晚期患者要不要检测乳腺癌易感基因

　　BRCA1和BRCA2等乳腺癌易感基因是重要的抑癌基因，一旦发生种系突变，容易发生乳腺癌等恶性肿瘤，而且对铂类或PARP抑制剂比较敏感、对其他化疗或靶向药物不太敏感。目前，乳腺癌易感基因检测主要用于尚未发生乳腺癌的高风险女性，或者用于预测早期乳腺癌术后患者对化疗或靶向治疗的效果。对于晚期乳腺癌患者，乳腺癌易感基因检测的临床意义尚不明确。

　　2021年3月29日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表德国埃尔朗根纽伦堡大学、法兰克福大学、慕尼黑理工大学、萨尔茨科滕圣约瑟夫医院、帕德博恩乳腺协作中心、安斯巴赫应用技术大学、柏林大学夏里特医院、柏林太阳神医院、海德堡大学、汉堡大学、博特罗普玛丽医院、乌尔姆大学、德累斯顿理工大学、亥姆霍兹中心、弗莱堡大学、杜塞尔多夫大学、图宾根大学、美国梅奥（妙佑）医学中心的PRAEGNANT研究报告，调查了晚期乳腺癌患者的乳腺癌易感基因突变率、突变患者临床特征、突变对患者生存结局的影响。

PRAEGNANT (NCT02338167): Prospective Academic Translational Research Network for the Optimization of the Oncological Health Care Quality in the Adjuvant and Advanced/Metastatic Setting: Health Care Research, Pharmacogenomics, Biomarkers, Health Economics

　　该多中心大样本前瞻队列研究于2014年7月～2018年3月对2595例晚期乳腺癌患者进行种系DNA癌症易感基因突变测序，将已知乳腺癌易感基因突变率与前瞻登记数据库非晚期乳腺癌患者采用相同测序方法和公开数据库参考对照者的测序结果进行比较，对突变状态和肿瘤特征与无进展生存和总生存的相关性进行分析。

　　结果发现，271例患者（10.4%）检出12种已知乳腺癌易感基因（包括BRCA1和BRCA2）种系突变，129例患者（5.0%）检出BRCA1或BRCA2种系突变。

　　BRCA1突变携带者与非突变携带者相比，脑转移比例较高（27.1%比12.8%）。

　　晚期乳腺癌患者与非晚期乳腺癌患者相比，突变比例显著较高（10.4%比6.6%，P<0.01）。

　　突变与未突变相比，晚期乳腺癌患者的无进展生存或总生存相似。

　　因此，该研究结果表明，对于晚期乳腺癌患者，由于BRCA1和BRCA2以及其他乳腺癌易感基因种系突变率较高，故可考虑进行多基因组合检测。虽然晚期乳腺癌突变携带者与非突变携带者的生存结局相似，但是肿瘤特征差异对于目前的治疗以及将来的靶向治疗研究都有意义。

J Clin Oncol. 2021 Mar 29. Online ahead of print.

Mutations in BRCA1/2 and Other Panel Genes in Patients With Metastatic Breast Cancer - Association With Patient and Disease Characteristics and Effect on Prognosis.

Fasching PA, Yadav S, Hu C, Wunderle M, Haberle L, Hart SN, Rübner M, Polley EC, Lee KY, Gnanaolivu RD, Hadji P, Hübner H, Tesch H, Ettl J, Overkamp F, Lux MP, Ekici AB, Volz B, Uhrig S, Lüftner D, Wallwiener M, Müller V, Belleville E, Untch M, Kolberg HC, Beckmann MW, Reis A, Hartmann A, Janni W, Wimberger P, Taran FA, Fehm TN, Wallwiener D, Brucker SY, Schneeweiss A, Hartkopf AD, Couch FJ.

Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; University Hospital Erlangen, Erlangen, Germany; Frankfurt Center of Bone Health, Frankfurt, Germany; Bethanien Hospital Frankfurt, Frankfurt, Germany; Technical University of Munich, Munich, Germany; Oncologianova GmbH, Recklinghausen, Germany; St Josefs-Krankenhaus, Salzkotten, Germany; Kooperatives Brustzentrum Paderborn, Paderborn, Germany; Ansbach University of Applied Sciences, Ansbach, Germany; Charité University Hospital, Berlin, Campus Benjamin Franklin, Berlin, Germany; Helios Clinics Berlin Buch, Berlin, Germany; University of Heidelberg, Heidelberg, Germany; German Cancer Research Center, Heidelberg, Germany; German Cancer Consortium, Heidelberg, Germany; National Center for Tumor Diseases, Heidelberg, Germany; Hamburg-Eppendorf University Medical Center, Hamburg, Germany; ClinSol GmbH & Co KG, Würzburg, Germany; Marienhospital Bottrop, Bottrop, Germany; Ulm University Hospital, Ulm, Germany; Technical University of Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany; University Hospital Freiburg, Freiburg, Germany; University Hospital Düsseldorf, Düsseldorf, Germany; University of Tuebingen, Tuebingen, Germany; Mayo Clinic, Rochester, MN.

PURPOSE: Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome.

PATIENTS AND METHODS: Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed.

RESULTS: Germline mutations in 12 established BC predisposition genes (including BRCA1 and BRCA2) were detected in 271 (10.4%) patients. A mutation in BRCA1 or BRCA2 was seen in 129 patients (5.0%). BRCA1 mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% v 6.6%, P < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC.

CONCLUSION: Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in BRCA1/2 and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies.

PMID: 33780288

DOI: 10.1200/JCO.20.01200