30年前，Mary-Claire King（哲学博士、美国癌症研究协会会士）及其同事首次证明了乳腺癌是可以遗传的。在他们发表于《科学》杂志上的开创性文章中，King等人发现了一个位于第17号染色体上的基因（后来命名为BRCA1），并报道该基因可导致乳腺癌易感性的遗传。这一发现推动了乳腺癌治疗和筛查的诸多进展，包括使用基因检测来识别乳腺癌患者的BRCA变异，从而可指导治疗方法的选择。
但是是否所有的乳腺癌患者都应该接受基因检测？在2020年12月8-11日在线举行的圣安东尼奥乳腺癌研讨会（SABCS）的最后一天，研究人员对这个问题进行了辩论。
通常来说，是否进行基因检测一般会参考美国国家综合癌症网络(NCCN)的指南。这些指南建议，只有符合特定标准（比如某些年龄组和癌症类型）的女性，才应该接受基因检测，所有患有乳腺癌的男性都应该接受基因检测。然而，美国乳腺外科学会最近建议，所有的乳腺癌患者都应该接受基因检测。
会议主持人，来自丹娜—法伯癌症研究所的Judy Garber（医学博士、公共卫生学硕士）邀请了该领域的两位专家——来自纪念斯隆-凯特琳癌症中心的Mark Robson（医学博士）和来自宾夕法尼亚大学的Susan Domchek（医学博士）——来讨论所有女性在确诊患有乳腺癌后接受基因检测的利弊。
详细内容请阅读下文
Thirty years ago, Mary-Claire King, PhD, FAACR, and colleagues were the first to demonstrate that breast cancer could be genetically inherited. In their seminal publication in Science, King and others mapped a gene—later named BRCA1—to chromosome 17, and reported that this gene was responsible for inherited susceptibility to breast cancer. This discovery set in motion a myriad of advancements in breast cancer treatment and screening, including the use of genetic testing to identify BRCA variants in patients with breast cancer to potentially guide treatment options.
But should all breast cancer patients receive genetic testing? This question was debated on the final day of this year’s San Antonio Breast Cancer Symposium (SABCS), held online December 8-11.
Decisions about genetic testing are typically shaped by guidelines from the National Comprehensive Cancer Network (NCCN). These guidelines suggest that only women who meet specific criteria, such as certain age groups and types of cancer, should receive genetic testing, and that all men with breast cancer should receive genetic testing. However, the American Society for Breast Surgery recently recommended that all patients with breast cancer should receive genetic testing.
Moderator of the session,Judy Garber, MD, MPH, from Dana-Farber Cancer Institute, invited two experts in the field—Mark Robson, MD, from Memorial Sloan Kettering Cancer Center, and Susan Domchek, MD, from the University of Pennsylvania—to discuss the pros and cons of all women receiving genetic testing upon diagnosis of breast cancer.
A CASE FOR UNSELECTED TESTING
Robson began his argument by highlighting two studies published in the Journal of Clinical Oncology, one published in 2018 and one published in 2020, which demonstrated that current NCCN criteria are somewhat insensitive for the detection of pathogenic variants. In both of these studies, a substantial portion of women who did not meet the NCCN criteria for genetic testing carried a germline pathogenic variant in predisposition genes. However, NCCN criteria were relatively sensitive in detecting BRCA1/2 variants. In the second study, expansion of the NCCN criteria to include all women ages 65 or younger resulted in more than 98 percent sensitivity for detecting BRCA1/2 variants, and over 90 percent sensitivity for the detection of variants in all nine predisposition genes analyzed.
Mark Robson, MD
Diagnostic yield for the identification of BRCA1/2 carriers is important for several reasons, Robson said. This information can help patients make more informed decisions about contralateral prophylactic mastectomy, can help clinicians to identify patients with metastatic disease as eligible for treatment with PARP inhibitors, and can potentially lead to the identification of family members who may also carry pathogenic variants through cascade testing.
An important consideration in unselected testing is whether or not such an approach is cost-effective. Robson pointed to a modeling study recently published in JAMA Oncology, which evaluated the lifetime costs and effects of unselected BRCA1/2/PALB2 testing of all patients with breast cancer compared with BRCA1/2 testing based on family history or clinical criteria. The authors found that the unselected testing approach was cost-effective.
Finally, Robson mentioned that unselected testing may help to reduce racial and socioeconomic inequities in testing access. “A policy of testing everyone who has breast cancer could potentially mitigate some of those inequities,” Robson said.
A CASE FOR RISK STRATIFICATION
Where does diagnostic screening end and population screening begin? This was the major theme of Domchek’s argument as she made her case to risk stratify patients for genetic testing.
Susan Domchek, MD
Domchek pointed out that having afirst-degree family member with breast cancer increases the likelihood ofcarrying a pathogenic variant. Disease phenotype, too, can increase the risk ofcarrying a pathogenic variant, as a substantial proportion of patients withtriple-negative breast cancer carry mutations in BRCA1/2. Finally, younger ageat diagnosis of breast cancer comes with a higher risk of having BRCA1/2mutations. These criteria help to shape the NCCN guidelines, and she said thatfew women with mutations in BRCA1/2/PALB2 are missed based on current NCCN criteria.
Domchek’s argument also focused on how overtesting can lead to overtreatment. Beyond BRCA1/2/PALB2, large panel testing identifies mutations in a variety of other genes, some of which have low penetrance and have questionable clinical utility, Domchek said. She noted that the detection of mutations to CHEK2 or APC that may not be pathogenic could lead patients to unnecessarily receive a preventative mastectomy. If you test for more, you will find more, whether relevant to the situation or not, Domchek said. Further, she noted that genetic testing for everyone is not risk-free, as it could potentially lead to inappropriate management if variants of unknown significance (VUS) are identified.
Domchek also noted that testing is not free, and it’s also not inexpensive—she said that the average cost submitted to insurance is around $1,500.
CONSENSUS?
Both Robson and Domchek agreed that genetic testing to identify mutations in BRCA1/2/PALB2 is important, and indicated that only a small portion of women harboring pathogenic variants in these three genes are missed based on current NCCN guidelines. They also agreed that a significant proportion of other variants identified in larger gene panels have less established clinical utility, and this information may have the potential to cause more harm than benefit.
When Garber polled the audience at the end of the debate, 60 percent agreed that all breast cancer patients should receive genetic testing, while 40 percent disagreed with an unselected testing approach.
Meanwhile, King remains a pivotal figure in this field of research. This year during SABCS, she delivered the William L. McGuire Award Lecture on the genetics of inherited breast cancer.
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