根据推测，大约10%的乳腺癌和卵巢癌由遗传原因引起。目前，已有针对乳腺癌患者的生殖细胞易感基因检测指南，以确定乳腺癌易感基因（BRCA）突变携带者，并且逐渐向多基因检测发展。不过，这些指南的检测适应证被认为过于严格，可能造成漏诊。
2018年12月7日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表德克萨斯达拉斯乳腺外科中心、田纳西纳什维尔乳腺医疗中心、哈佛大学麻省总医院、加利福尼亚撒马利亚好心人医院、北伊利诺伊高级外科治疗中心、南卡罗来纳罗珀·圣弗朗西斯医院、康奈尔大学威尔医学院、新墨西哥琳达·安·史密斯医院、加利福尼亚北谷乳腺专科医院、伊利诺伊阿灵顿海茨乳腺高级医疗中心、纽约州立大学斯塔滕岛医院、阿拉斯加乳腺专科医院、洛杉矶丹尼斯·霍姆斯医院、密歇根特洛伊乳腺综合医疗中心、亚利桑纳艾恩伍德癌症研究中心、宾夕法尼亚天普大学圣路加医院、夏威夷莱昂斯医院、弗吉尼亚切萨皮克地区医疗中心、加利福尼亚霍格医院、加利福尼亚拉古纳山乳腺癌治疗中心、靶向医学教育联盟、旧金山Invitae基因检测公司的研究报告，对美国国家综合癌症网络（NCCN）多基因检测指南确定乳腺癌患者致病突变的能力进行了评估。
该多中心前瞻研究于2017年4月～2018年9月，由20个癌症基因检测和咨询经验丰富的社区和学术机构，经伦理审查委员会批准，连续入组年龄18～90岁、尚未进行单基因或多基因检测的原有或新诊断乳腺癌患者1001例，知情同意后进行80个基因检测。通过符合《医疗保险便利与责任法案》的电子病例报告表格，收集患者人口统计学、诊断，表现分型和检测结果的信息。
结果，信息完整可靠的患者共计959例，符合和不符NCCN检测指南适应证的患者为479例和480例（49.95%、50.05%）。
总体而言，致病或可能致病突变患者83例（8.65%）。其中：
检测符合NCCN指征：检测结果致病或可能致病突变患者45例（9.39%）
检测不符NCCN指征：检测结果致病或可能致病突变患者38例（7.92%）
两组之间阳性结果差异无统计学意义（费希尔精确检验，P=0.4241）
因此，该研究结果表明，大约一半患者不符NCCN检测指南适应证，而将近一半临床可控的致病或可能致病突变乳腺癌患者被该检测指南漏诊，故推荐对所有被诊断为乳腺癌的患者进行多基因检测。
对此，密歇根大学癌症中心的遗传学家和肿瘤学家发表同期述评：乳腺癌患者基因检测进展、高质量决策与资源合理分配。
J Clin Oncol. 2018 Dec 7. [Epub ahead of print]
Underdiagnosis of Hereditary Breast Cancer: Are Genetic Testing Guidelines a Tool or an Obstacle?
Peter D. Beitsch, Pat W. Whitworth, Kevin Hughes, Rakesh Patel, Barry Rosen, Gia Compagnoni, Paul Baron, Rache Simmons, Linda Ann Smith, Ian Grady, Michael Kinney, Cynara Coomer, Karen Barbosa, Dennis R. Holmes, Eric Brown, Linsey Gold, Patricia Clark, Lee Riley, Samuel Lyons, Antonio Ruiz, Sadia Kahn, Heather MacDonald, Lisa Curcio, Mary Kay Hardwick, Shan Yang, Ed D. Esplin, Robert L. Nussbaum.
Dallas Surgical Group-Targeted Medical Education/Breast Care Network, Dallas, TX; Nashville Breast-Targeted Medical Education/Breast Care Network, Nashville, TN; Massachusetts General Hospital, Boston, MA; Good Samaritan Hospital-Targeted Medical Education/Breast Care Network, Los Gatos, CA; Advanced Surgical Care of Northern Illinois, Barrington, IL; Roper St Francis Healthcare, Charleston, SC; Weill Cornell Medicine, New York, NY; Linda Ann Smith, MD, Albuquerque, NM; North Valley Breast Clinic, Redding, CA; Center for Advanced Breast Care, Arlington Heights, IL; Staten Island University Hospital, Staten Island, NY; Alaska Breast Care Specialists, Anchorage, AK; Dennis R. Holmes, MD, Los Angeles, CA; Comprehensive Breast Care, Troy, MI; Ironwood Cancer and Research Center, Scottsdale, AZ; St Luke's University Health Network, Easton, PA; Lyons Care Associates, Kahului, HI; Chesapeake Regional Medical Center, Chesapeake, VA; Hoag Hospital, Newport Beach, CA; Breastlink, Laguna Hills, CA; Targeted Medical Education, Allentown, PA; Invitae, San Francisco, CA.
PURPOSE: An estimated 10% of breast and ovarian cancers result from hereditary causes. Current testing guidelines for germ line susceptibility genes in patients with breast carcinoma were developed to identify carriers of BRCA1/2 variants and have evolved in the panel-testing era. We evaluated the capability of the National Comprehensive Cancer Network (NCCN) guidelines to identify patients with breast cancer with pathogenic variants in expanded panel testing.
METHODS: An institutional review board-approved multicenter prospective registry was initiated with 20 community and academic sites experienced in cancer genetic testing and counseling. Eligibility criteria included patients with a previously or newly diagnosed breast cancer who had not undergone either single- or multigene testing. Consecutive patients 18 to 90 years of age were consented and underwent an 80-gene panel test. Health Insurance Portability and Accountability Act-compliant electronic case report forms collected information on patient demographics, diagnoses, phenotypes, and test results.
RESULTS: More than 1,000 patients were enrolled, and data records for 959 patients were analyzed; 49.95% met NCCN criteria, and 50.05% did not. Overall, 8.65% of patients had a pathogenic/likely pathogenic (P/LP) variant. Of patients who met NCCN guidelines with test results, 9.39% had a P/LP variant. Of patients who did not meet guidelines, 7.9% had a P/LP variant. The difference in positive results between these groups was not statistically significant (Fisher's exact test P = .4241).
CONCLUSION: Our results indicate that nearly half of patients with breast cancer with a P/LP variant with clinically actionable and/or management guidelines in development are missed by current testing guidelines. We recommend that all patients with a diagnosis of breast cancer undergo expanded panel testing.
DOI: 10.1200/JCO.18.01631
J Clin Oncol. 2018 Dec 7. [Epub ahead of print]
Advances in Genetic Testing in Patients With Breast Cancer, High-Quality Decision Making, and Responsible Resource Allocation.
Kara J. Milliron, Jennifer J. Griggs.
University of Michigan Cancer Center, Ann Arbor, MI.
DOI: 10.1200/JCO.18.01952
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