Liu Yan, Ide Yoshimi, Inuzuka Mayuko, Tazawa Sakiko, Kanada Yoko, Matsunaga Yuki, Kuwayama Takashi, Sawada Terumasa, Akashi-Tanaka Sadako, Nakamura Seigo
The 3rd Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of Education, Tianjin, China.
Mol Genet Genomic Med. 2019 Mar;7(3):e493. doi: 10.1002/mgg3.493. Epub 2019 Jan 16.
Ductal carcinoma in situ (DCIS) is considered a component of the clinical spectrum of breast cancer even in those with BRCA1/2 mutation. The aim of this study was to report the feature of DCIS raised in Japanese women with BRCA1/2 mutations.
A total of 325 Japanese women with breast cancer (BC) (with or without invasive cancer) were referred for genetic counseling and underwent genetic testing for mutations in the BRCA1 and BRCA2 genes in Showa University Hospital between December 2011 and August 2016. And 49 of them who were pathologically diagnosed as DCIS were included in this study. Logistic regression models were fit to determine the associations between potential predictive factors and BRCA status. A Cox proportional hazards model is used to predictive value of parameters for Ipsilateral breast tumor recurrence (IBTR) and contralateral breast tumor recurrence (CBTR).
(a) Of 325 patients (with or without invasive cancer), 19.1% (62/325) tested positive for BRCA1/BRCA2 mutations. And 18.4% (9/49) was positive for BRCA1/BRCA2 mutations in DCIS, compared with 19.2% (53/276) in IDC (p = 1.000). Among BRCA mutations, 14.5% (9/62) had DCIS compared with nonmutations (15.2%, 40/263). Incidence of DCIS was 3.0% (1/33) of BRCA1 mutations and 27.5% (8/29) of BRCA2 mutation (p = 0.009). (b) Median age of diagnosis in BRCA mutation carriers was 39 years, compared with 46 years in noncarriers. Age, Family history (FH) of BC, FH of first or second BC and total number of relatives with BC diagnosis (DX) has significant difference between BRCA mutation carriers and noncarriers in univariate analysis. In a multivariate logistic model, total relatives with BC DX ≥ 2 (odds ratio [OR], 5.128; 95% confidence interval [CI], 1.266-20.763; p = 0.022), age at diagnosis ≤35 years (OR 0.149, 95% CI 0.023-0.954, p = 0.045) and ER+/HER2+ status (OR 5.034, 95% CI 1.092-23.210, p = 0.038) remained as independent significant predictors for BRCA mutation. Ki67 index (cut off by 14% or 30%) did not differ between BRCA mutation carriers and noncarriers (p = 0.459 and p = 0.651). (c) There was a significant difference in ER-positive tumors among BRCA2 carriers and noncarriers (p = 0.042). Subgroup analysis showed BRCA2 carriers tend to be of higher grade (Grade 2 and 3), more frequently ER+/PR+ (p = 0.041) and lower proliferation (Ki67 index) than noncarriers, whereas differences in nuclear grade and ki67 index were not found significantly in our study. (d) BRCA mutation was not associated with an increased risk of IBTR and CBTR.
DCIS is equally as prevalent in patients who were BRCA mutation carriers as in high familial-risk women who were noncarriers, but occurs at earlier age. BRCA2 carriers have higher incidence in DCIS than that of BRCA1 carriers, and tend to be higher grade and more frequently ER positive and lower proliferation. Total relatives with BC DX ≥2, age at diagnosis ≤35 years and ER+/HER2+ might be independent predictors for BRCA mutation in Japanese women with DCIS and patients of these risk factors should be recommended to receive genetic counseling and BRCA testing.
即使在携带BRCA1/2突变的女性中，导管原位癌（DCIS）也被认为是乳腺癌临床谱系的一部分。本研究的目的是报告日本携带BRCA1/2突变女性中DCIS的特征。
2011年12月至2016年8月期间，共有325名日本乳腺癌（BC）女性（有或无浸润性癌）被转诊至昭和大学医院进行遗传咨询，并接受BRCA1和BRCA2基因的突变检测。其中49例经病理诊断为DCIS的患者纳入本研究。采用逻辑回归模型确定潜在预测因素与BRCA状态之间的关联。采用Cox比例风险模型预测同侧乳腺肿瘤复发（IBTR）和对侧乳腺肿瘤复发（CBTR）参数的预测价值。
（a）在325例患者（有或无浸润性癌）中，19.1%（62/325）BRCA1/BRCA2突变检测呈阳性。DCIS中BRCA1/BRCA2突变阳性率为18.4%（9/49），浸润性导管癌（IDC）中为19.2%（53/276）（p = 1.000）。在BRCA突变中，14.5%（9/62）有DCIS，非突变者为15.2%（40/263）。DCIS的发生率在BRCA1突变中为3.0%（1/33），在BRCA2突变中为27.5%（8/29）（p = 0.009）。（b）BRCA突变携带者的诊断中位年龄为39岁，非携带者为46岁。在单因素分析中，BRCA突变携带者和非携带者在年龄、乳腺癌家族史（FH）、一级或二级乳腺癌家族史以及诊断为乳腺癌的亲属总数（DX）方面存在显著差异。在多因素逻辑模型中，诊断为乳腺癌的亲属总数≥2（比值比[OR]，5.128；95%置信区间[CI]，1.266 - 20.763；p = 0.022）、诊断年龄≤35岁（OR 0.149, 95% CI 0.023 - 0.954, p = 0.045）和ER+/HER2+状态（OR 5.034, 95% CI 1.092 - 23.210, p = 0.038）仍然是BRCA突变的独立显著预测因素。BRCA突变携带者和非携带者之间的Ki67指数（以14%或30%为界）无差异（p = 0.459和p = 0.651）。（c）BRCA2携带者和非携带者之间ER阳性肿瘤存在显著差异（p = 0.042）。亚组分析显示，BRCA2携带者比非携带者更倾向于高分级（2级和3级）、更频繁地ER+/PR+（p = 0.041）和增殖较低（Ki67指数），而在我们的研究中未发现核分级和ki67指数有显著差异。（d）BRCA突变与IBTR和CBTR风险增加无关。
DCIS在BRCA突变携带者中的患病率与非携带者的高家族风险女性相同，但发病年龄更早。BRCA2携带者中DCIS的发生率高于BRCA1携带者，且倾向于高分级、更频繁地ER阳性和增殖较低。诊断为乳腺癌的亲属总数≥2、诊断年龄≤35岁和ER+/HER2+可能是日本DCIS女性中BRCA突变的独立预测因素，对于这些有风险因素的患者，应建议接受遗传咨询和BRCA检测。
