乳腺小叶浸润癌要不要多基因检测
乳腺癌易感基因BRCA1和BRCA2等多基因检测已被证实有助于乳腺导管浸润癌的治疗方案选择和癌症遗传筛查。不过，乳腺小叶浸润癌大约仅占乳腺浸润癌的10%～15%，既往关于常见癌症易感基因致病变异的乳腺小叶浸润癌临床研究较少、样本量较小，因此多基因检测的临床意义尚不明确。
2021年10月21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、宾夕法尼亚大学、拉丁美洲肿瘤学院、犹他大学、哈佛大学、罗斯威尔帕克综合癌症中心、国家环境卫生科学研究所、威斯康星大学、美国癌症学会、波士顿大学、希望之城国家医学中心贝克曼研究所、加利福尼亚大学圣迭戈分校、弗雷德哈钦森癌症研究中心、斯坦福大学、南加利福尼亚大学、密尔沃基威斯康星大学分校、加利福尼亚大学欧文分校、安布里基因的大样本研究报告，调查了常见癌症易感基因种系致病变异对乳腺小叶浸润癌的影响。
该研究包括来自美国癌症易感基因联盟（CARRIERS）人群队列的2999例乳腺小叶浸润癌女性、20323例乳腺导管浸润癌女性、32544例无癌对照女性，来自临床队列进行临床多基因检测的的3796例乳腺小叶浸润癌女性、37405例乳腺导管浸润癌女性。对乳腺小叶浸润癌女性、乳腺导管浸润癌女性、无癌对照女性的12种乳腺癌易感基因（ATM、BARD1、BRCA1、BRCA2、BRIP1、CDH1、CHEK2、PALB2、PTEN、RAD51C、RAD51D、TP53）种系致病变异率进行比较。
结果发现，乳腺小叶浸润癌女性的乳腺癌易感基因致病变异率：
临床队列：6.5%
人群队列：5.2%
根据病例对照分析：
CDH1和BRCA2致病变异与未变异的女性相比：乳腺小叶浸润癌比值比高于4倍
CHEK2、ATM和PALB2致病变异与未变异的女性相比：乳腺小叶浸润癌比值比高于2～4倍
BRCA1致病性变异和CHEK2短臂Ile157Thr变异与未变异的女性相比：乳腺小叶浸润癌比值比低于2倍
乳腺小叶浸润癌与乳腺导管浸润癌相比，CDH1致病变异富集高于10倍，而BRCA1致病变异显著较少。
因此，该大样本研究结果表明，ATM、BRCA2、CDH1、CHEK2、PALB2致病变异与未变异的女性相比，乳腺小叶浸润癌风险显著较高，而常见于乳腺导管浸润癌的BRCA1致病变异对乳腺小叶浸润癌风险影响不大。乳腺小叶浸润癌与乳腺导管浸润癌相比，总体致病变异率相似，表明乳腺癌组织学类型不影响进行基因检测的决定。与乳腺导管浸润癌相比，常用的多基因检测可能也适用于乳腺小叶浸润癌，也可能有助于治疗方案选择，但是对于CDH1应该另当别论。
相关链接
J Clin Oncol. 2021 Oct 21. Online ahead of print.
Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast.
Yadav S, Hu C, Nathanson KL, Weitzel JN, Goldgar DE, Kraft P, Gnanaolivu RD, Na J, Huang H, Boddicker NJ, Larson N, Gao C, Yao S, Weinberg C, Vachon CM, Trentham-Dietz A, Taylor JA, Sandler DR, Patel A, Palmer JR, Olson JE, Neuhausen S, Martinez E, Lindstrom S, Lacey JV, Kurian AW, John EM, Haiman C, Bernstein L, Auer PW, Anton-Culver H, Ambrosone CB, Karam R, Chao E, Yussuf A, Pesaran T, Dolinsky JS, Hart SN, LaDuca H, Polley EC, Domchek SM, Couch FJ.
Mayo Clinic, Rochester, MN; University of Pennsylvania, Philadelphia, PA; Latin American School of Oncology, Sierra Madre, CA; University of Utah, Salt Lake City, UT; Harvard University T.H. Chan School of Public Health, Boston, MA; Roswell Park Comprehensive Cancer Center, Buffalo, NY; NIEHS, Durham, NC; University of Wisconsin-Madison, Madison, WI; American Cancer Society, Atlanta, GA; Boston University, Boston, MA; Beckman Research Institute of City of Hope, Duarte, CA; University of California, San Diego, CA; Fred Hutchinson Cancer Research Center, Seattle, WA; Stanford University School of Medicine, Stanford, CA; University of Southern California, Los Angeles, CA; UWM Joseph J. Zilber School of Public Health, Milwaukee, WI; University of California, Irvine, CA; Ambry Genetics Inc, Aliso Viejo, CA.
PURPOSE: To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast.
MATERIALS AND METHODS: The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC).
RESULTS: The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC.
CONCLUSION: The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.
KEY OBJECTIVE: Women diagnosed with invasive lobular carcinoma (ILC) of the breast rarely benefit from hereditary cancer testing because the involvement of pathogenic variants (PVs) from cancer predisposition genes in ILC is not well-defined. In this study, population-based and clinical high-risk ILC cohorts were used to assess the risks of ILC conferred by inherited PVs.
KNOWLEDGE GENERATED: The frequency of PVs in breast cancer predisposition genes was 6.5% in the clinical cohort and 5.2% in the population-based cohort. PVs in CDH1, BRCA2, CHEK2, ATM, and PALB2 were associated with increased risk of ILC, whereas PVs in BRCA1 were not.
RELEVANCE: Multigene panel testing is appropriate for women with ILC and to identify women at risk of ILC because PVs in several genes predispose to this form of breast cancer. Predisposing PVs may also inform the selection of therapy for women with ILC.
PMID: 34672684
DOI: 10.1200/JCO.21.00640