Menstrual cycle associated changes in hormone-related gene expression in oestrogen receptor positive breast cancer.

The major changes in hormone levels that occur through the menstrual cycle have been postulated to affect the expression of hormone-regulated and proliferation-associated genes (PAGs) in premenopausal ER+ breast cancer. Whilst previous studies have demonstrated differences in gene expression, here, we investigated if there are within patient changes in the expression of oestrogen- and progesterone-regulated genes (ERGs and PRGs) and PAGs in ER+ breast cancer during the menstrual cycle. Samples from 96 patients in two independent prospective studies of the effect of menstrual cycle on ER+ breast cancer were used. Plasma hormone measurements were used to assign tumours to one of three pre-defined menstrual cycle windows: W1 (days 27-35 and 1-6; low oestradiol and low progesterone), W2 (days 7-16; high oestradiol and low progesterone) and W3 (days 17-26; intermediate oestradiol and high progesterone). RNA expression of 50 genes, including 27 ERGs, 11 putative PRGs and seven PAGs was measured. The AvERG (geomean of PGR, GREB1, TFF1 and PDZK1) was used as a composite measure of ERG expression and showed significant changes between the three windows of the menstrual cycle increasing over 2.2-fold between W1 and W2 and decreasing between W2 and W3 and between W3 and W1. Proliferation gene expression also varied significantly, following the same pattern of changes as ERG expression, but the changes were of lower magnitude (1.4-fold increase between W1 and W2). Significant changes in the expression of eight individual ERGs, including GREB1, PGR and TFF1, and two PAGs were observed between W1 and either W2 or W3 with all genes showing higher levels in W2 or W3 (1.3-2.4-fold; FDR 0.016-0.05). The AvProg, a composite measure of PRG expression, increased significantly (1.5-fold) in W3 compared to W1 or W2 but no significant changes were observed for individual PRGs. In conclusion, we observed significant changes in ERG, PRG and PAG expression in ER+ breast tumours during the menstrual cycle that may affect the assessment and interpretation of prominent biomarkers (e.g. PgR) and commonly used multigene prognostic signatures in premenopausal ER+ breast cancer.

Molecular changes in premenopausal oestrogen receptor-positive primary breast cancer in Vietnamese women after oophorectomy.

For premenopausal women with primary ER + breast cancer, oophorectomy (OvX) is an evidence-based cost-effective option and is standard treatment in many countries. However, there is virtually no data describing the effects of OvX on breast tumour biology. We therefore, characterised the endocrine and genome-wide transcriptional impact of OvX in 56 premenopausal women with ER + breast cancer for 2 weeks prior to mastectomy. Plasma estradiol concentrations decreased from 406 ± 41 to 20.7 ± 2.6 pmol/l (mean ± sem) 24 h after OvX, and to 8.1 ± 0.8 pmol/l 2 weeks later at mastectomy. Ki67 decreased in 33/36 (91.7%) tumours. The expression of 655 genes changed significantly (FDR < 1%) with an absolute mean fold-change (FC) ≥ 1.25 (257 up, 398 down). Archetypal oestrogen-regulated genes (TFF1, GREB1, PGR and PDZK1) showed large decreases in expression (FC = 0.20-0.69; p < 1e-6-1e-7). Proliferation-associated genes (e.g. TOP2A, AURKA and UBE2C) were also strongly downregulated (FC = 0.38-0.56; p < 1e-7) along with putative progesterone-regulated genes (e.g. FKBP4, MYB; FC = 0.64-0.68; p < 1e-4-1e-7). The gene expression changes did not differ according to HER2 status and correlated strongly with the changes reported previously after aromatase inhibitor (AI) treatment in postmenopausal women (rho = 0.55, p < 1e-04). However, after OvX the mean FC was significantly higher compared to AI (p < 1e-04). In conclusion, changes in tumoural gene expression after OvX were largely similar, but of a greater magnitude to those observed after AI in postmenopausal patients; however, OvX appeared to have a greater effect on progesterone-regulated genes than AI.

Mastectomy and oophorectomy by menstrual cycle phase in women with operable breast cancer.

