Premenopausal ER Research Articles

Vascular endothelial growth factor expression and T-regulatory cells in premenopausal breast cancer

Estradiol (E2) plays a key role in human reproduction through the induction of vascular endothelial growth factor (VEGF) and T-regulatory cells (T-Regs), which are also important in breast cancer (BC) growth. The primary endpoint of the present study was the investigation of whether E2 suppression, chemotherapy and radiation therapy decreased the levels of VEGF and T-Regs of premenopausal patients with high-risk early BC. The secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). Between April 2003 and July 2008, 100 premenopausal women with early, high-risk BC were entered into the study. The characteristics of the patients were as follows: median age, 43 years (range, 26–45); median number of positive axillary nodes, 3.3; median Ki-67, 33%. Plasma E2, VEGF and T-Reg were measured at baseline and every year. Treatment comprised luteneizing hormone-releasing hormone (LH-RH) analogue, tailored chemotherapy, radiation therapy and hormonal therapy in oestrogen receptor-positive (ER+) tumours. At 4 years, a statistically significant decrease in E2, VEGF and T-Reg levels was observed; the PFS and OS rates were 94 and 98%, respectively. Hot flushes and G1 osteopenia occurred following LH-RH analogue administration, while no unexpected toxicity was observed following chemotherapy. E2 deprivation with an LH-RH analogue, tailored chemotherapy, radiation therapy and hormonal therapy in ER+ tumours decreased plasma VEGF levels and T-Regs numbers in premenopausal high-risk ER+ and ER- BC patients. In addition, a favorable impact on PFS and OS was observed.

Height, Sitting Height, and Leg Length in Relation with Breast Cancer Risk in the E3N Cohort

If height is a well-established risk factor for breast cancer, leg length and sitting height are usually considered as better candidate biomarkers of growth hormone exposure than height, respectively, in pre- and postpuberty. Risk of breast cancer associated with quartiles of height, sitting height, and leg length were estimated in the French E3N cohort (N = 50,704, including 2,065 breast cancer cases), stratified on both menopausal and hormone receptor statuses. Height was associated with an increased postmenopausal breast cancer risk [HR = 1.22 (1.06-1.41) when comparing extreme categories, P(trend) = 0.002], which was exclusively driven by the association with leg length [HR = 1.21 (1.05-1.39), P(trend) = 0.013] and not sitting height [HR = 1.03 (0.89-1.18), P(trend) = 0.379]. Leg length was associated with an increased ER(+) breast cancer risk in postmenopausal [HR = 1.24 (1.06-1.46), P(trend) = 0.004], whereas sitting height was associated with a borderline decreased ER(-) premenopausal breast cancer risk [HR = 0.45 (0.20-1.01), P(trend) = 0.011]. The positive associations observed in the overall population between leg length and breast cancer risk were actually restricted to women who had a short birth length [HR = 1.82 (1.22-2.72), P(trend) = 0.022] and those with a low birth weight [HR = 1.43 (1.00-2.04), P(trend) = 0.054]. The two components of height risk are differentially associated with breast cancer risk: leg length with an increased risk of postmenopausal ER(+) tumors and sitting height with a decreased risk of premenopausal ER(-) tumors. Future prospective studies should no longer consider height a single risk factor for breast cancer risk.

Association of response to neoadjuvant chemotherapy (NAC) in premenopausal patients with hormone receptor-positive early breast cancer with chemotherapy-induced ovarian function suppression by NAC.

e11017 Background: The purpose of this study is to assess the additive endocrine effect by chemotherapy-induced ovarian function suppression (CIOS) for premenopausal women with early breast cancer in neoadjuvant chemotherapy (NAC). Methods: We retrospectively compared the clinical efficacy to NAC between premenopausal and postmenopausal patients with early breast cancer to evaluate the endocrine effect by CIOS. One-hundred twenty two patients received NAC with anthracycline-containing regimen and/or taxane in Kumamoto University Hospital between April 2004 and March 2011. Results: Objective response rate by NAC in premenopausal ER-positive/HER2-negative patients is greater than that in postmenopausal ER-/HER2+ patients (premenopausal 93% vs. postmenopausal 63%, p=0.0121). Reduction rate of primary tumor by NAC on imaging studies in premenopausal ER+/HER2- patients is greater than that in postmenopausal ER-/HER2+ patients (premenopausal 54% vs. postmenopausal 40%, p=0.006). However, no significant difference in response rate between in premenopausal patients with other subtypes and postmenopausal patients with those was found (ER+/HER2+; premenopausal 50% vs. postmenopausal 48%, ER-/HER2+; premenopausal 43% vs. postmenopausal 77%, Triple-negative; premenopausal 86% vs. postmenopausal 65%). All of premenopausal women were suppressed ovarian function within two months after initiation of NAC. Expression levels of progesterone receptor on primary tumor in premenopausal ER+ cancer were significantly decreased after NAC compared with that in postmenopausal ER+ cancer (premenopausal -40.3% vs. postmenopausal +3.6%, p<0.001). Conclusions: These data suggests that CIOS by NAC contributes the additive effects through the endocrine fashion in premenopausal patients with ER+/HER2- breast cancer.

