{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T11:01:46Z","timestamp":1774868506218,"version":"3.50.1"},"reference-count":43,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T00:00:00Z","timestamp":1774742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Contralateral breast cancer (CBC) is a significant concern among breast cancer survivors, particularly in those with moderator-high penetrance germline mutations such as BRCA1, BRCA2, CHEK2, and ATM. While radiotherapy (RT) is a crucial component of breast cancer (BC) treatment, its potential role in increasing CBC risk remains unclear. This systematic review and meta-analysis aim to evaluate the incidence of radiation-induced CBC in germline mutation carriers. Methods: Following PRISMA guidelines, we conducted a comprehensive search in six electronic databases (PubMed, Scopus, Cochrane Library, ProQuest, EBSCO, and Epistemonikos) for studies published fifteen years prior, up to August 2025. We included cohort and case\u2013control studies assessing the association between RT and CBC incidence in germline mutation carriers. A meta-analysis was performed using a random-effects model to estimate cumulative risk (CR) and rate ratios (RR). Results: Seven studies were included. The 5-year cumulative risk (CR) of contralateral breast cancer (CBC) was 0.55 for BRCA1\/2, 0.89 for ATM, and 0.80 for CHEK2 carriers. At 10 years, overall CR increased to 0.65, with ATM and CHEK2 remaining high. Rate ratio (RR) analysis showed a significant risk for ATM (2.98), while overall RR indicated more than a two-fold increased CBC risk with radiotherapy (RR = 2.70 common-effect; 2.53 random-effects). Conclusions: Radiotherapy significantly increases contralateral breast cancer risk, particularly in ATM and CHEK2 carriers, emphasizing the importance of personalized genetic risk stratification in treatment decisions.<\/jats:p>","DOI":"10.3390\/cancers18071106","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T09:57:24Z","timestamp":1774864644000},"page":"1106","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Risk of Radiation-Associated Contralateral Breast Cancer in Germline Mutation Carriers: A Meta-Analysis and Systematic Review"],"prefix":"10.3390","volume":"18","author":[{"given":"Christina Hari Nawangsih","family":"Prihharsanti","sequence":"first","affiliation":[{"name":"Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Universitas Diponegoro, Semarang 50275, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2659-9923","authenticated-orcid":false,"given":"Yan Wisnu","family":"Prajoko","sequence":"additional","affiliation":[{"name":"Department of Oncology Surgery, Faculty of Medicine, Universitas Diponegoro, Semarang 50275, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7725-8263","authenticated-orcid":false,"given":"Danendra Rakha Putra","family":"Respati","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Universitas Diponegoro, Semarang 50275, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3821-8446","authenticated-orcid":false,"given":"Kevin Christian","family":"Tjandra","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Universitas Diponegoro, Semarang 50275, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fitri","family":"Mutmainnah","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Universitas Andalas, Padang 25163, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maritza Bintang","family":"Rismadha","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Universitas Diponegoro, Semarang 50275, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5450-4568","authenticated-orcid":false,"given":"Annisa Salsabilla Dwi","family":"Nugrahani","sequence":"additional","affiliation":[{"name":"Medical Science in Clinical Investigation, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0660-4037","authenticated-orcid":false,"given":"Davendra Putra","family":"Aryasatya","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Universitas Diponegoro, Semarang 50275, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea Valerie","family":"Manik","sequence":"additional","affiliation":[{"name":"Oncology Research, University of Manchester, Manchester M13 9PL, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2151-0854","authenticated-orcid":false,"given":"Fahrul","family":"Nurkolis","sequence":"additional","affiliation":[{"name":"Program of Basic Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya 60131, Indonesia"},{"name":"Medical Research Center of Indonesia, Surabaya 60281, Indonesia"},{"name":"Institute for Research and Community Service, State Islamic University of Sunan Kalijaga (UIN Sunan Kalijaga), Yogyakarta 55281, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward Kurnia Setiawan","family":"Limijadi","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology, Faculty of Medicine, Universitas Diponegoro, Semarang 50275, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.clbc.2023.10.003","article-title":"Unlocking the power of the homing phenomenon: Why breast conserving surgery outshines mastectomy in overall survival","volume":"24","author":"Mokbel","year":"2024","journal-title":"Clin. Breast Cancer"},{"key":"ref_2","first-page":"855","article-title":"Epidemiology of contralateral breast cancer","volume":"8","author":"Chen","year":"1999","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1016\/S0959-8049(98)00208-1","article-title":"Evolving perspectives in contralateral breast cancer","volume":"34","author":"Dawson","year":"1998","journal-title":"Eur. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1200\/JCO.22.01239","article-title":"Contralateral breast cancer risk among carriers of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2","volume":"41","author":"Yadav","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.soc.2023.03.002","article-title":"Advances in radiotherapy for breast cancer","volume":"32","author":"Upadhyay","year":"2023","journal-title":"Surg. Oncol. Clin. N. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1056\/NEJM199203193261201","article-title":"Cancer in the contralateral breast after radiotherapy for breast cancer","volume":"326","author":"Boice","year":"1992","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0167-8140(01)00369-3","article-title":"Contralateral breast cancer risk","volume":"60","author":"Unnithan","year":"2001","journal-title":"Radiother. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"98","DOI":"10.3892\/mco.2017.1260","article-title":"Current condition of genetic medicine for hereditary breast cancer","volume":"7","author":"Yoshida","year":"2017","journal-title":"Mol. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1056\/NEJMsr1501341","article-title":"Gene-panel sequencing and the prediction of breast-cancer risk","volume":"372","author":"Easton","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s10549-014-2890-1","article-title":"Surgical management of breast cancer in BRCA-mutation carriers: A systematic review and meta-analysis","volume":"144","author":"Valachis","year":"2014","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"E1200","DOI":"10.1002\/humu.21202","article-title":"Characterization of BRCA1 and BRCA2 deleterious mutations in unilateral and bilateral breast cancer: WECARE Study","volume":"31","author":"Borg","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Leung, J.H., Karmakar, R., Mukundan, A., Thongsit, P., Chen, M.M., Chang, W.Y., and Wang, H.C. (2024). Systematic meta-analysis of computer-aided detection of breast cancer using hyperspectral imaging. Bioengineering, 11.","DOI":"10.3390\/bioengineering11111060"},{"key":"ref_13","unstructured":"(2004). CHEK2 Breast Cancer Case-Control Consortium. CHEK2*1100delC and susceptibility to breast cancer. Am. J. Hum. Genet., 74, 1175\u20131182."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5912","DOI":"10.1038\/sj.onc.1209877","article-title":"The CHEK2 gene and inherited breast cancer susceptibility","volume":"25","author":"Nevanlinna","year":"2006","journal-title":"Oncogene"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s13058-024-01765-1","article-title":"Genome-wide association study of contralateral breast cancer","volume":"26","author":"Sun","year":"2024","journal-title":"Breast Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: Updated guideline","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"108602","DOI":"10.1016\/j.envint.2024.108602","article-title":"ROBINS-E tool for bias assessment","volume":"186","author":"Higgins","year":"2024","journal-title":"Environ. Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1002\/jrsm.1411","article-title":"robvis: Visualization tool for bias assessment","volume":"12","author":"McGuinness","year":"2021","journal-title":"Res. Synth. Methods"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"R26","DOI":"10.1186\/bcr1668","article-title":"Radiation-induced breast cancer risk identification","volume":"9","author":"Broeks","year":"2007","journal-title":"Breast Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1200\/JCO.22.00833","article-title":"BRCA-CRisk prediction model","volume":"41","author":"Sun","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16142","DOI":"10.1002\/cam4.6272","article-title":"CHEK2 variant and CBC risk","volume":"12","author":"Morra","year":"2023","journal-title":"Cancer Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1038\/bjc.2014.306","article-title":"CHEK2 survival outcomes","volume":"111","author":"Kriege","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s10549-015-3597-7","article-title":"Radiotherapy in BRCA carriers","volume":"154","author":"Drooger","year":"2015","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1016\/j.ejca.2013.04.028","article-title":"CBC after radiotherapy in BRCA carriers","volume":"49","author":"Bernstein","year":"2013","journal-title":"Eur. J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1093\/jnci\/djaa031","article-title":"Radiation and genetic variants in CBC risk","volume":"112","author":"Reiner","year":"2020","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_26","first-page":"1318","article-title":"CBC risk in BRCA1\/2 with radiation","volume":"115","author":"Barele","year":"2023","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s10549-010-0894-z","article-title":"Local therapy in BRCA mutation carriers","volume":"121","author":"Pierce","year":"2010","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1023\/B:BREA.0000010697.49896.03","article-title":"CHEK2 mutation and CBC risk","volume":"83","author":"Broeks","year":"2004","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_29","first-page":"728","article-title":"CHEK2 mutation and CBC risk","volume":"98","author":"Mellemkjaer","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.ajhg.2023.02.003","article-title":"Germline variants and CBC risk","volume":"110","author":"Morra","year":"2023","journal-title":"Am. J. Hum. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1200\/JCO.2004.04.033","article-title":"Contralateral breast cancer in BRCA carriers","volume":"22","author":"Metcalfe","year":"2004","journal-title":"J. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5887","DOI":"10.1200\/JCO.2008.19.9430","article-title":"CBC risk in BRCA mutation carriers","volume":"27","author":"Graeser","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s13053-024-00300-9","article-title":"Breast cancer and ATM mutations","volume":"22","author":"Seca","year":"2024","journal-title":"Hered. Cancer Clin. Pract."},{"key":"ref_34","first-page":"1502","article-title":"Risk-reducing mastectomy outcomes","volume":"31","author":"Hooning","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2394","DOI":"10.1056\/NEJMoa2105215","article-title":"Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer","volume":"384","author":"Tutt","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1093\/annonc\/mdz012","article-title":"OlympiAD final survival results","volume":"30","author":"Robson","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1056\/NEJMoa1802905","article-title":"Talazoparib in advanced breast cancer","volume":"379","author":"Litton","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1667\/RADE-23-00014.1","article-title":"Trends in radiation dose to contralateral breast","volume":"200","author":"Watt","year":"2023","journal-title":"Radiat. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1051\/radiopro\/2022029","article-title":"3DCRT breast planning evaluation study","volume":"57","author":"Saeed","year":"2022","journal-title":"Radioprotection"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"567","DOI":"10.2147\/BCTT.S463024","article-title":"IMRT versus 3DCRT dosimetry comparison","volume":"16","author":"Ghazy","year":"2024","journal-title":"Breast Cancer Targets Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"349","DOI":"10.4048\/jbc.2022.25.e37","article-title":"IMRT and VMAT in breast cancer","volume":"25","author":"Chang","year":"2022","journal-title":"J. Breast Cancer"},{"key":"ref_42","first-page":"e40","article-title":"Image-guided brachytherapy in cervical cancer","volume":"31","author":"Liu","year":"2020","journal-title":"J. Gynecol. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.ijrobp.2021.05.110","article-title":"Proton therapy for breast cancer: A consensus statement from the Particle Therapy Cooperative Group (PTCOG) Breast Cancer Subcommittee","volume":"111","author":"Mutter","year":"2021","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/7\/1106\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T10:10:32Z","timestamp":1774865432000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/7\/1106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,29]]},"references-count":43,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["cancers18071106"],"URL":"https:\/\/doi.org\/10.3390\/cancers18071106","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,29]]}}}