BACKGROUND: It is unclear whether the phase of the menstrual cycle in which primary surgical treatment occurs influences disease-free survival (DFS) and overall survival (OS) in premenopausal women with breast cancer. We investigated this question in the context of a clinical trial comparing mastectomy alone with mastectomy plus adjuvant oophorectomy and tamoxifen in premenopausal women with operable breast cancer. METHODS: The date of the first day of the last menstrual period (LMP) was used to estimate the phase of the menstrual cycle when the surgeries were done. Follicular phase was defined as day 1-14 from LMP. Luteal phase was defined as day 15-42 from LMP. DFS and OS statistics were determined and analyzed by Cox proportional hazards ratios and Kaplan-Meier methods. All statistical tests were two-sided. RESULTS: We analyzed results for 565 women who reported an LMP within 42 days before surgery. For women in the mastectomy only arm (n = 289), there were no differences in DFS or OS by menstrual cycle phase. For women in the adjuvant treatment arm (n = 276), those whose surgery occurred during the luteal phase (n = 158) had better DFS (relative risk [RR] = 0.54; 95% confidence interval [CI] = 0.32 to 0.96; P =.02) and OS (RR = 0.53; 95% CI = 0.30 to 0.95; P =.03) than those whose surgery occurred during the follicular phase (n = 118). Moreover, women whose surgery occurred during the luteal phase and who received adjuvant therapy had better 5-year DFS than did women whose surgery occurred during the follicular phase (84%; 95% CI = 78% to 90% versus 67%; 95% CI = 58% to 78%; P =.02); they also had better OS (85%; 95% CI = 78% to 92% versus 75%; 95% CI = 66% to 84%; P =.03). CONCLUSIONS: The phase of the menstrual cycle at which surgery was done had no impact on survival for women who received mastectomy only. However, women who received a mastectomy and surgical oophorectomy and tamoxifen during the luteal phase had better outcomes than women who received surgery during the follicular phase.

Oophorectomy and tamoxifen adjuvant therapy in premenopausal Vietnamese and Chinese women with operable breast cancer.

PURPOSE: In 1992, the Early Breast Cancer Trialists' Collaborative Group reported that a meta-analysis of six randomized trials in European and North American women begun from 1948 to 1972 demonstrated disease-free and overall survival benefit from adjuvant ovarian ablation. Approximately 350,000 new cases of breast cancer are diagnosed annually in premenopausal Asian women who have lower levels of estrogen than western women. PATIENTS AND METHODS: From 1993 to 1999, we recruited 709 premenopausal women with operable breast cancer (652 from Vietnam, 47 from China) to a randomized clinical trial of adjuvant oophorectomy and tamoxifen (20 mg orally every day) for 5 years or observation and this combined hormonal treatment on recurrence. At later dates estrogen- and progesterone-receptor protein assays by immunohistochemistry were performed for 470 of the cases (66%). RESULTS: Treatment arms were well balanced. With a median follow-up of 3.6 years, there have been 84 events and 69 deaths in the adjuvant treatment group and 127 events and 91 deaths in the observation group, with 5-year disease-free survival rates of 75% and 58% (P =.0003 unadjusted; P =.0075 adjusted), and overall survival rates of 78% and 70% (P =.041 unadjusted) for the adjuvant and observation groups, respectively. Only patients with hormone receptor-positive tumors benefited from the adjuvant treatment. In Vietnam, for women unselected for hormone receptor status, a cost-effectiveness analysis suggests that this intervention costs $350 per year of life saved. CONCLUSION: Vietnamese and Chinese women with hormone receptor-positive operable breast cancer benefit from adjuvant treatment with surgical oophorectomy and tamoxifen.

Young age as an adverse prognostic factor in premenopausal women with operable breast cancer.

Data regarding young age as an independent prognostic factor have been conflicting. We investigated this variable in 696 premenopausal Vietnamese and Chinese women with operable breast cancer who participated in a clinical trial of adjuvant surgical oophorectomy and tamoxifen. Tumor size and axillary lymph node status did not vary with age. Women < 35 years had a greater fraction of histologic grade III tumors (P = 0.06), and in the two thirds of patients with available data, in women < 35 years, there was a lower percentage of estrogen- and progesterone receptor-positive tumors and a higher percentage of HER2/neu-positive tumors (P > 0.14 for each group). In univariate analyses, compared to women > or = 45 years, women < 35 years and 35-39 years were at greater risk for death (P = 0.002 and P = 0.023, respectively), and compared to women > or = 40, women < 40 were at greater risk of death (P = 0.002). Multivariate analyses supported a conclusion that younger age was an independent adverse prognostic factor for survival (P = 0.005, age as a continuous variable). Kaplan-Meier analyses in all patients and in oophorectomy and tamoxifen-treated patients, but not in observation-only patients, showed statistically significant poorer disease-free and overall survival in women < 40 years compared to those > or = 40 years. Thus, despite efficacy of the combined adjuvant hormonal therapy, younger age was a risk factor for poorer survival.