admin 百科大全 2023-01-10 15:34:24

五基因致病突变的对侧乳腺癌风险

　　准确估计单侧乳腺癌患者的对侧乳腺癌以及其他癌症风险，对指导合理监测、是否切除对侧乳房降低风险的策略至关重要。普通人群乳腺癌女性发生对侧乳腺癌的风险大约为每年0.5%，癌症易感基因种系（又称胚系、生殖系、可遗传）突变状态、种族民族、诊断时年龄、绝经状态对风险有显著影响。对于普通人群，5%～7%的乳腺癌女性患者可检测到ATM、BRCA1、BRCA2、CHEK2、PALB2基因种系致病变异，并且与未变异女性相比，乳腺癌风险显著增加。种系致病变异携带者，尤其ATM、CHEK2、PALB2基因的致病变异携带者的对侧乳腺癌风险尚不明确。即使对于BRCA1和BRCA2种系致病变异携带者，目前的对侧乳腺癌风险估计方法，主要来自诊断时年龄较小或有乳腺卵巢癌症家族史而符合基因检测资格的高风险乳腺癌女性，可能不适用于普通人群的女性。由于缺乏乳腺癌易感基因致病变异患者对侧乳腺癌风险的大样本前瞻数据，合理的预防性对侧乳房切除手术管理和监测策略亦不明确。

　　2023年1月9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、芝加哥大学、美国癌症学会、希望之城医学中心贝克曼癌症研究所、圣迭戈加利福尼亚大学、南加利福尼亚大学、斯坦福大学、国家环境健康科学研究所、欧文加利福尼亚大学、波士顿大学、犹他大学、宾夕法尼亚大学、拉丁美洲肿瘤学院、哈佛大学陈曾熙公共卫生学院的CARRIERS联盟10项前瞻研究分析报告，提供了ATM、BRCA1、BRCA2、CHEK2、PALB2种系致病变异携带者对侧乳腺癌风险目前最大样本量数据。这些研究绝大多数女性被诊断为乳腺癌时并不知道她们的种系致病变异状态，这使得可以公正地评估种系致病变异状态对对侧乳腺癌风险的影响。

CARRIERS: Cancer Risk Estimates Related to Susceptibility

　　CARRIERS研究人群包括1万5104例单侧乳腺浸润癌手术治疗前瞻随访女性，其中无致病变异女性1万4444例。通过多因素比例风险回归分析，对死亡竞争风险、患者特征和肿瘤特征进行校正后，比较各个基因致病变异携带者与无致病变异女性的对侧乳腺癌风险。主要分析关注整个队列和普通人群的女性。次要分析关注种族民族、原发乳腺癌诊断时年龄、绝经状态、肿瘤雌激素受体状态的相关性。

　　结果发现，致病变异携带者与无致病变异女性相比：

ATM：对侧乳腺癌风险相似
BRCA1：对侧乳腺癌风险高2.7倍（95%置信区间：2.0～3.8，P<0.001）
BRCA2：对侧乳腺癌风险高3.0倍（95%置信区间：2.1～4.3，P<0.001）
CHEK2：对侧乳腺癌风险高1.9倍（95%置信区间：1.1～3.3，P=0.03）
PALB2：对侧雌激素受体阴性乳腺癌风险高2.9倍（95%置信区间：1.4～6.4，P=0.006）

　　非洲裔美国人与非西班牙裔白人相比，致病变异携带者对侧乳腺癌风险增加相似。

　　单侧乳腺癌诊断年龄、绝经状态、雌激素受体状态显著影响致病变异携带者的对侧乳腺癌风险。

　　对于绝经前女性，致病变异携带者对侧乳腺癌10年累积发病率：

BRCA1：33.4%
BRCA2：27.2%
CHEK2：13.2%
PALB2：12.2%（雌激素受体阴性乳腺癌达35.5%）

　　对于绝经后女性，致病变异携带者对侧乳腺癌10年累积发病率：

BRCA1：11.5%
BRCA2：9.4%
CHEK2：4.3%

　　因此，该研究结果表明，被诊断为乳腺癌且已知携带BRCA1、BRCA2、CHEK2、PALB2种系致病变异女性与无致病变异女性相比，对侧乳腺癌风险显著增加，可能有助于决定是否选择预防性对侧乳房切除手术，或为那些反对选择对侧乳房切除手术的女性加强筛查监测策略。

J Clin Oncol. 2023 Jan 9. IF: 50.717

Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2.

Yadav S, Boddicker NJ, Na J, Polley EC, Hu C, Hart SN, Gnanaolivu RD, Larson N, Holtegaard S, Huang H, Dunn CA, Teras LR, Patel AV, Lacey JV, Neuhausen SL, Martinez E, Haiman C, Chen F, Ruddy KJ, Olson JE, John EM, Kurian AW, Sandler DP, O'Brien KM, Taylor JA, Weinberg CR, Anton-Culver H, Ziogas A, Zirpoli G, Goldgar DE, Palmer JR, Domchek SM, Weitzel JN, Nathanson KL, Kraft P, Couch FJ.

Mayo Clinic, Rochester, MN; University of Chicago, Chicago, IL; American Cancer Society, Atlanta, GA; Beckman Research Institute of City of Hope, Duarte, CA; University of California, San Diego, CA; University of Southern California, Los Angeles, CA; Stanford University School of Medicine, Stanford, CA; National Institute of Environmental Health Sciences, Durham, NC; University of California, Irvine, CA; Slone Epidemiology Center at Boston University, Boston, MA; University of Utah, Salt Lake City, UT; University of Pennsylvania, Philadelphia, PA; Latin American School of Oncology, Sierra Madre, CA; Harvard University T.H. Chan School of Public Health, Boston, MA.

PURPOSE: To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2.

METHODS: The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status.

RESULTS: Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2.

CONCLUSION: Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

KEY OBJECTIVE: To estimate the risk of contralateral breast cancer (CBC) in carriers of germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2 from prospective studies.

KNOWLEDGE GENERATED: Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at a significantly elevated risk of CBC, whereas only the PALB2 PV carriers with estrogen receptor-negative breast cancer had elevated risks. By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Age at diagnosis, menopausal status, and estrogen receptor status of the initial breast cancer significantly influenced the CBC risk in PV carriers.

RELEVANCE: Patients with genetic mutations who have had an index breast cancer often assume that they are at high risk of developing another cancer in the other breast. The ability to better predict risk can guide decisions about prophylactic surgery and enhanced screening strategies for those who opt against bilateral mastectomy.

PMID: 36623243

DOI: 10.1200/JCO.22.01239