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Title: Overall Survival and Clinical Characteristics of BRCA-Associated Cholangiocarcinoma: A Multicenter Retrospective Study.
Author: Golan T, Raitses-Gurevich M, Kelley RK, Bocobo AG, Borgida A, Shroff RT, Holter S, Gallinger S, Ahn DH, Aderka D, Apurva J, Bekaii-Saab T, Friedman E, Javle M.
Journal: Oncologist; 2017 Jul; 22(7):804-810. PubMed ID: 28487467.
Abstract:
BACKGROUND: Biliary tract malignancies, in particular cholangiocarcinomas (CCA), are rare tumors that carry a poor prognosis. BRCA2 mutation carriers have an increased risk of developing CCA with a reported relative risk of ∼5 according to the Breast Cancer Linkage Consortium. In addition to this risk, there are potential therapeutic implications in those harboring somatic and/or germline (GL) BRCA mutations. Therefore, it is important to define the clinical characteristics of GL/somatic BRCA1/2 variants in CCA patients. MATERIALS AND METHODS: We performed a multicenter retrospective analysis of CCA patients diagnosed between January 2000 and December 2013 with GL or somatic variants in BRCA1/2 genes detected by GL mutations testing and/or by tumor next generation sequencing. Cases were identified from clinical databases at participating institutions. Data including demographics, clinical history, surgical procedures, and systemic chemotherapy or radiation were extracted from patients' records. RESULTS: Overall, 18 cases were identified: 5 carriers of GL BRCA1/2 mutations (4 BRCA2; 1 BRCA1) and 13 harboring somatic variations (7 BRCA1; 6 BRCA2). Mean age at diagnosis was 60, SD ± 10 years (range 36-75 years), with male and female prevalence rates of 61.2% and 38.8%, respectively. Stage at diagnosis was I (n = 4), II (n = 3), III (n = 3), and IV (n = 8). Six patients had extrahepatic CCA and the rest intrahepatic CCA. Thirteen patients received platinum-based therapy and four were treated with poly ADP ribose polymerase inhibitors, of whom one experienced sustained disease response with a progression-free survival of 42.6 months. Median overall survival from diagnosis for patients with stage I/II in this study was 40.3 months (95% confidence interval [CI], 6.73-108.15) and with stages III/IV was 25 months (95% CI, 15.23-40.57). CONCLUSION: BRCA-associated CCA is uncommon. This multicenter retrospective study provides a thorough clinical analysis of a BRCA-associated CCA cohort, which can serve as a benchmark for future development and design of expanded analyses and clinical trials. IMPLICATIONS FOR PRACTICE: BRCA-associated CCA is uncommon but a very important subtype of hepatic malignancies, due to its rising prevalence. Better clinical characterization of this subtype might allow application of targeted therapy for CCA patients with germline or somatic mutations in BRCA1/2 genes, especially due to previously reported success of such therapies in other BRCA-associated malignancies. Thus this study, first of its kind, provides a basis for future multi-centered analyses in larger cohorts, as well as clinical trials. Additionally, this study emphasizes the importance of both germline and somatic genotyping for all CCA patients. 摘要 背景. 胆道恶性肿瘤, 尤其是胆管癌（CCA）是一类预后不良的罕见肿瘤。BRCA2突变携带者罹患CCA的风险增加, 乳腺癌联合协作组报告的相对风险约为5。除上述风险以外, 这对于携带体细胞和/或胚系（GL）BRCA突变的患者而言还具有潜在治疗意义。因此, 确定CCA患者中GL/体细胞BRCA1/2变异体的临床特征至关重要。 材料和方法. 我们针对2000年1月至2013年12月期间诊断的携带GL或体细胞BRCA1/2基因变异体（通过GL突变检测方法和/或新一代肿瘤测序技术检测）的CCA患者进行了一项多中心回顾性分析。从参与机构的临床数据库中检索病例。研究数据包括人口统计学、临床病史、手术方式以及全身化疗或放疗, 以上信息摘自患者记录。 结果. 共计检索到18例病例：5例携带GL BRCA1/2突变（4例BRCA2；1例BRCA1）, 13例携带体细胞变异（7例BRCA1；6例BRCA2）。诊断时的平均年龄为60岁, SD±10岁（范围：36‐75岁）, 男性和女性的患病率分别为61.2%和38.8%。诊断时的疾病分期包括I期（n=4）、II期（n=3）、III期（n=3）和IV期（n=8）。6例患者为肝外CCA, 其余为肝内CCA。13例患者接受以铂类药物为基础的治疗, 4例患者接受多聚ADP核糖聚合酶抑制剂（PARPi）治疗, 其中1例患者获得了持久性疾病缓解, 无进展生存期为42.6个月。在本研究中, 自诊断时起, I/II期患者的中位总生存期为40.3个月[95%置信区间（CI）：6.73‐108.15], III/IV期患者的中位总生存期为25个月（95% CI：15.23‐40.57）。 结论. BRCA相关性CCA并不常见。本项多中心回顾性研究针对一个BRCA相关性CCA队列进行了全面的临床分析, 在日后开发和设计扩展分析和临床试验时可以此作为基准。

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