{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T17:45:35Z","timestamp":1793123135742,"version":"4.5.0"},"reference-count":33,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:00:00Z","timestamp":1768435200000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,1]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n \n Inactivating\n BRCA1\/2<\/jats:italic>\n mutations confer sensitivity to poly(ADP\u2010ribose) polymerase inhibitors (PARPi) in prostate cancer (PCA). However, secondary\n BRCA1\/2<\/jats:italic>\n reversion mutations (\n BRCA<\/jats:italic>\n rev) can restore\n BRCA<\/jats:italic>\n function and mediate acquired PARPi resistance. While\n BRCA<\/jats:italic>\n rev typically arise under PARPi selective pressure, their occurrence in PARPi\u2010na\u00efve settings remains incompletely understood. We sought to characterize the frequency, clinical context, and therapeutic correlates of\n BRCA<\/jats:italic>\n rev detection in men with advanced PCA, including those without prior PARPi exposure.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We restrospectively analyzed clinical liquid biopsy results from men with PCA using FoundationOneLiquid CDx between January and December 2023.\n BRCA<\/jats:italic>\n rev were defined as sequence alterations predicted to restore open reading frame of\n BRCA1<\/jats:italic>\n or\n BRCA2<\/jats:italic>\n harboring pathogenic inactivating variants. Clinical and treatment histories, including chemotherapy and PARPi exposure, were abstracted from medical records.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Over a one\u2010year period, we identified 10 PCA patients with inactivating\n BRCA1\/2<\/jats:italic>\n alterations,\n BRCA<\/jats:italic>\n rev and available treatment history.\n BRCA<\/jats:italic>\n rev were detected in three of 10 (30%) patients who had not received prior PARPi therapy. All three PARP\u2010na\u00efve patients had previously received chemotherapy (platinum or docetaxel) and radiation, and each exhibited multiple\n BRCA<\/jats:italic>\n rev events. The remaining 7 patients (70%) had prior olaparib exposure. Among these, the duration of PARPi response was longer in chemo\u2010na\u00efve patients compared with previously treated with chemotherapy (median: 22 vs. 7.5\u2009months, respectively).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n BRCA<\/jats:italic>\n rev can emerge in PCA in the absence of prior PARPi therapy, particularly following exposure to cytotoxic chemotherapy and radiation. These findings support that DNA\u2010damaging therapies may promote\n BRCA<\/jats:italic>\n rev formation, potentially predisposing to primary PARPi resistance. Early integration of PARPi therapy before chemotherapy may enhance clinical benefit and circumvent emergence of primary resistance.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/cam4.71489","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T16:38:52Z","timestamp":1768495132000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Emergence of\n BRCA<\/i>\n Reversion Mutations in Prostate Cancer Prior to PARP Inhibitor Exposure: Clinical and Therapeutic Implications"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0105-9760","authenticated-orcid":false,"given":"Douglas I.","family":"Lin","sequence":"first","affiliation":[{"name":"Foundation Medicine, Inc. Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Lawrence","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc. Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Danziger","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc. Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8307-9492","authenticated-orcid":false,"given":"Huihui","family":"Ye","sequence":"additional","affiliation":[{"name":"Cedars\u2010Sinai Medical Center Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brennan","family":"Decker","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc. Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole","family":"Gjoerup","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc. Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryon P.","family":"Graf","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc. Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey S.","family":"Ross","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc. Boston Massachusetts USA"},{"name":"Upstate University Medical Center Syracuse New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8395-5168","authenticated-orcid":false,"given":"Richard S. P.","family":"Huang","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc. Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia A.","family":"Elvin","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc. Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8059-8668","authenticated-orcid":false,"given":"Douglas A.","family":"Mata","sequence":"additional","affiliation":[{"name":"Foundation Medicine, Inc. Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana R.","family":"McKay","sequence":"additional","affiliation":[{"name":"University of California\u2010San Diego San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,15]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1603144"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.001"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/PO.17.00029"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1200\/PO.18.00283"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2011.07.001"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aam7344"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01055-3"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.01649"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.01868"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2214676"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1911440"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-0261"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-0146"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-0715"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.16033"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06461-2"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf9246"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2024.103684"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34109-8"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2022.09.010"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0237802"},{"key":"e_1_2_10_23_1","unstructured":"E. M.Schaeffer R. H.Lurie N.Adra et\u00a0al. \u201cNCCN Guidelines Version 4.2024 Prostate Cancer \u201dhttps:\/\/www.nccn.org\/home\/."},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.70.4627"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14410"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-020-6657-2"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euo.2023.11.014"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/oncolo\/oyac181"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-024-00526-9"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCO.0000000000000867"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17127-2"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2021.39.15_suppl.5505"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-24-0293"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41417-024-00815-2"}],"container-title":["Cancer Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.71489","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cam4.71489","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.71489","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T11:00:34Z","timestamp":1772967634000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cam4.71489"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/cam4.71489"],"URL":"https:\/\/doi.org\/10.1002\/cam4.71489","archive":["Portico"],"relation":{},"ISSN":["2045-7634","2045-7634"],"issn-type":[{"value":"2045-7634","type":"print"},{"value":"2045-7634","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"2025-09-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e71489"}}