Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update

Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80%, and following the first diagnosis the 10-year risk of contralateral breast cancer is approximately 30%. It has been shown that both tamoxifen and oophorectomy prevent contralateral breast cancer, but it is not clear whether there is a benefit in giving tamoxifen to women who have previously undergone an oophorectomy. Furthermore, the relative degree of protection in BRCA1 and BRCA2 carriers has not been well evaluated. We studied 285 women with bilateral breast cancer and a BRCA1 or BRCA2 mutation, and 751 control women with unilateral breast cancer and a BRCA1 or BRCA2 mutation in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of breast cancer and had been followed for as long as the case for a second primary breast cancer. The history of tamoxifen use for treating the first breast cancer was compared between bilateral and unilateral cases. The multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 for carriers of BRCA1 mutations (95% CI, 0.30-0.85) and was 0.42 for carriers of BRCA2 mutations (95% CI, 0.17-1.02). The protective effect of tamoxifen was not seen among women who had undergone an oophorectomy (OR = 0.83; 95%CI, 0.24-2.89) but this subgroup was small. In contrast, a strong protective effect of tamoxifen was apparent among women who were premenopausal or who had undergone natural menopause (OR = 0.44; 95% CI, 0.27-0.65).     

BRCA1-related breast cancer in Austrian breast and ovarian cancer families: Specific BRCA1 mutations and pathological characteristics

We identified 17 BRCA1mutations in 86 Austrian breast and ovarian cancer families (20%) that were screened for mutations by denaturing high-performance liquid chromatography (DHPLC) and the protein<0B> <0R>truncation test (PTT). Eleven distinct mutations were detected, 4 of them (962del4, 2795del4, 3135del4 and L3376stop) not previously reported in families of non-Austrian origin. In addition, 6 rare missense mutations (allele frequency < 1%) with unknown biological effects were identified. Four mutations occurred more than once in the Austrian population: 2795del4 (3 times), Cys61Gly (3 times) 5382insC (2 times) and Q1806stop (2 times). Haplotype analysis of the 4 recurrent mutations suggested a common ancestor for each of these. Thirty-four breast cancer cases from 17 families with BRCA1 mutations were further analyzed. We observed a low median age of onset (39.5 years). Sixty-eight percent of all BRCA1 breast cancer cases had negative axillary lymph nodes. This group showed a significant prevalence of a negative estrogen and progesterone receptor status and stage I tumors compared with an age-related, node-negative control group. The prevalence of grade III tumors was marginally significant . Survival analysis either with a control group matched for age (within 5 years), grade, histologic subtype and estrogen receptor status, or with an age-related, node-negative comparison group, showed no statistical difference. Int. J. Cancer 77:354–360, 1998. © 1998 Wiley-Liss, Inc.     

Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological type.

PURPOSE: BRCA1-related breast cancers are more frequently estrogen receptor (ER) negative than are either BRCA2-related or nonhereditary breast cancers. The relationship between ER status and other clinical features of hereditary breast cancers has not been well studied. EXPERIMENTAL DESIGN: ER status, grade, and histological tumor type were evaluated in 1131 women with invasive breast cancer, ascertained at 10 centers in North America. There were 208 BRCA1 mutation carriers, 88 BRCA2 carriers, and 804 women without a known mutation. We stratified the patients by mutation status, grade, age, and histological type and calculated the percentage of ER-positive tumors within each stratum. RESULTS: BRCA1 mutation carriers were more likely to have ER-negative breast cancers than were women in other groups, after adjustment for age, grade, and histological subtype (P < 0.001). Only 3.9% of BRCA1-related breast cancers were ER-positive cancers occurring in women in their postmenopausal years. The direction and magnitude of the change in ER status with increasing age at diagnosis in BRCA1 carriers was significantly different from in BRCA2 carriers (P(intercept) = 0.0002, P(slope) = 0.04). Notably, changes in ER status with age at diagnosis for BRCA1 carriers and noncarriers were almost identical (P(slope) = 0.98). CONCLUSIONS: The strong relationship between the presence of a BRCA1 mutation and the ER-negative status of the breast cancers is neither a consequence of the young age at onset nor the high grade but is an intrinsic property of BRCA1-related cancers. The ER-negative status of these cancers may reflect the cell of origin of BRCA1-related cancers.     

