目前针对乳腺癌患者进行BRCA检测的指南不足以检测出所有的突变携带者。
Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers.
作者信息
Grindedal Eli Marie, Heramb Cecilie, Karsrud Inga, Ariansen Sarah Louise, Mæhle Lovise, Undlien Dag Erik, Norum Jan, Schlichting Ellen
机构信息
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Norwegian National Advisory Unit on Women's Health, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
出版信息
BMC Cancer. 2017 Jun 21;17(1):438. doi: 10.1186/s12885-017-3422-2.
BACKGROUND
Identification of BRCA mutations in breast cancer (BC) patients influences treatment and survival and may be of importance for their relatives. Testing is often restricted to women fulfilling high-risk criteria. However, there is limited knowledge of the sensitivity of such a strategy, and of the clinical aspects of BC caused by BRCA mutations in less selected BC cohorts. The aim of this report was to address these issues by evaluating the results of BRCA testing of BC patients in South-Eastern Norway.
METHODS
1371 newly diagnosed BC patients were tested with sequencing and Multi Ligation Probe Amplification (MLPA). Prevalence of mutations was calculated, and BC characteristics among carriers and non-carriers compared. Sensitivity and specificity of common guidelines for BRCA testing to identify carriers was analyzed. Number of identified female mutation positive relatives was evaluated.
RESULTS
A pathogenic BRCA mutation was identified in 3.1%. Carriers differed from non-carriers in terms of age at diagnosis, family history, grade, ER/PR-status, triple negativity (TNBC) and Ki67, but not in HER2 and TNM status. One mutation positive female relative was identified per mutation positive BC patient. Using age of onset below 40 or TNBC as criteria for testing identified 32-34% of carriers. Common guidelines for testing identified 45-90%, and testing all below 60 years identified 90%. Thirty-seven percent of carriers had a family history of cancer that would have qualified for predictive BRCA testing. A Variant of Uncertain Significance (VUS) was identified in 4.9%.
CONCLUSIONS
Mutation positive BC patients differed as a group from mutation negative. However, the commonly used guidelines for testing were insufficient to detect all mutation carriers in the BC cohort. Thirty-seven percent had a family history of cancer that would have qualified for predictive testing before they were diagnosed with BC. Based on our combined observations, we suggest it is time to discuss whether all BC patients should be offered BRCA testing, both to optimize treatment and improve survival for these women, but also to enable identification of healthy mutation carriers within their families. Health services need to be aware of referral possibility for healthy women with cancer in their family.
背景
乳腺癌（BC）患者中BRCA突变的鉴定会影响治疗和生存，对其亲属也可能具有重要意义。检测通常仅限于符合高风险标准的女性。然而，对于这种策略的敏感性以及在未经过严格筛选的BC队列中由BRCA突变引起的BC的临床特征，人们了解有限。本报告的目的是通过评估挪威东南部BC患者的BRCA检测结果来解决这些问题。
方法
对1371例新诊断的BC患者进行测序和多重连接探针扩增（MLPA）检测。计算突变患病率，并比较携带者和非携带者的BC特征。分析用于识别携带者的BRCA检测常用指南的敏感性和特异性。评估已识别的女性突变阳性亲属的数量。
结果
发现致病性BRCA突变的比例为3.1%。携带者与非携带者在诊断年龄、家族史、分级、雌激素受体/孕激素受体状态、三阴性（TNBC）和Ki67方面存在差异，但在人表皮生长因子受体2（HER2）和肿瘤分期（TNM）状态方面无差异。每例突变阳性的BC患者可识别出一名突变阳性的女性亲属。以发病年龄低于40岁或TNBC作为检测标准可识别出32% - 34%的携带者。常用检测指南可识别出45% - 90%的携带者，对所有60岁以下患者进行检测可识别出90%的携带者。37%的携带者有癌症家族史，这本可使她们有资格接受预测性BRCA检测。发现意义未明的变异（VUS）的比例为4.9%。
结论
突变阳性的BC患者作为一个群体与突变阴性患者不同。然而，常用的检测指南不足以检测出BC队列中的所有突变携带者。37%的患者在被诊断为BC之前有癌症家族史，这本可使她们有资格接受预测性检测。基于我们的综合观察，我们认为是时候讨论是否应为所有BC患者提供BRCA检测了，这不仅是为了优化这些女性的治疗并提高生存率，也是为了能够识别其家族中的健康突变携带者。医疗服务机构需要意识到为家族中有癌症患者的健康女性提供转诊检测的可能性。
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