Hip circumference is associated with the risk of premenopausal ER−/PR− breast cancer

We evaluated the relationship between hip and waist circumferences (HCs, WCs), waist-to-hip ratio, height, weight and body mass index (BMI) and breast cancer risk according to menopausal status of women and cancer hormone receptor status. We used data from the French E3N longitudinal prospective cohort. In the total population of 63 726 women who were analyzed, 1887 breast cancer cases were diagnosed during follow-up. Among postmenopausal women, the risk of ER+/PR+ breast cancer increased with increasing weight, BMI, and both HCs and WCs, although these two associations disappeared after adjustment for BMI. No association was seen with ER-/PR- breast cancers. Among premenopausal women, among the different factors studied, HC only (no association was observed for any of the different factors studied except for HC) was associated with an increased risk of ER+/PR+ breast cancer after adjustment for BMI (hazard ratio (HR)=1.65; (1.04-2.62) when comparing the highest to lowest tertile; P-trend across tertiles=0.03) and of ER-/PR- breast cancer both before and after adjustment for BMI (HR=2.85 (1.33-6.13); P-trend <0.01, and HR=3.13 (1.19-8.27) P-trend =0.02, respectively). In the latter group, the association with HC was observed whatever the WC (HR=2.81 (1.18-6.70) and HR=2.79 (1.16-6.76) in women with high HC/low WC and high HC/high WC, respectively). The increase in risk of premenopausal breast cancer associated with large HC for both ER+/PR+ and ER-/PR- subtypes may provide insight into a specific risk factor for premenopausal breast cancer.

The OPTION trial of adjuvant ovarian protection by goserelin in adjuvant chemotherapy for early breast cancer.

590 Background: Nonrandomised studies suggest that goserelin may protect the ovaries against chemotherapy induced premature menopause. The primary objective of the open, randomised multicentre OPTION trial was to determine the impact of goserelin on the incidence of premature ovarian failure following chemotherapy for operable breast cancer. Secondary objectives were to record menstruation (diary) and pregnancies, assess quality of life (FACT-ES) and menopausal symptoms, and measure changes in bone mineral density (BMD) and bone turnover markers, hormone levels (including AMH and inhibin B). Methods: All premenopausal ER negative women (or ER positive women for whom ovarian suppression was not considered necessary) planned for adjuvant or neoadjuvant chemotherapy, were considered for inclusion. Women were stratified by age >/ = 40 or < 40 years at randomisation, and by centre. Chemotherapy regimens comprised any 6-8 cycles of chemotherapy containing cyclophosphamide and/or anthracycline. Regimens could include taxanes. Goserelin was randomly allocated to start before or at first chemotherapy cycle and continued 3-4 weekly to final cycle. For the purposes of the sample size calculation, the rates of premature menopause were assumed to be 40% in the under 40 age group and 80% in the over 40 age group (Bines et al, J Clin Oncol 14(5):1718-29 1996). Reported rates of preservation of ovarian function using goserelin with chemotherapy in uncontrolled studies are around 80%, (possibly higher in the under 40's): i.e. rates of premature menopause with goserelin of around 20% or less. Based on a one sided test with 5% false positive rate, the groups required approximately 140 and 70 patients respectively to have a 80% chance of detecting an absolute reduction in premature menopause rate of 20% and 25% respectively, that is from 40% to 20% in the under 40 age group and from 80% to 55% in the over 40 age group. A total of 210 patients were therefore required. Results: At trial closure, 31/12/09, 227 patients had been randomised. Conclusions: The primary accrual endpoint of more than 210 patients has been achieved and so we expect the statistical requirements to be met. Primary and selected secondary endpoints will be presented. No significant financial relationships to disclose.

