":["RR180035"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30 CA016672"],"award-info":[{"award-number":["P30 CA016672"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000982","name":"Conquer Cancer Foundation","doi-asserted-by":"publisher","award":["2022CDA-7604125121"],"award-info":[{"award-number":["2022CDA-7604125121"]}],"id":[{"id":"10.13039\/100000982","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,10,22]]},"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Only a subset of polymerase epsilon (\n                      <jats:italic>POLE<\/jats:italic>\n                      ) mutations is associated with hypermutant phenotype; we hypothesized that only loss-of-proofreading (LOP)\n                      <jats:italic>POLE<\/jats:italic>\n                      mutations are associated with favorable immunotherapy response.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This retrospective cohort study included a pan-cancer cohort of 69,223 patients from cBioPortal and a cohort of patients with 41\n                      <jats:italic>POLE<\/jats:italic>\n                      mutant metastatic colorectal (CRC) treated with immunotherapy at the MD Anderson Cancer Center between January 2017 and May 2023. We evaluated prognosis according to\n                      <jats:italic>POLE<\/jats:italic>\n                      mutation functionality.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In the pan-cancer cBioPortal cohort (n=69,223)\n                      <jats:italic>POLE<\/jats:italic>\n                      was mutated in 2.8% (1,965) of tumors; of these, only 7.5% (n=148) had LOP\n                      <jats:italic>POLE<\/jats:italic>\n                      mutations (0.0% of entire cohort). Endometrial cancer (6.6%) and CRC (1.2%) were the only tumor types with greater than 1% incidence of LOP\n                      <jats:italic>POLE<\/jats:italic>\n                      mutation. Overall survival was similar between non-LOP\n                      <jats:italic>POLE<\/jats:italic>\n                      and\n                      <jats:italic>POLE<\/jats:italic>\n                      wildtype patients (HR=0.94, 95%\u2009CI 0.82 to 1.07, p=0.34); conversely, LOP\n                      <jats:italic>POLE<\/jats:italic>\n                      patients had significantly better outcomes (HR=0.23, 95%\u2009CI 0.16 to 0.32, p&lt;0.0001). In the clinical cohort, all nine patients with LOP\n                      <jats:italic>POLE<\/jats:italic>\n                      mutations achieved durable clinical benefit (objective response rate (ORR) 88.9%, complete response rate (CR) 33.3%, disease control rate (DCR) 100%) and median progression-free survival (PFS) was not reached at the time of analysis, after median follow-up of 32 months. None of the nine patients with microsatellite stable (MSS), non-LOP\n                      <jats:italic>POLE<\/jats:italic>\n                      tumors achieved an ORR of 0%, with median PFS of 3.7 months (HR 0.05 LOP relative to non-LOP\n                      <jats:italic>POLE<\/jats:italic>\n                      , 95%\u2009CI 0.01 to 0.19, p&lt;0.0001). Interestingly, median PFS on first-line cytotoxic agents was significantly shorter for patients with LOP\n                      <jats:italic>POLE<\/jats:italic>\n                      compared with patients with MSS non-LOP\n                      <jats:italic>POLE<\/jats:italic>\n                      mutant tumors (2.1 vs 9.7 months, HR 3.33, 95%\u2009CI 0.87 to 12.74, p=0.012).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Identifying the subset of\n                      <jats:italic>POLE<\/jats:italic>\n                      mutations that cause LOP is critical to distinguish patients likely to respond to immunotherapy. Patients with CRC with LOP\n                      <jats:italic>POLE<\/jats:italic>\n                      mutant tumors experienced deep, sustained response to immunotherapy but were resistant to standard cytotoxic chemotherapy, in stark contrast to those with non-LOP\n                      <jats:italic>POLE<\/jats:italic>\n                      mutations.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-012190","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T13:15:18Z","timestamp":1763471718000},"page":"e012190","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Prognosis and treatment response stratification according to loss of proofreading (LOP)\n                    <i>POLE<\/i>\n                    variants"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1714-1171","authenticated-orcid":false,"given":"Giulia","family":"Maddalena","sequence":"first","affiliation":[{"name":"Gastrointestinal Medical Oncology, University of Texas System, Houston, Texas, USA"},{"name":"Oncology Unit 1, Veneto Institute of Oncology-IRCCS, Padova, Italy"},{"name":"Department of Surgery, Oncology and Gastroenterology, University of Padua, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadl A","family":"Zeineddine","sequence":"additional","affiliation":[{"name":"Gastrointestinal Medical Oncology, University of Texas System, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saikat","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"Gastrointestinal Medical Oncology, University of Texas System, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad 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