老年女性要不要检测乳腺癌易感基因

　　乳腺癌易感基因检测对于乳腺癌的预防和治疗决策至关重要。对于有乳腺癌或卵巢癌家族史、德裔犹太人血统、雌激素受体阴性等风险因素的年轻女性，乳腺癌易感基因可遗传致病变异率高达10%。不过，对于年龄>65岁的老年女性，乳腺癌易感基因可遗传致病变异率尚不明确。美国国家综合癌症网络指南建议，对于年龄>65岁被诊断为乳腺癌的女性，外显率较高的基因出现致病变异概率可能小于2.5%，如果没有特定风险因素，那么乳腺癌易感基因检测的临床意义不大。

　　2021年7月22日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表梅奥医学中心、希望之城国家医学中心贝克曼研究所、哈佛大学陈曾熙公共卫生学院、宾夕法尼亚大学佩雷尔曼医学院、犹他大学、安布里遗传学、罗斯威尔帕克综合癌症中心、威斯康星大学、美国癌症学会、国家环境卫生科学研究所、波士顿大学斯隆流行病学中心、西雅图华盛顿大学、夏威夷大学癌症中心、弗雷德哈钦森癌症研究中心、南加利福尼亚大学凯克医学院、威斯康星大学密尔沃基分校约瑟夫齐伯公共卫生学院、英国牛津大学的研究报告，调查了年龄>65岁女性各个易感基因的致病变异率和剩余寿命乳腺癌风险。

　　该多中心大样本人群研究对6项前瞻队列嵌套乳腺癌病例对照研究（BWHS、CPSII、CTS、MEC、NHS、WHI）、3项病例队列研究（CPS3、MMHS、SISTER）、3项乳腺癌病例对照研究（MCBCS、WCHS、WWHS）的2万6707例年龄>65岁女性（其中乳腺癌患者占51.5%）进行乳腺癌易感基因（ATM、BARD1、BRCA1、BRCA2、CDH1、CHEK2、NF1、PALB2、PTEN、RAD51C、RAD51D、TP53）可遗传致病变异检测。对致病变异率以及各个基因致病变异与乳腺癌的相关性进行评定，并对携带致病变异非西班牙裔白人女性的剩余寿命乳腺癌风险进行估算。

　　结果，年龄>65岁女性易感基因致病变异率：

• 有乳腺癌女性：3.18%

• 无乳腺癌女性：1.48%

　　BRCA1、BRCA2、PALB2致病变异率：

• 雌激素受体阴性乳腺癌女性：3.42%

• 雌激素受体阳性乳腺癌女性：1.0%

• 三阴性乳腺癌女性：3.01%

　　无一级亲属乳腺癌家族史女性的致病变异率显著较低。

　　CHEK2、PALB2、BRCA2、BRCA1致病变异与否相比，乳腺癌风险高2.9～4.0倍。

　　BRCA1、BRCA2、PALB2、CHEK2、ATM致病变异携带者的剩余寿命乳腺癌风险分别为18.4%、18.7%、15.9%、14.9%、9.9%。

　　因此，该研究结果表明，对于年龄>65岁伴三阴性乳腺癌或雌激素受体阴性乳腺癌的女性都应该进行基因检测，对于年龄>65岁伴BRCA1、BRCA2致病变异和可能伴PALB2、CHEK2致病变异的女性应该考虑进行磁共振成像筛查。

J Clin Oncol. 2021 Jul 22. Online ahead of print.

Risk of Late-Onset Breast Cancer in Genetically Predisposed Women.

Boddicker NJ, Hu C, Weitzel JN, Kraft P, Nathanson KL, Goldgar DE, Na J, Huang H, Gnanaolivu RD, Larson N, Yussuf A, Yao S, Vachon CM, Trentham-Dietz A, Teras L, Taylor JA, Scott CE, Sandler DP, Pesaran T, Patel AV, Palmer JR, Ong IM, Olson JE, O'Brien K, Neuhausen S, Martinez E, Ma H, Lindstrom S, Le Marchand L, Kooperberg C, Karam R, Hunter DJ, Hodge JM, Haiman C, Gaudet MM, Gao C, LaDuca H, Lacey JV, Dolinsky JS, Chao E, Carter BD, Burnside ES, Bertrand KA, Bernstein L, Auer PW, Ambrosone C, Yadav S, Hart SN, Polley EC, Domchek SM, Couch FJ.

Mayo Clinic, Rochester, MN; Beckman Research Institute of City of Hope, Duarte, CA; Harvard University T.H. Chan School of Public Health, Boston, MA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; University of Utah, Salt Lake City, UT; Ambry Genetics, Aliso Viejo, CA; Roswell Park Comprehensive Cancer Center, Buffalo, NY; University of Wisconsin-Madison, Madison, WI; American Cancer Society, Atlanta, GA; NIEHS, Durham, NC; Slone Epidemiology Center at Boston University, Boston, MA; University of Washington, Seattle, WA; University of Hawaii Cancer Center, Honolulu, HI; Fred Hutchinson Cancer Research Center, Seattle, WA; University of Oxford, Oxford, United Kingdom; Keck School of Medicine, University of Southern California, Los Angeles, CA; UWM Joseph J. Zilber School of Public Health, Milwaukee, WI.

PURPOSE: The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years.

METHODS: A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs.

RESULTS: The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)-negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2.

CONCLUSION: This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.

KEY OBJECTIVE: Women over age 65 years with pathogenic variants (PVs) in cancer predisposition genes rarely benefit from hereditary cancer genetic testing. This population-based study examined whether women in this age category may qualify for clinical genetic testing and magnetic resonance imaging screening (≥ 20% lifetime risk of breast cancer).

KNOWLEDGE GENERATED: Women with estrogen receptor-negative breast cancer diagnosed over age 65 years and triple-negative breast cancer diagnosed over age 60 years had > 2.5% probability of PVs in the high-risk BRCA1, BRCA2, and PALB2 genes. Carriers of BRCA1 and BRCA2 PVs had estimated remaining lifetime risks approaching 20%, whereas PALB2 and CHEK2 carriers had 15% remaining risks.

RELEVANCE: All BRCA1, BRCA2, and PALB2 PV carriers with estrogen receptor-negative breast cancer or triple-negative breast cancer diagnosed over age 65 and 60 years, respectively, should receive genetic testing. Women with BRCA1 and BRCA2 PVs and perhaps those with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.

PMID: 34292776

DOI: 10.1200/JCO.21.00531