{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:14:42Z","timestamp":1785428082237,"version":"3.56.0"},"reference-count":34,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005788","name":"Medical University of Vienna","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005788","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/05n3x4p02","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00kkwkq76","id-type":"ROR","asserted-by":"publisher"}]},{"name":"AstraZeneca"},{"id":[{"id":"https:\/\/ror.org\/018nw3344","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Many studies evaluating central nervous system (CNS) metastases in breast cancer (BC) combine germline BRCA1 and BRCA2 pathogenic variant carriers, limiting gene-specific interpretation. We evaluated gene-specific overall survival (OS) after CNS metastasis and time to CNS involvement. Methods: We retrospectively identified BC patients with confirmed CNS metastases (1995\u20132022) from the Medical University of Vienna and the kConFab consortium. Germline status was classified as gBRCA1 PV, gBRCA2 PV, or non-carrier. Primary endpoint was OS from CNS metastasis diagnosis; secondary endpoint was CNS metastasis-free interval from primary BC diagnosis. Kaplan\u2013Meier\/log-rank tests were used for group comparisons. Multivariable Cox models assessed OS in complete cases, stratified by molecular subtype and adjusted for prognostic factors. Sensitivity analyses included subtype-adjusted and time-period models. Results: Among 115 patients (gBRCA1 n = 32, gBRCA2 n = 18, and non-carriers n = 65), median OS differed by germline status (p = 0.019): 20.0 months (95% CI 6.7\u201360.0) for gBRCA2 versus 7.1 months (95% CI 3.7\u201310.0) for gBRCA1 and 7.6 months (95% CI 3.4\u201312.0) for non-carriers. In subtype-stratified analyses, gBRCA1 showed similar mortality to non-carriers (HR 0.90, 95% CI 0.49\u20131.64, p = 0.730), while gBRCA2 showed a lower but non-significant hazard (HR 0.48, 95% CI 0.18\u20131.25, p = 0.131). Median CNS metastasis-free interval was longer for gBRCA2 (8.4 years) versus gBRCA1 (3.0 years) and non-carriers (3.1 years; p = 0.020). Sensitivity analyses were consistent. Conclusions: gBRCA2 carriers demonstrated longer unadjusted OS after CNS metastasis and a longer CNS metastasis-free interval compared with gBRCA1 carriers and non-carriers. However, these associations were attenuated and not statistically significant after adjustment, and should therefore be interpreted as hypothesis-generating. These findings supports further investigation of gene-specific CNS disease trajectories in larger cohorts.<\/jats:p>","DOI":"10.3390\/cancers18081240","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T10:29:08Z","timestamp":1776162548000},"page":"1240","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gene-Specific Outcomes After Central Nervous System Metastases in Germline BRCA1- and BRCA2-Associated Breast Cancer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7076-2043","authenticated-orcid":false,"given":"Alice","family":"Decaminada","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8297-118X","authenticated-orcid":false,"given":"Raute","family":"Sunder-Plassmann","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8269-7344","authenticated-orcid":false,"given":"Weang-Kee","family":"Ho","sequence":"additional","affiliation":[{"name":"Faculty of Medical and Life Sciences, Sunway University, Petaling Jaya 47500, Selangor, Malaysia"},{"name":"Cancer Research Malaysia, Subang Jaya 47500, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Muhr","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika M.","family":"Starzer","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division of Oncology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Sophie","family":"Berghoff","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division of Oncology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rupert","family":"Bartsch","sequence":"additional","affiliation":[{"name":"Department of Medicine I, Division of Oncology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1294-0027","authenticated-orcid":false,"given":"Christian F.","family":"Singer","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"kConFab Investigators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1063-5352","authenticated-orcid":false,"given":"Yen Y.","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3773","DOI":"10.1200\/JCO.20.01255","article-title":"Survival in Patients With Brain Metastases: Summary Report on the Updated Diagnosis-Specific Graded Prognostic Assessment and Definition of the Eligibility Quotient","volume":"38","author":"Sperduto","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1200\/OP.23.00794","article-title":"Breast Cancer Brain Metastasis: A Comprehensive Review","volume":"20","author":"Raghavendra","year":"2024","journal-title":"JCO Oncol. Pract."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1093\/neuonc\/noab101","article-title":"Epidemiology of brain metastases and leptomeningeal disease","volume":"23","author":"Lamba","year":"2021","journal-title":"Neuro Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"102324","DOI":"10.1016\/j.ctrv.2021.102324","article-title":"Targeting brain metastases in breast cancer","volume":"103","author":"Corti","year":"2022","journal-title":"Cancer Treat. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41582-020-0391-x","article-title":"Management of brain metastases according to molecular subtypes","volume":"16","author":"Soffietti","year":"2020","journal-title":"Nat. Rev. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/s11060-016-2075-3","article-title":"Brain metastasis in breast cancer: A comprehensive literature review","volume":"127","author":"Rostami","year":"2016","journal-title":"J. Neurooncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1200\/JCO.21.02314","article-title":"Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline","volume":"40","author":"Vogelbaum","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1016\/j.annonc.2021.07.016","article-title":"EANO\u2013ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours","volume":"32","author":"Guckenberger","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1159\/000362389","article-title":"Treatment of brain metastases","volume":"87","author":"Lukas","year":"2014","journal-title":"Oncology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s11912-026-01753-y","article-title":"Breast Cancer Brain Metastases: Current Understanding and Future Directions","volume":"28","author":"Alabdulrahman","year":"2026","journal-title":"Curr. Oncol. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2610","DOI":"10.1200\/JCO.20.00775","article-title":"Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial","volume":"38","author":"Lin","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3717","DOI":"10.1038\/s41591-024-03261-7","article-title":"Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: A phase 3b\/4 trial","volume":"30","author":"Harbeck","year":"2024","journal-title":"Nat. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.1038\/s41591-022-01935-8","article-title":"Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: A single-arm, phase 2 trial","volume":"28","author":"Bartsch","year":"2022","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1093\/neuonc\/noac144","article-title":"Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: The DEBBRAH trial","volume":"25","author":"Cortez","year":"2023","journal-title":"Neuro Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1056\/NEJMoa1706450","article-title":"Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation","volume":"377","author":"Robson","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1093\/annonc\/mdz012","article-title":"OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician\u2019s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer","volume":"30","author":"Robson","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1056\/NEJMoa1802905","article-title":"Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation","volume":"379","author":"Litton","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1016\/j.annonc.2020.08.2098","article-title":"Talazoparib versus chemotherapy in patients with germline BRCA1\/2-mutated HER2-negative advanced breast cancer: Final overall survival results from the EMBRACA trial","volume":"31","author":"Litton","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1200\/JCO.2021.39.15_suppl.1090","article-title":"Clinical outcomes in patients (pts) with a history of central nervous system (CNS) metastases receiving talazoparib (TALA) or physician\u2019s choice of chemotherapy (PCT) in the phase 3 EMBRACA trial","volume":"39","author":"Litton","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1002\/ijc.34525","article-title":"Olaparib efficacy in patients with germline BRCA-mutated, HER2-negative metastatic breast cancer: Subgroup analyses from the phase III OlympiAD trial","volume":"153","author":"Senkus","year":"2023","journal-title":"Int. J. Cancer"},{"key":"ref_21","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. GeneReviews((R)), Available online: https:\/\/europepmc.org\/article\/NBK\/nbk1247."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1200\/JCO.2002.09.023","article-title":"The pathology of familial breast cancer: Predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2","volume":"20","author":"Lakhani","year":"2002","journal-title":"J. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1158\/1055-9965.EPI-11-0775","article-title":"Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: Results from the Consortium of Investigators of Modifiers of BRCA1\/2 (CIMBA)","volume":"21","author":"Mavaddat","year":"2012","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/s41698-024-00761-0","article-title":"Breast cancer brain metastases genomic profiling identifies alterations targetable by immune-checkpoint and PARP inhibitors","volume":"8","author":"Giannoudis","year":"2024","journal-title":"NPJ Precis. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1093\/annonc\/mdy216","article-title":"Breast cancer brain metastases show increased levels of genomic aberration-based homologous recombination deficiency scores relative to their corresponding primary tumors","volume":"29","author":"Diossy","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"dju145","DOI":"10.1093\/jnci\/dju145","article-title":"DNA Double-Strand Break Repair Genes and Oxidative Damage in Brain Metastasis of Breast Cancer","volume":"106","author":"Woditschka","year":"2014","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"16129","DOI":"10.1002\/cam4.6267","article-title":"Risk of metastasis in BRCA2 carriers diagnosed with triple-negative breast cancer","volume":"12","author":"Moreno","year":"2023","journal-title":"Cancer Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/s41523-022-00407-z","article-title":"Incidence and impact of brain metastasis in patients with hereditary BRCA1 or BRCA2 mutated invasive breast cancer","volume":"8","author":"Garber","year":"2022","journal-title":"NPJ Breast Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1002\/cncr.32540","article-title":"Patterns of recurrence and metastasis in BRCA1\/BRCA2-associated breast cancers","volume":"126","author":"Song","year":"2020","journal-title":"Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.1093\/annonc\/mdi351","article-title":"Spectrum of breast cancer metastasis in BRCA1 mutation carriers: Highly increased incidence of brain metastases","volume":"16","author":"Albiges","year":"2005","journal-title":"Ann. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Ben-Zion Berliner, M., Yust-Katz, S., Lavie, I., Goldberg, Y., Kedar, I., and Yerushalmi, R. (2024). Central nervous system metastases in breast cancer patients with germline BRCA pathogenic variants compared to non-carriers: A matched-pair analysis. BMC Cancer, 24.","DOI":"10.1186\/s12885-024-11975-7"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1056\/NEJMra1001389","article-title":"Triple-Negative Breast Cancer","volume":"363","author":"Foulkes","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Tyran, M., Carbuccia, N., Garnier, S., Guille, A., Adela\u00efde, J., Finetti, P., Touzlian, J., Viens, P., Tallet, A., and Goncalves, A. (2019). A Comparison of DNA Mutation and Copy Number Profiles of Primary Breast Cancers and Paired Brain Metastases for Identifying Clinically Relevant Genetic Alterations in Brain Metastases. Cancers, 11.","DOI":"10.3390\/cancers11050665"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1038\/s41467-022-27987-5","article-title":"Mapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities","volume":"13","author":"Cosgrove","year":"2022","journal-title":"Nat. Commun."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/8\/1240\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T04:11:21Z","timestamp":1776312681000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/8\/1240"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,14]]},"references-count":34,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["cancers18081240"],"URL":"https:\/\/doi.org\/10.3390\/cancers18081240","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,14]]}}}