Breast epithelial cell proliferation is markedly increased with short-term high levels of endogenous estrogen secondary to controlled ovarian hyperstimulation.

Oocyte donors have high serum estradiol (E2) levels similar to the serum levels seen in the first trimester of pregnancy. We report in this article our studies comparing cell proliferation, Ki67 (MIB1), and estrogen and progesterone receptor levels (ERα, PRA, and PRB) in the breast terminal duct lobular units of oocyte donors, women in early pregnancy, and in normally cycling women. Breast tissue and blood samples were obtained from 10 oocyte donors, and 30 pregnant women at 5-18 weeks of gestation. Breast tissue samples were also obtained from 26 normally cycling women. In the oocyte donors: peak E2 (mean ~15,300 pmol/l) was reached on the day before oocyte (and tissue) donation; peak progesterone (P4; mean 36.3 nmol/l) was reached on the day of donation; Ki67 was positively associated with level of E2, and the mean Ki67 was 7.0% significantly greater than the mean 1.8% of cycling women. In the pregnant women: mean E2 rose from ~2,000 pmol/l at 5 weeks of gestation to ~27,000 pmol/l at 18 weeks; mean P4 did not change from ~40 nmol/l until around gestational week 11 when it increased to ~80 nmol/l; mean Ki67 was 15.4% and did not vary with gestational age or E2. Oocyte donors have greatly increased levels of E2 and of breast-cell proliferation, both comparable in the majority of donors to the levels seen in the first trimester of pregnancy. Whether their short durations of greatly increased E2 levels are associated with any long-term beneficial effects on the breast, as occurring in rodent models, is not known.

Progesterone and estrogen receptors in pregnant and premenopausal non-pregnant normal human breast.

We report here our studies of nuclear staining for the progesterone and estrogen receptors (PRA, PRB, ERalpha) and cell proliferation (MIB1) in the breast terminal duct lobular unit epithelium of 26 naturally cycling premenopausal women and 30 pregnant women (median 8.1 weeks gestation). Square root transformations of the PRA, PRB and ERalpha values, and a logarithmic transformation of the MIB1 values, were made to achieve more normal distributions of the values. PRA expression decreased from a mean of 17.8% of epithelial cells in cycling subjects to 6.2% in pregnant subjects (P = 0.013). MIB1 expression increased from 1.7% in cycling subjects to 16.0% in pregnant subjects (P < 0.001). PRB and ERalpha expression was slightly lower in pregnant subjects but the differences were not statistically significant. Sixteen of the non-pregnant subjects were nulliparous and ten were parous so that we had limited power to detect changes associated with parity. PRA was statistically significantly lower in parous women than in nulliparous women (32.2% in nulliparous women vs. 10.2%; P = 0.014). PRB (23.5 vs. 12.9%), ERalpha (14.4 vs. 8.6%) and MIB1 (2.2 vs. 1.2%) were also lower in parous women, but the differences were not statistically significant. The marked decreases in PRA in pregnancy and in parous women has also been found in the rat. A reduction in PRA expression may be a useful marker of the reduction in risk with pregnancy and may be of use in evaluating the effect of any chemoprevention regimen aimed at mimicking pregnancy. Short-term changes in PRA expression while the chemoprevention is being administered may be a more useful marker.

Aerobic and Resistance Exercise Improves Shoulder Function in Women Who Are Overweight or Obese and Have Breast Cancer: A Randomized Controlled Trial.