Abstract A60: A randomized, 3-arm phase II presurgical trial of weekly tamoxifen or raloxifene versus placebo in premenopausal breast cancer patients: Preliminary results

Abstract A60 The presurgical model is a useful tool to screen and evaluate drug activity and select new chemopreventive agents. Cancer cell proliferation measured by Ki-67 is considered to be a reliable surrogate biomarker in assessing the efficacy of chemopreventive agents. We previously demonstrated that tamoxifen (Tam) given in breast cancer (BC) patients at lower daily doses (1 and 5 mg/d) before surgery for 4 weeks reduced the tissue expression of Ki-67 to the same extent of the standard 20 mg/d dose. Given the long half-life of Tam and its metabolites a weekly dose (10mg/w) may be worth testing to assess the minimal active dose. Raloxifene (Ral), another SERM, has been shown to reduce Ki-67 in a preoperative setting and has been shown to be an effective BC preventive agent only in postmenopausal women so far. The primary endpoint of the present study was to assess the activity of Tam 10mg/w or Ral 60 mg/d relative to placebo as measured by Ki-67 percentage change in premenopausal ER positive BC patients treated for 6 weeks before surgery. Estimating a 20% relative increase of Ki-67 in the placebo arm and a 25% decrease in both treatment arms with a 80% power and a two-tailed test 5% significance, a total of 90 subjects (18 in the placebo arm and 36 in each treatment arm) was required. Secondary endpoints were changes in ER and PgR expression, apoptosis, gene expression profile focusing on nuclear receptor coregulators (AIB1, SRC1, TIF-2/GRIP1, N-CoR and SMRT) on frozen tissue, circulating biomarkers (hormones, markers of inflammation and hemostasis, growth factors, bone markers) and genomic DNA analyses of genetic polymorphisms related to breast cancer, hormone metabolism, response to DNA damage, and cardiovascular events. Ninety-four patients were allocated to either Tam 10 mg/w (n=37), or Ral 60 mg/d (n=38) or placebo (n=19). Baseline median age and BMI were 44, 46, 44 years, and 22, 23, 23 in the Tam, Ral and placebo group respectively. Baseline median ki-67 was 22, 22, 15 in the Tam, Ral and placebo arm, respectively. After adjustment for baseline values, Ls means of changes of ki67 were -0.3 (-3.7, 3.1), 0.3 (-3, 3.6), -2.4 (-7.3, 2.5), ls means of changes of PgR were -1.2 (-9.4, 7), -6.4 (-14.4, 1.6), 6.7 (-5, 18.4) and ls means of changes of ER were -0.5 (-5.6, 4.6), 0.4 (-4.7, 5.4), 0.6 (-6.7, 7.9) in the Tam, Ral and Placebo arm, respectively. No statistically significant differences among arms nor between treatments and placebo have been observed. Overall compliance measured with pill count was above 80%. No severe AEs occurred. Contrary to previous observation with daily administration of low dose Tam, a weekly dose of 10 mg did not show a significant antiproliferative effect in premenopausal women. Likewise, Ral had a similar null effect on ki-67. ER and PgR were not significantly modulated by both drugs. Our results indicate that administration of weekly Tam and Ral at the standard dose and schedule did not change the proliferative index of breast cancer in premenopausal women with early BC. Evaluation of hormonal metabolism, growth factors (e.g., IGFs), ER/PgR coregulators, is ongoing and will help in elucidating these biological effects. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A60.

Goserelin plus anastrozole (G+A) as first-line systemic therapy for premenopausal estrogen receptor positive (ER+) advanced breast cancer (ABC)— clinical and endocrine data

1091 Background: Trials have shown superiority of aromatase inhibitors over tamoxifen for postmenopausal ER+ ABC. We previously reported the use of G+A as second-line endocrine therapy for premenopausal ER+ ABC. We report clinical and endocrine data from G+A as first-line systemic therapy. Methods: Thirty-six patients (median age = 44 [30–59] years) with UICC assessable disease (metastatic = 30; else = locally advanced) were administered G+A (3.6 mg 4-weekly + 1 mg daily respectively) for ≥6 months (unless progressed prior). Serum estradiol, DHEAS, testosterone, FSH and LH levels were measured by standardized and sensitive (estradiol only) hormone assays in six patients who consented for blood samples. Results: Thirty-two patients (67%) derived clinical benefit (CB) (5% complete response, 31% partial response, 31% stable disease for ≥6 months) with median time-to-progression and duration of CB of 7(2–48) and 23+(6–64+) months, respectively. Therapy was well tolerated with no withdrawals. Thirteen patients...

Estrogen receptor status as a prognostic indicator for stage I breast cancer patients.

The prognostic value of estrogen receptor determination was studied for 510 stage I (axillary node negative) breast cancer patients treated by mastectomy alone. Results at 60 months after mastectomy indicate that stage I patients whose tumors lack estrogen receptors fall into a significantly poorer prognostic group for both recurrence and survival than those whose tumors contain estrogen receptors. Within the postmenopausal group, estrogen receptor negative (ER -) patients are recurring more rapidly than estrogen receptor positive (ER +) patients. Within the premenopausal group, ER + patients have a recurrence rate identical to ER - patients, which is apparent only after prolonged follow-up. In contrast to postmenopausal ER + patients, premenopausal ER + patients appear to have no prognostic advantage over the ER - patients, and thus constitute a high risk group for which adjuvant endocrine therapy might prove beneficial.