Clinical Breast Care Project, Chan Soon-Shiong Institute for Molecular Medicine at Windber, Windber, PA 15963, USA.
Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Mil Med. 2021 Jul 1;186(7-8):e737-e742. doi: 10.1093/milmed/usaa485.
The majority of active duty service women (ADS) are young, have access to healthcare, and meet fitness standards set by the U.S. military, suggesting that ADS represent a healthy population at low risk of cancer. Breast cancer is, however, the most common cancer in ADS and may have a significant effect on troop readiness with lengthy absence during treatment and inability to return to duty after the treatment. The identification of unaffected ADS who carry germline mutations in cancer predisposition genes ("previvors") would provide the opportunity to prevent or detect cancer at an early stage, thus minimizing effects on troop readiness. In this study, we determined (1) how many high-risk ADS without cancer pursued genetic testing, (2) how many previvors employed risk-reducing strategies, and (3) the number of undiagnosed previvors within an ADS population.
The Clinical Breast Care Project (protocol WRNMMC IRB #20704) database of the Murtha Cancer Center/Walter Reed National Military Medical Center was queried to identify all ADS with no current or previous history of cancer. Classification as high genetic risk was calculated using National Comprehensive Cancer Network 2019 guidelines for genetic testing for breast, ovary, colon, and gastric cancer. The history of clinical genetic testing and risk-reducing strategies was extracted from the database. Genomic DNA from ADS with blood specimens available for research purposes were subjected to next-generation sequencing technologies using a cancer predisposition gene panel.
Of the 336 cancer-free ADS enrolled in the Clinical Breast Care Project, 77 had a family history that met National Comprehensive Cancer Network criteria for genetic testing for BRCA1/2 and 2 had a family history of colon cancer meeting the criteria for genetic testing for Lynch syndrome. Of the 28 (35%) high-risk women who underwent clinical genetic testing, 11 had pathogenic mutations in the breast cancer genes BRCA1 (n = 5), BRCA2 (n = 5), or CHEK2 (n = 1). Five of the six ADS who had a relative with a known pathogenic mutation were carriers of the tested mutation. All of the women who had pathogenic mutations detected through clinical genetic testing underwent prophylactic double mastectomy, and three also had risk-reducing salpingo-oophorectomy. Two (6%) of the 33 high-risk ADS tested only in the research setting had a family history of breast/ovarian cancer and carried pathogenic mutations: one carried a BRCA2 mutation, whereas the other carried a mutation in the colon cancer predisposition gene PMS2. No mutations were detected in the 177 low-risk women tested in the research setting.
Within this unaffected cohort of ADS, 23% were classified as high risk. Although all of the previvors engaged in risk-reduction strategies, only one-third of the high-risk women sought genetic testing. These data suggest that detailed family histories of cancer should be collected in ADS and genetic testing should be encouraged in those at high risk. The identification of previvors and concomitant use of risk-reduction strategies may improve health in the ADS and optimize military readiness by decreasing cancer incidence.
大多数现役女性（ADS）都很年轻，能够获得医疗保健，并且符合美国军队设定的健康标准，这表明 ADS 代表了癌症风险较低的健康人群。然而，乳腺癌是 ADS 中最常见的癌症，可能会对部队的准备状态产生重大影响，因为在治疗期间需要长时间缺勤，并且在治疗后无法重返工作岗位。确定携带种系突变的无癌 ADS （“先存者”），将有机会在早期预防或发现癌症，从而将对部队准备状态的影响降到最低。在这项研究中，我们确定了：（1）有多少无癌的高风险 ADS 接受了基因检测，（2）有多少先存者采用了降低风险的策略，以及（3）ADS 人群中未确诊的先存者数量。
查询 Murtha 癌症中心/沃尔特·里德国家军事医疗中心的临床乳房护理项目（协议 WRNMMC IRB #20704）数据库，以确定所有当前或以前没有癌症史的 ADS。使用 2019 年美国国家综合癌症网络的乳腺癌、卵巢癌、结肠癌和胃癌基因检测指南计算遗传风险高的分类。从数据库中提取临床基因检测和降低风险策略的历史记录。对有血液样本可供研究目的的 ADS 进行下一代测序技术，使用癌症易感性基因检测面板。
在参加临床乳房护理项目的 336 名无癌症的 ADS 中，有 77 人有家族史，符合 BRCA1/2 基因检测的国家综合癌症网络标准，有 2 人有家族史结肠癌符合林奇综合征基因检测标准。在 28 名（35%）接受临床基因检测的高风险女性中，有 11 人携带乳腺癌基因 BRCA1（n=5）、BRCA2（n=5）或 CHEK2（n=1）的致病性突变。有 6 名已知有致病性突变的亲属的 ADS 中，有 5 名是携带者。所有通过临床基因检测发现致病性突变的女性均接受了预防性双侧乳房切除术，其中 3 人还接受了预防性输卵管卵巢切除术。在研究环境中仅检测到 2 名（6%）高风险 ADS 有乳腺癌/卵巢癌家族史，携带致病性突变：一名携带 BRCA2 突变，另一名携带结肠癌易感性基因 PMS2 突变。在研究环境中检测的 177 名低风险女性未发现突变。
在这个未受影响的 ADS 队列中，有 23%被归类为高危。尽管所有的先存者都采取了降低风险的策略，但只有三分之一的高风险女性寻求基因检测。这些数据表明，应该在 ADS 中收集详细的癌症家族史，并鼓励高危人群进行基因检测。先存者的鉴定和同时使用降低风险的策略可能会改善 ADS 的健康状况，并通过降低癌症发病率来优化部队的战备状态。