BACKGROUND: Adverse upper limb musculoskeletal effects occur after surgical procedures and radiotherapy for breast cancer and can interfere with activities of daily living. OBJECTIVE: The objective of this study was to examine the effects of a 16-week exercise intervention on shoulder function in women who are overweight or obese and have breast cancer. DESIGN: This study was a randomized controlled trial. SETTING: The study was performed at the Division of Biokinesiology and Physical Therapy at the University of Southern California. PARTICIPANTS: One hundred women with breast cancer were randomly allocated to exercise or usual-care groups. The mean (SD) age of the women was 53.5 (10.4) years, 55% were Hispanic white, and their mean (SD) body mass index was 33.5 (5.5) kg/m2. INTERVENTION: The 16-week exercise intervention consisted of supervised, progressive, moderate to vigorous aerobic and resistance exercise 3 times per week. MEASUREMENTS: Shoulder active range of motion, isometric muscular strength, and patient-reported outcome measures (including Disabilities of the Arm, Shoulder, and Hand and the Penn Shoulder Scale) were assessed at baseline, after the intervention, and at the 3-month follow-up (exercise group only). Differences in mean changes for outcomes were evaluated using mixed-model repeated-measures analysis. RESULTS: Compared with the usual-care group, the exercise group experienced significant increases in shoulder active range of motion (the mean between-group differences and 95% confidence intervals (CIs) were as follows: shoulder flexion = 36.6° [95% CI = 55.2-20.7°], external rotation at 0° = 23.4° [95% CI = 31.1-12.5°], and external rotation at 90° = 34.3° [95% CI = 45.9-26.2°]), improved upper extremity isometric strength, and improved Disabilities of the Arm, Shoulder, and Hand and Penn Shoulder Scale scores. LIMITATIONS: Limitations include a lack of masking of assessors after the intervention, an attention control group, and statistical robustness (shoulder function was a secondary end point). CONCLUSIONS: A 16-week exercise intervention effectively improved shoulder function following breast cancer treatment in women who were overweight or obese, who were ethnically diverse, and who had breast cancer.

Reduced mammographic density with use of a gonadotropin-releasing hormone agonist-based chemoprevention regimen in BRCA1 carriers.

PURPOSE: Women with a BRCA1 mutation (BRCA1(mut)) need risk reduction options beyond mastectomy and oophorectomy. We evaluated the efficacy, safety, and tolerability of hormonal chemoprevention with a gonadotropin-releasing hormone agonist (GnRHA) with low-dose add-back steroids in BRCA1(mut) carriers. EXPERIMENTAL DESIGN: The 12-month open label clinical trial used the GnRHA deslorelin, ultra-low-dose estradiol (E(2)), and replacement testosterone, administered via daily intranasal spray in premenopausal women with a BRCA1(mut), and intermittent oral medroxyprogesterone acetate. The end points included mammographic percent density, bone mineral density, endometrial hyperplasia, symptom inventory, and quality of life (Medical Outcomes SF-36 survey). RESULTS: Six of eight BRCA1(mut) women (mean age, 30.3 years; range, 25-36 years) completed the study. Mammographic percent density was significantly reduced at 12 months (median absolute mammographic percent density decrease, 8.3%; P = 0.043), representing a 29.2% median reduction in mammographic percent density. Bone mineral density remained within reference limits for all participants; there were no cases of atypical endometrial hyperplasia and menses resumed within a median of 67 days (range, 35-110 days) after last drug treatment day. The treatment was well tolerated; hypoestrogenic side effects were minimal and transient; and there were no significant changes in quality of life. CONCLUSIONS: The GnRHA deslorelin, with low-dose add-back steroids, was well tolerated and significantly decreased mammographic percent density in BRCA1(mut) carriers. This regimen may reduce breast cancer risk and improve the usefulness of mammographic surveillance by reducing density. This is the first demonstration, to our knowledge, of a direct reduction of mammographic densities in young BRCA1(mut) carriers.

Effects of Aerobic and Resistance Exercise on Metabolic Syndrome, Sarcopenic Obesity, and Circulating Biomarkers in Overweight or Obese Survivors of Breast Cancer: A Randomized Controlled Trial.

