Androgen receptor CAG repeat length and estrogen receptor status in postmenopausal breast cancer prognosis.

PURPOSE: The influence of the androgen receptor (AR) CAG repeat polymorphism on breast cancer is controversial. We investigated the combined effects of CAG repeat length and estrogen receptor (ER) status on prognosis in 355 postmenopausal women with primary breast cancer. METHODS: CAG repeat length was determined by the HUMARA test. Relapse-free survival (RFS) and overall survival (OS) according to the X-weighted CAG repeat biallelic mean (XWBM) were investigated by univariate and multivariate analysis. RESULTS: XWBM was not associated with RFS or OS, but a significant interaction between XWBM and ER status (p = 0.002) was found for OS. ER-negative patients with median XWBM <20 showed lower OS than ER-negative/XWBM ≥20 patients (HR = 0.270; 95% Cl: 0.073-0.999). ER-negative/XWBM <20 patients also had significantly lower OS than ER-positive women, irrespective of CAG repeat length (p<0.001). Accordingly, estimated OS was lowest in ER-negative patients with XWBM <20 (OS: 0.63, 95% CI: 0.41-0.79) and highest in ER-positive patients with XWBM <20 (OS: 0.95, 95% CI: 0.90-0.97). CONCLUSIONS: Our data suggest that short CAG repeat length is associated with increased risk of death in ER-negative disease but is related to better survival when ER is expressed. These findings are in agreement with the hypothesis that AR may stimulate or inhibit breast cancer growth depending on ER status, AR transactivation, and the endocrine-metabolic environment of breast tumors. Evaluation of CAG repeat length together with ER status could help improve the estimation of the risk of death, with possible implications for the optimization of standard breast cancer treatment and implementation of prevention strategies.

Metformin decreases circulating androgen and estrogen levels in nondiabetic women with breast cancer.

INTRODUCTION: Diabetic patients treated with metformin have a lower risk of developing BC or a better BC prognosis. Metformin might reduce cancer growth through direct antiproliferative effects or through indirect mechanisms, particularly the reduction of insulin. In a randomized study on nondiabetic BC patients in natural menopause with high testosterone levels, we observed a significant decrease in insulin and in testosterone levels with metformin 1500 mg/d compared with 1000 mg/d. We present the results of a new analysis of our study on the effect of metformin on the bioavailability of sex hormones. PATIENTS AND METHODS: One hundred twenty-four eligible women were initially invited to take metformin 500 mg/d for 3 months. The 108 women who completed the first 3 months continued the study using 1000 mg/d for 1 month. The women were then randomized into 2 groups, and, for the subsequent 5 months, 1 group increased the dose to 1500 mg/d, and the other group continued with 1000 mg/d. RESULTS: Ninety-six women completed the study, 43 receiving metformin 1500 mg/day, and 53 receiving 1000 mg/day. The women receiving 1500 mg/d showed a greater and significant reduction of free testosterone (-29%) and estradiol (-38%), a borderline significant reduction of estrone and insulin-like growth factor-1, and a nonsignificant reduction of androstenedione. They also showed a nonsignificant increase of dehydroepiandrosterone sulfate. CONCLUSION: Metformin does not interfere with the production of dehydroepiandrosterone sulfate. Besides, it decreases estradiol levels, basically through the reduction of testosterone. These hormonal changes might have clinical relevance.

Androgen receptors and serum testosterone levels identify different subsets of postmenopausal breast cancers.

BACKGROUND: Androgen receptors (AR) are frequently expressed in breast cancers, but their implication in cancer growth is still controversial. In the present study, we further investigated the role of the androgen/AR pathway in breast cancer development. METHODS: AR expression was evaluated by immunochemistry in a cohort of 528 postmenopausal breast cancer patients previously examined for the association of serum testosterone levels with patient and tumor characteristics. AR expression was classified according to the percentage of stained cells: AR-absent (0%) and AR-poorly (1%-30%), AR-moderately (>30%-60%), and AR-highly (>60%) positive. RESULTS: Statistical analysis was performed in 451 patients who experienced natural menopause. AR-high expression was significantly related with low histologic grade and estrogen receptor (ER)- and progesterone receptor (PR)-positive status (P trend<0.001). Mean testosterone levels were significantly higher in the AR-high category than in the other categories combined (P=0.022), although a trend across the AR expression categories was not present. When women defined by ER status were analyzed separately, regression analysis in the ER-positive group showed a significant association of high testosterone levels with AR-highly-positive expression (OR 1.86; 95% CI, 1.10-3.16), but the association was essentially due to patients greater than or equal to 65 years (OR 2.42; 95% CI, 1.22-4.82). In ER-positive group, elevated testosterone levels appeared also associated with AR-absent expression, although the small number of patients in this category limited the appearance of significant effects (OR 1.92; 95% CI, 0.73-5.02): the association was present in both age groups (<65 and ≥65 years). In the ER-negative group, elevated testosterone levels were found associated (borderline significance) with AR-absent expression (OR 2.82, 95% CI, 0.98-8.06). In this ER-negative/AR-absent subset of tumors, elevated testosterone levels cannot stimulate cancer growth either directly or after conversion into estrogens, but they probably induce increased synthesis of some other substance that is responsible for cancer growth through binding to its specific receptor. CONCLUSIONS: The findings in the present study confirm that testosterone levels are a marker of hormone-dependent breast cancer and suggest that the contemporary evaluation of ER status, AR expression, and circulating testosterone levels may identify different subsets of cancers whose growth may be influenced by androgens.

Circulating sex hormones and tumor characteristics in postmenopausal breast cancer patients. A cross-sectional study.

BACKGROUND: To further investigate the role of sex hormones in breast cancer, we assessed the relations of circulating estradiol and testosterone to tumor size and estrogen receptor (ER) status. METHOD: This was a cross-sectional study including 492 postmenopausal breast cancer patients. The relation of circulating hormones to patient and tumor characteristics was assessed using the Fisher or Cuzick tests. Multivariable logistic regression was used to estimate the odds ratios (ORs) of having tumors =2 cm (vs and <2 cm) and having ER-positive tumors (vs ER-negative) with increasing quartiles of estradiol and testosterone. RESULTS: Mean estradiol and testosterone levels increased significantly with increasing tumor size. The ORs of tumors =2 cm increased significantly with increasing quartiles of estradiol (Ptrend and <0.001) and testosterone (Ptrend=0.005). When adjusted for estradiol, the association between testosterone and tumor size was no longer significant. Mean testosterone levels were higher in ER-positive than ER-negative patients (p and <0.001), while mean estradiol levels did not differ significantly between the two ER categories (p=0.192). The ORs of having an ER-positive tumor increased significantly with increasing quartiles of testosterone (Ptrend=0.002), whereas the increase with increasing estradiol quartiles was not significant (Ptrend=0.07). CONCLUSION: The association of both hormones with tumor size implies that both are involved in tumor growth, testosterone mainly by conversion to estradiol. The strong association of testosterone with ER contrasts with the weak association of estradiol with ER and confirms testosterone as a marker of hormone-dependent tumors. These findings suggest that testosterone evaluation might be useful to better identify patients with hormone-dependent disease.