Fasching Peter A, Hu Chunling, Hart Steven N, Ruebner Matthias, Polley Eric C, Gnanaolivu Rohan D, Hartkopf Andreas D, Huebner Hanna, Janni Wolfgang, Hadji Peyman, Tesch Hans, Uhrig Sabrina, Ettl Johannes, Lux Michael P, Lüftner Diana, Wallwiener Markus, Wurmthaler Lena A, Goossens Chloë, Müller Volkmar, Beckmann Matthias W, Hein Alexander, Anetsberger Daniel, Belleville Erik, Wimberger Pauline, Untch Michael, Ekici Arif B, Kolberg Hans-Christian, Hartmann Arndt, Taran Florin-Andrei, Fehm Tanja N, Wallwiener Diethelm, Brucker Sara Y, Schneeweiss Andreas, Häberle Lothar, Couch Fergus J
Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
NPJ Breast Cancer. 2024 Jul 13;10(1):57. doi: 10.1038/s41523-024-00667-x.
Germline mutations in BRCA1 and BRCA2 (gBRCA1/2) are required for a PARP inhibitor therapy in patients with HER2-negative (HER2-) advanced breast cancer (aBC). However, little is known about the prognostic impact of gBRCA1/2 mutations in aBC patients treated with chemotherapy. This study aimed to investigate the frequencies and prognosis of germline and somatic BRCA1/2 mutations in HER2- aBC patients receiving the first chemotherapy in the advanced setting. Patients receiving their first chemotherapy for HER2- aBC were retrospectively selected from the prospective PRAEGNANT registry (NCT02338167). Genotyping of 26 cancer predisposition genes was performed with germline DNA of 471 patients and somatic tumor DNA of 94 patients. Mutation frequencies, progression-free and overall survival (PFS, OS) according to germline mutation status were assessed. gBRCA1/2 mutations were present in 23 patients (4.9%), and 33 patients (7.0%) had mutations in other cancer risk genes. Patients with a gBRCA1/2 mutation had a better OS compared to non-mutation carriers (HR: 0.38; 95%CI: 0.17-0.86). PFS comparison was not statistically significant. Mutations in other risk genes did not affect prognosis. Two somatic BRCA2 mutations were found in 94 patients without gBRCA1/2 mutations. Most frequently somatic mutated genes were TP53 (44.7%), CDH1 (10.6%) and PTEN (6.4%). In conclusion, aBC patients with gBRCA1/2 mutations had a more favorable prognosis under chemotherapy compared to non-mutation carriers. The mutation frequency of ~5% with gBRCA1/2 mutations together with improved outcome indicates that germline genotyping of all metastatic patients for whom a PARP inhibitor therapy is indicated should be considered.
对于人表皮生长因子受体2阴性（HER2-）的晚期乳腺癌（aBC）患者，BRCA1和BRCA2基因种系突变（gBRCA1/2）是PARP抑制剂治疗所必需的。然而，关于gBRCA1/2突变对接受化疗的aBC患者的预后影响知之甚少。本研究旨在调查晚期HER2-aBC患者首次接受化疗时种系和体细胞BRCA1/2突变的频率及预后情况。从前瞻性PRAEGNANT注册研究（NCT02338167）中回顾性选取首次接受HER2-aBC化疗的患者。对471例患者的种系DNA和94例患者的体细胞肿瘤DNA进行了26个癌症易感基因的基因分型。评估了根据种系突变状态的突变频率、无进展生存期和总生存期（PFS、OS）。23例患者（4.9%）存在gBRCA1/2突变，33例患者（7.0%）在其他癌症风险基因中有突变。与非突变携带者相比，gBRCA1/2突变患者的总生存期更好（HR：0.38；95%CI：0.17 - 0.86）。PFS比较无统计学意义。其他风险基因的突变不影响预后。在94例无gBRCA1/2突变的患者中发现了2例体细胞BRCA2突变。最常见的体细胞突变基因是TP53（44.7%）、CDH1（10.6%）和PTEN（6.4%）。总之，与非突变携带者相比，gBRCA1/2突变的aBC患者在化疗下预后更有利。gBRCA1/2突变频率约为5%以及预后改善表明，对于所有适合PARP抑制剂治疗的转移性患者，应考虑进行种系基因分型。