乳腺癌中BRCA1基因突变与雌激素受体研究进展

乳腺癌的发生是一系列基因改变的结果。BRCA1是遗传性乳腺癌易感基因，其结构、功能异常与乳腺癌的发生发展有十分密切的联系。雌激素受体（ER）作为乳腺癌的生物学标志物，是目前较为可靠的指导治疗和判定预后的重要指标。研究乳腺癌中BRCA1基因突变与雌激素受体的关系，对阐明乳腺癌的发病机制、早期诊断及治疗有意义。     

Vav3 oncogene activates estrogen receptor and its overexpression may be involved in human breast cancer

Background  

Our previous study revealed that Vav3 oncogene is overexpressed in human prostate cancer, activates androgen receptor, and stimulates growth in prostate cancer cells. The current study is to determine a potential role of Vav3 oncogene in human breast cancer and impact on estrogen receptor a (ERα)-mediated signaling axis.     

Increased progesterone receptor expression in benign epithelium of BRCA1-related breast cancers

The study of pathologically normal breast epithelium of BRCA mutation carriers may yield insights into the early natural history of breast tumorigenesis. Hormone receptor expression was assessed in 24 cases of invasive breast cancer associated with a mutation in BRCA1 (n = 15) or BRCA2 (n = 9) and in 39 sporadic cases matched for patient age and tumor hormone receptor status. Expression of progesterone receptor was significantly (P = 0.0003) more common in normal breast epithelium adjacent to invasive breast carcinoma in BRCA1-linked cases compared with sporadic cases. The wild-type BRCA allele was retained in normal epithelium of all cases tested. We conclude that deregulation of progesterone receptor expression, as a result of BRCA1 haploinsufficiency, may represent an early event in BRCA1-linked breast tumorigenesis.     

Relation of smoking to breast cancer by estrogen receptor status

It has been suggested that smoking is associated with estrogen-negative breast cancer but not with estrogen-positive breast cancer. A population-based case-control study was conducted in Geneva, Switzerland, to determine the relation of passive and active smoking to breast cancer when the referent unexposed category consisted of women unexposed to active and passive smoke. The 242 patients with breast cancer (cases), in whom estrogen receptor (ER) status was determined on biopsy material, were compared with 1,059 women free of breast cancer (controls). Lifetime history of active and passive smoking was recorded year by year, between age 10 and the date of interview. Prevalence rates of ER⁺ tumors were 74.7% in pre-menopausal women and 74.2% in post-menopausal women. Post-menopausal active smokers had a lower prevalence of ER⁺ tumors (70.0%, p = ns). Among pre-menopausal women, the age-adjusted ORs of breast cancer with having smoked an average of ≥20 cigarettes per day (cpd) during lifetime were 2.7 for ER⁻ tumors and 2.6 for ER⁺ tumors. Among post-menopausal women, corresponding ORs were 5.7 for ER⁻ tumors and 2.4 for ER⁺ tumors. Smoking was related to both ER⁻ and ER⁺ breast cancer in pre- and post-menopausal women, but the strength of the association appeared to be greater for ER⁻ tumors among post-menopausal women. Int. J. Cancer 75:339–342, 1998. © 1998 Wiley-Liss, Inc.     

Mammographic density and estrogen receptor status of breast cancer.

BACKGROUND: The density of breast tissue on a mammogram is a strong predictor of breast cancer risk and may reflect cumulative estrogen effect on breast tissue. Endogenous and exogenous estrogen exposure increases the risk of estrogen receptor (ER)-positive breast cancer. We determined if mammographic density is associated more strongly with ER-positive breast cancer than with ER-negative breast cancer.METHODS: We analyzed data from 44,811 participants in the San Francisco Mammography Registry of whom 701 developed invasive breast cancer. Mammographic density was measured using the Breast Imaging Reporting and Data System (BI-RADS) classification system (1 = almost entirely fat, 2 = scattered fibroglandular, 3 = heterogeneously dense, 4 = extremely dense). We tested for associations between mammographic density and ER-positive and ER-negative breast cancer separately. Analyses were adjusted for age, body mass index, postmenopausal hormone use, family history of breast cancer, menopausal status, parity, and race/ethnicity.RESULTS: Mammographic density was strongly associated with both ER-positive and ER-negative breast cancers. Compared with women with BI-RADS 2, women with BI-RADS 1 (lowest density) had a lower risk of ER-positive cancer [adjusted hazard ratio (HR), 0.28; 95% confidence interval (95% CI), 0.16-0.50] and ER-negative cancer (adjusted HR, 0.17; 95% CI, 0.04-0.70). Women with BI-RADS 4 (highest density) had an increased risk of ER-positive breast cancer (adjusted HR, 2.21; 95% CI, 1.64-3.04) and an increased risk of ER-negative breast cancer (adjusted HR, 2.21; 95% CI, 1.16-4.18).CONCLUSION: Surprisingly, women with high mammographic density have an increased risk of both ER-positive and ER-negative breast cancers. The association between mammographic density and breast cancer may be due to factors besides estrogen exposure.