Purpose Metabolic syndrome is associated with an increased risk of cardiovascular disease, type 2 diabetes, and breast cancer recurrence in survivors of breast cancer. This randomized controlled trial assessed the effects of a 16-week combined aerobic and resistance exercise intervention on metabolic syndrome, sarcopenic obesity, and serum biomarkers among ethnically diverse, sedentary, overweight, or obese survivors of breast cancer. Methods Eligible survivors of breast cancer (N = 100) were randomly assigned to exercise (n = 50) or usual care (n = 50). The exercise group participated in supervised moderate-to-vigorous-65% to 85% of heart rate maximum-aerobic and resistance exercise three times per week for 16 weeks. Metabolic syndrome z-score (primary outcome), sarcopenic obesity, and serum biomarkers were measured at baseline, postintervention (4 months), and 3-month follow-up (exercise only). Results Participants were age 53 ± 10.4 years, 46% were obese, and 74% were ethnic minorities. Adherence to the intervention was 95%, and postintervention assessments were available in 91% of participants. Postintervention metabolic syndrome z-score was significantly improved in exercise versus usual care (between-group difference, -4.4; 95% CI, -5.9 to -2.7; P < .001). Sarcopenic obesity (appendicular skeletal mass index, P = .001; body mass index, P = .001) and circulating biomarkers, including insulin ( P = .002), IGF-1 ( P = .001), leptin ( P = .001), and adiponectin ( P = .001), were significantly improved postintervention compared with usual care. At 3-month follow-up, all metabolic syndrome variables remained significantly improved compared with baseline in the exercise group ( P < .01). Conclusion Combined resistance and aerobic exercise effectively attenuated metabolic syndrome, sarcopenic obesity, and relevant biomarkers in an ethnically diverse sample of sedentary, overweight, or obese survivors of breast cancer. Our findings suggest a targeted exercise prescription for improving metabolic syndrome in survivors of breast cancer and support the incorporation of supervised clinical exercise programs into breast cancer treatment and survivorship care plans.

Treatment of Endometriosis with the GnRHa Deslorelin and Add-Back Estradiol and Supplementary Testosterone.

BACKGROUND: This randomized, multicenter, open-label clinical trial was intended to generate pilot data on the efficacy and safety of the gonadotropin-releasing hormone agonist (GnRHa) deslorelin (D) with low-dose estradiol ± testosterone (E2 ± T) add-back for endometriosis-related pelvic pain. METHODS: Women with pelvic pain and laparoscopically confirmed endometriosis were treated with a six-month course of daily intranasal D with concurrent administration of either transdermal E2, intranasal E2, or intranasal E2 + T. Efficacy data included evaluation of dyspareunia, dysmenorrhea, pelvic pain, tenderness, and induration. Cognition and quality of life were also assessed. Safety parameters included assessment of endometrial hyperplasia, bone mineral density (BMD), and hot flashes. RESULTS: Endometriosis symptoms and signs scores decreased in all treatment arms from a baseline average of 7.4 to 2.5 after 3 months of treatment and 3.4 after 6 months. BMD changes and incidence of hot flashes were minimal, and no endometrial hyperplasia was observed. Patient-reported outcomes showed significant improvement across multiple domains. CONCLUSIONS: Daily intranasal D with low dose E2 ± T add-back resulted in significant reduction in severity of endometriosis symptoms and signs with few safety signals and minimal hypoestrogenic symptoms that would be expected with the use of a GnRHa alone.

Biological effects of green tea capsule supplementation in pre-surgery postmenopausal breast cancer patients.

