Breast Services Section, Department of General Surgery, Cleveland Clinic, Cleveland, OH; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
Department of Hospital Medicine, Cleveland Clinic, Cleveland, OH.
J Am Coll Surg. 2018 Apr;226(4):560-565. doi: 10.1016/j.jamcollsurg.2017.12.037. Epub 2018 Jan 31.
With the advent of multigene panel testing for breast cancer patients, germline mutations with unknown association with cancer risk, known as variants of uncertain significance (VUS), are being increasingly identified. Some studies have shown higher rates of contralateral prophylactic mastectomies (CPM) in these patients, despite lack of evidence to support this intervention. We analyzed surgical choices in patients who were identified to have VUS.
A retrospective review was performed of patients with triple-negative breast cancer treated at a single institution after multigene panel tests became available (September 1, 2013 to February 28, 2017). Rates of genetic testing, results of testing, and surgical decision making were evaluated. Chi-square or Fisher's exact test was used to compare categorical variables. A p value <0.05 was considered statistically significant.
There were 477 triple-negative breast cancer patients identified; 331 met established criteria for genetic testing and 226 (68.3%) underwent genetic testing (multigene panel, n = 130 and BRCA1/2 testing, n = 96). All of them received risk-appropriate genetic counseling and follow-up. Of these, 29 (12.8%) patients had pathogenic mutations in BRCA1/2 or PALB2 (Mut+), 42 (18.6%) had VUS (VUS+), and 155 (68.6%) had no mutations identified (Mut-). Variants of uncertain significance in 6 of 42 patients (14.3%) were later reclassified as normal variants. Eighty-eight percent of Mut+ patients underwent CPM compared with 20.1% of Mut- and 21.4% of VUS+ patients (p < 0.001 for both). Rates of CPM were not significantly different between VUS+ and Mut- (p = 0.37). Multigene panel testing detected pathogenic mutations in non-breast cancer-associated genes in 6 patients, with significant management implications.
When combined with risk-appropriate genetic counseling, detection of VUS did not lead to excessive CPM in this cohort of triple-negative breast cancer patients. Furthermore, panel testing detected mutations in non-breast cancer-associated genes, which had significant implications on management and outcomes.
随着多基因panel 检测在乳腺癌患者中的应用，越来越多的种系突变被发现，这些突变与癌症风险相关，但目前尚不清楚其意义，被称为意义未明的变异（VUS）。一些研究表明，这些患者的对侧预防性乳房切除术（CPM）发生率更高，尽管缺乏支持这种干预的证据。我们分析了在单中心接受多基因panel 检测的三阴性乳腺癌患者的手术选择。
对 2013 年 9 月 1 日至 2017 年 2 月 28 日期间在一家机构接受治疗的三阴性乳腺癌患者进行了回顾性分析。评估了基因检测的比例、检测结果和手术决策。采用卡方检验或 Fisher 精确检验比较分类变量。p 值<0.05 被认为具有统计学意义。
共确定了 477 例三阴性乳腺癌患者；331 例符合基因检测的既定标准，226 例（68.3%）接受了基因检测（多基因 panel 检测 n=130 例，BRCA1/2 检测 n=96 例）。所有患者均接受了风险适当的遗传咨询和随访。其中，29 例（12.8%）患者的 BRCA1/2 或 PALB2 存在致病性突变（Mut+），42 例（18.6%）患者存在意义未明的变异（VUS+），155 例（68.6%）患者未发现突变（Mut-）。42 例患者中的 6 例（14.3%）的意义未明的变异后来被重新分类为正常变异。与 Mut-和 VUS+患者相比，88%的 Mut+患者接受了 CPM，而 Mut-和 VUS+患者分别为 20.1%和 21.4%（两者均 p<0.001）。VUS+与 Mut-患者的 CPM 发生率无显著差异（p=0.37）。多基因 panel 检测在 6 例患者中发现了非乳腺癌相关基因的致病性突变，对管理有重要意义。
在这组三阴性乳腺癌患者中，与风险适当的遗传咨询相结合，VUS 的检测并未导致 CPM 过度增加。此外，panel 检测还发现了非乳腺癌相关基因的突变，这对管理和结果有重大影响。
