乳腺癌易感基因BRCA1和BRCA2等多基因檢測已被證實(shí)有助于乳腺導(dǎo)管浸潤癌的治療方案選擇和癌癥遺傳篩查。不過，乳腺小葉浸潤癌大約僅占乳腺浸潤癌的10%～15%，既往關(guān)于常見癌癥易感基因致病變異的乳腺小葉浸潤癌臨床研究較少、樣本量較小，因此多基因檢測的臨床意義尚不明確。
2021年10月21日，美國臨床腫瘤學(xué)會(huì)《臨床腫瘤學(xué)雜志》在線發(fā)表梅奧醫(yī)學(xué)中心、賓夕法尼亞大學(xué)、拉丁美洲腫瘤學(xué)院、猶他大學(xué)、哈佛大學(xué)、羅斯威爾帕克綜合癌癥中心、國家環(huán)境衛(wèi)生科學(xué)研究所、威斯康星大學(xué)、美國癌癥學(xué)會(huì)、波士頓大學(xué)、希望之城國家醫(yī)學(xué)中心貝克曼研究所、加利福尼亞大學(xué)圣迭戈分校、弗雷德哈欽森癌癥研究中心、斯坦福大學(xué)、南加利福尼亞大學(xué)、密爾沃基威斯康星大學(xué)分校、加利福尼亞大學(xué)歐文分校、安布里基因的大樣本研究報(bào)告，調(diào)查了常見癌癥易感基因種系致病變異對乳腺小葉浸潤癌的影響。
該研究包括來自美國癌癥易感基因聯(lián)盟（CARRIERS）人群隊(duì)列的2999例乳腺小葉浸潤癌女性、20323例乳腺導(dǎo)管浸潤癌女性、32544例無癌對照女性，來自臨床隊(duì)列進(jìn)行臨床多基因檢測的的3796例乳腺小葉浸潤癌女性、37405例乳腺導(dǎo)管浸潤癌女性。對乳腺小葉浸潤癌女性、乳腺導(dǎo)管浸潤癌女性、無癌對照女性的12種乳腺癌易感基因（ATM、BARD1、BRCA1、BRCA2、BRIP1、CDH1、CHEK2、PALB2、PTEN、RAD51C、RAD51D、TP53）種系致病變異率進(jìn)行比較。
結(jié)果發(fā)現(xiàn)，乳腺小葉浸潤癌女性的乳腺癌易感基因致病變異率：
臨床隊(duì)列：6.5%
人群隊(duì)列：5.2%
根據(jù)病例對照分析：
CDH1和BRCA2致病變異與未變異的女性相比：乳腺小葉浸潤癌比值比高于4倍
CHEK2、ATM和PALB2致病變異與未變異的女性相比：乳腺小葉浸潤癌比值比高于2～4倍
BRCA1致病性變異和CHEK2短臂Ile157Thr變異與未變異的女性相比：乳腺小葉浸潤癌比值比低于2倍
乳腺小葉浸潤癌與乳腺導(dǎo)管浸潤癌相比，CDH1致病變異富集高于10倍，而BRCA1致病變異顯著較少。
因此，該大樣本研究結(jié)果表明，ATM、BRCA2、CDH1、CHEK2、PALB2致病變異與未變異的女性相比，乳腺小葉浸潤癌風(fēng)險(xiǎn)顯著較高，而常見于乳腺導(dǎo)管浸潤癌的BRCA1致病變異對乳腺小葉浸潤癌風(fēng)險(xiǎn)影響不大。乳腺小葉浸潤癌與乳腺導(dǎo)管浸潤癌相比，總體致病變異率相似，表明乳腺癌組織學(xué)類型不影響進(jìn)行基因檢測的決定。與乳腺導(dǎo)管浸潤癌相比，常用的多基因檢測可能也適用于乳腺小葉浸潤癌，也可能有助于治療方案選擇，但是對于CDH1應(yīng)該另當(dāng)別論。
相關(guān)鏈接
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
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