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Targeted next-generation sequencing was performed on circulating tumor DNA (ctDNA) extracted from blood collected at base line and progression on olaparib (Guardant360). The primary objective was to evaluate the frequency of\n                      <jats:italic>BRCA1\/2<\/jats:italic>\n                      reversion mutations in this group.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      From November 2021 to October 2023, 60 patients were enrolled. The median age was 50.5\u00a0years (32\u201385). Of these, 12 (20.0%) had germline\n                      <jats:italic>BRCA1<\/jats:italic>\n                      mutation and 48 (80.0%) had germline\n                      <jats:italic>BRCA2<\/jats:italic>\n                      mutation. The median number of prior chemotherapies was 2 (0\u20137). Two patients had received platinum. Among patients with tumor progression on olaparib who had available ctDNA results,\n                      <jats:italic>BRCA1\/2<\/jats:italic>\n                      reversion mutations were identified in 25.0% (2\/8; 95% CI 3.2\u201365.1%) with germline\n                      <jats:italic>BRCA1<\/jats:italic>\n                      mutation and 23.5% (8\/34, 95% CI 10.7\u201341.2%) with germline\n                      <jats:italic>BRCA2<\/jats:italic>\n                      mutation. In one patient,\n                      <jats:italic>BRCA2<\/jats:italic>\n                      reversion mutations were found in ctDNA seven months before radiological confirmation of progression on olaparib and again after progression. Among the ten cases with\n                      <jats:italic>BRCA1\/2<\/jats:italic>\n                      reversion mutations, all but one case involved secondary indels on primary indel sites. Reversion mutations were not observed in the C-terminal regions of\n                      <jats:italic>BRCA1\/2<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>BRCA1\/2<\/jats:italic>\n                      reversion mutations were detected in ctDNA as a mechanism of resistance to olaparib. Certain genomic regions and mutation types appeared to be particularly prone to reversion mutations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial registration<\/jats:title>\n                    <jats:p>UMIN000046007.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s12282-026-01855-2","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T09:15:04Z","timestamp":1775812504000},"page":"790-797","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["BRCA1\/2 Reversion Mutations in Japanese Patients with Metastatic Breast Cancer Progressing on Olaparib: OLIVE (WJOG15321B)"],"prefix":"10.1007","volume":"33","clinical-trial-number":[{"clinical-trial-number":"umin000046007","registry":"10.18810\/umin-japan"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8396-9121","authenticated-orcid":false,"given":"Hitomi","family":"Sakai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rika","family":"Kusumoto-Matsuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"Hosonaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Nozawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Futamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Tanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Mukohara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Shiraishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Toyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Yasojima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriyuki","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Iwasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobumichi","family":"Takeuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Tada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuko","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natsuko","family":"Chiba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshimi","family":"Takano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junji","family":"Tsurutani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"1855_CR1","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1056\/NEJMoa1706450","volume":"377","author":"M Robson","year":"2017","unstructured":"Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. 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MF received honoraria from Chugai and Daiichi Sankyo. TM received research funding (to the institution) from MSD, AstraZeneca, Eisai, Sanofi, Novartis Pharma, Bayer, ONO Pharmaceutical, Daiichi Sankyo, Chugai Pharmaceutical, Pfizer, Gilead Sciences, Merck Biopharma, Seagen, Astellas Pharma, Sysmex, and Exact Sciences; and honoraria from Terumo, Bayer, MICIN, Kyowa Kirin, Daiichi Sankyo, Eli Lilly, MI-Force, AstraZeneca, Eisai, Taiho Pharmaceutical, Chugai Pharmaceutical, Shionogi, Pfizer, and Ono Pharmaceutical. He is an advisory board member of Pfizer and AstraZeneca. TaT received honoraria from Chugai, Daiichi Sankyo, Pfizer, MSD, Eli Lilly, Novartis, and Taiho. HT received honoraria from Chugai Pharmaceutical, Eli Lilly, Pfizer, and Daiichi Sankyo. KS received honoraria for lectures from Takeda Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., and Qiagen, Inc., and honoraria for manuscript writing from Life Technologies Japan Ltd. NC received research funding from AstraZeneca outside the submitted work. ToT received honoraria from Daiichi Sankyo, Eli Lilly, and Gilead Sciences. JT received research funding from Daiichi Sankyo Co., Ltd., outside the submitted work; honoraria from Daiichi Sankyo Co., Ltd., AstraZeneca K.K., Eli Lilly Japan K.K., Pfizer Japan Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Taiho Pharmaceutical Co., Ltd., MSD K.K., and Gilead Sciences, Inc.; consulting fees from Daiichi Sankyo Co., Ltd., AstraZeneca K.K., Seagen Inc., Pfizer Japan Inc., and Gilead Sciences, Inc.; and his institution received research funding from Eli Lilly Japan K.K., Kyowa Kirin Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., MSD K.K., and Eisai Co., Ltd., outside the submitted work. All other authors declare no competing financial or non-financial interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Study protocol was approved by the institutional review board (Approval number: 21-029-B). Informed consent was obtained from all participants involved in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}}]}}