Regular green tea intake has been associated with an inverse risk of breast cancer. There are compelling experimental evidence that green tea, particularly, epigallocatechin gallate, the most potent green tea catechin, possesses a range of anti-cancer properties. We conducted a pre-surgical study of green tea capsules vs. no-green tea in women with primary breast cancer to determine the effects of green tea supplementation on markers of biological response. Postmenopausal women with ductal carcinoma in situ (DCIS) or stage I or II breast cancer took green tea capsules (940 mg per day) for an average of 35 days prior to surgery (n = 13) or received no green tea (n = 18). Paired diagnostic core biopsy and surgical specimen samples were analyzed for cell proliferation (Ki-67), apoptosis (caspase-3), and angiogenesis (CD34) separately in benign and malignant cell components. There were no significant changes in caspase-3 and CD34 in the green tea and no green tea groups and there were no significant differences in the change in these markers between the two groups. However, Ki-67 levels declined in both benign and malignant cell components in the green tea group; the decline in Ki-67 positivity in malignant cells was not statistically significant (P = 0.10) but was statistically significant in benign cells (P = 0.007). Ki-67 levels in benign and malignant cells did not change significantly in the no green tea group. There was a statistically significant difference in the change in Ki-67 in benign cells (P = 0.033) between the green tea and the no green tea groups. The trend of a consistent reduction in Ki-67 in both benign and malignant cells in the green tea group warrants further investigations in a larger study of breast cancer patients or high-risk women.

Lowering oral contraceptive norethindrone dose increases estrogen and progesterone receptor levels with no reduction in proliferation of breast epithelium: a randomized trial.

BACKGROUND: This study was conducted to compare breast epithelial-cell proliferation and estrogen and progesterone receptor levels in women taking one of two oral contraceptives (OCs) containing the same dose of estrogen but different doses of the progestin norethindrone (NET). STUDY DESIGN: Thirty-three women were randomly assigned 1:1 to one of two OCs with 35-mcg ethinylestradiol (EE2) but different doses of NET - 1 or 0.4 mg. At the end of the active pill phase of the third OC cycle, a breast biopsy was performed and the percentages of epithelial cells of the terminal duct lobular units were measured for Ki67 (MIB1), progesterone receptors A and B (PRA and PRB, respectively), and estrogen receptor α (ERα). RESULTS: The biopsies from 27 women had sufficient epithelium for analysis. The percentages of cells positive for PRA, PRB and ERα were approximately double with the lower progestin dose (PRA: p=.041; PRB: p=.030; ERα: p=.056). The Ki67 percentage was not reduced with the lower progestin dose (12.5% for 0.4-mg NET vs. 7.8% for 1.0-mg NET). CONCLUSIONS: The increase in PRA-, PRB- and ERα-positive cells with the 60% lower progestin dose OC appears likely to account for its failure to decrease breast-cell proliferation. This breast-cell proliferation result is contrary to that predicted from the results of lowering the medroxyprogesterone acetate dose in menopausal hormone therapy.

Characteristics of triple-negative breast cancer in patients with a BRCA1 mutation: results from a population-based study of young women.

PURPOSE: Triple-negative breast cancers (TNBCs) are tumors with low or no expression of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. These tumors have a poor prognosis, remain a clinical challenge, and are more common among women with BRCA1 mutations. We tested whether there are distinguishing features of TNBC after BRCA1 mutation status has been taken into account. PATIENTS AND METHODS: We sequenced BRCA1 and BRCA2 genes in a population-based sample of 1,469 patients with incident breast cancer age 20 to 49 years from Los Angeles County (California). Information on tumor receptor status was available for 1,167 women. Clinical, pathologic, and hormone-related lifestyle characteristics were compared across patient subgroups defined by BRCA1 mutation status and triple-negative receptor status. RESULTS: Forty-eight percent of BRCA1 mutation carriers had TNBC compared with only 12% of noncarriers. Within BRCA1 mutation carriers, as well as within noncarriers, triple-negative receptor status was associated with younger age at diagnosis and higher tumor grade. Among women without a BRCA1 mutation, we observed that women with TNBC had higher premenopausal body mass index and earlier age at first full-term pregnancy than those with non-TNBC. Age at menarche and other reproductive factors were not associated with triple-negative status regardless of BRCA1 mutation status. Within BRCA1 mutation carriers, Ashkenazi Jewish women were about five times more likely to have TNBC than non-Ashkenazi Jewish women. CONCLUSION: Our results suggest that among BRCA1 mutation carriers, as among noncarriers, there are unique characteristics associated with the triple-negative subtype. The findings in Ashkenazi Jewish BRCA1 mutation carriers should be confirmed.