The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L).

BACKGROUND: The purpose of this study was to evaluate changes in serum lipid parameters {cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein(a) [Lp(a)]}, in postmenopausal women receiving letrozole or placebo after adjuvant tamoxifen for early stage breast cancer (NCIC CTG MA.17L). PATIENTS AND METHODS: MA.17L is a substudy of MA.17, a randomized, double-blind, placebo-controlled trial of letrozole 2.5 mg taken daily for 5 years in postmenopausal women with primary breast cancer completing approximately 5 years of prior adjuvant tamoxifen. Patients consenting to participate in this companion study had blood drawn and lipid parameters (total cholesterol, HDL cholesterol, LDL cholesterol, Lp(a), triglycerides) evaluated at baseline, 6 months, 12 months and yearly thereafter until completion of protocol therapy. It was required that women be non-hyperlipidemic and not taking lipid-lowering drugs at time of entry on this trial. RESULTS: Three hundred and forty seven women were enrolled in the study. The letrozole and the placebo groups demonstrated marginally significant differences in the percentage change from baseline in HDL cholesterol at 6 months (P=0.049), in LDL cholesterol at 12 months (P=0.033) and triglycerides at 24 months (P=0.036). All comparisons of lipid parameters at other time points were not significantly different between the two treatment groups. No statistically significant differences in the number of patients exceeding the thresholds defined for the lipid parameters were found between the two treatment groups. CONCLUSIONS: The MA.17 trial demonstrated a significant improvement in disease-free survival with the use of letrozole as extended adjuvant therapy post tamoxifen. Results from this study suggests that letrozole does not significantly alter serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides or Lp(a) in non-hyperlidiemic postmenopausal women with primary breast cancer treated up to 36 months following at least 5 years of adjuvant tamoxifen therapy. These findings further support the tolerability of extended adjuvant letrozole in postmenopausal women following standard tamoxifen therapy.     

Anthropometric measures, endogenous sex steroids and breast cancer risk in postmenopausal women: a study within the EPIC cohort

In a large case-control study on breast cancer risk and serum hormone concentrations, nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we examined to what extent the relationship of excess body weight with breast cancer risk may be explained by changes in sex steroids. Height, weight, waist and hip circumferences, and serum measurements of testosterone [T], androstenedione [Delta4], dehydroepiandrosterone sulphate [DHEAS], estradiol [E2], estrone [E1] and sex-hormone binding globulin [SHBG] were available for 613 breast cancer cases, and 1,139 matched controls, who were all menopausal at the time of blood donation. Free T [fT] and free E2 [fE2] were calculated using mass action equations. Breast cancer risk was related to body mass index (BMI) (RR = 1.11 [0.99-1.25], per 5 kg/m2 increase in BMI), and waist (RR = 1.12 [1.02-1.24], per 10 cm increase) and hip circumferences (RR = 1.14 [1.02-1.27], per 10 cm increase). The increase in breast cancer risk associated with adiposity was substantially reduced after adjustment for any estrogens, especially for fE2 (from 1.11 [0.99-1.25] to 0.99 [0.87-1.12], from 1.12 [1.02-1.24] to 1.02 [0.92-1.14] and from 1.14 [1.02-1.27] to 1.05 [0.93-1.18] for BMI, waist and hip circumferences, respectively). A modest attenuation in excess risk was observed after adjustment for fT, but the remaining androgens had little effect on the association of body adiposity with breast cancer. Our data indicate that the relationship of adiposity with breast cancer in postmenopausal women could be partially explained by the increases in endogenous estrogens, and by a decrease in levels of SHBG.     

Serum enterolactone and postmenopausal breast cancer risk by estrogen, progesterone and herceptin 2 receptor status

Lignans are a group of estrogenic compounds present in plants. Several epidemiological studies proposed that lignans may protect against breast cancer by exerting anticarcinogenic activity. Levels of enterolactone were determined in serum samples of 1,250 cases and 2,164 controls from a large population-based case-control study. We assessed the association between serum enterolactone and postmenopausal breast cancer risk using conditional logistic regression accounting for potential risk and confounding factors. Fractional polynomials were used to determine the function that best fitted the data. Moreover, we assessed heterogeneity by estrogen/progesterone/herceptin (ER/PR/HER2) status of the tumor. Additionally, a meta-analysis with seven further studies addressing enterolactone concentrations and breast cancer risk was performed. Postmenopausal breast cancer risk decreased with increasing serum enterolactone levels [highest compared to lowest quintile: [odds ratio = 0.65; 95% confidence interval (CI) 0.52-0.83, p(trend) = < 0.0001]. A significant inverse association for ER+/PR+ as well as ER-/PR- tumors was observed, with a significantly stronger association for ER-/PR- tumors (p(heterogeneity) = 0.03). The association for ER-/PR- tumors did not differ by expression of HER2 (p(heterogeneity) = 0.3). The meta-analysis yielded a significant reduced pooled risk estimate of: 0.66; 95% CI: 0.55-0.77) comparing the highest to the lowest quantiles of enterolactone levels. We found strong evidence for a significant inverse association between serum enterolactone and postmenopausal breast cancer risk, which was stronger for ER-PR- than for ER+PR+ tumors but not differential by further expression of HER2. The overall evidence together with other studies supports an inverse association between higher serum enterolactone levels and postmenopausal breast cancer risk.     

Urinary steroids at time of surgery in postmenopausal women with breast cancer

Urinary steroid metabolites were measured by capillary gaschromatography in 22 postmenopausal women with operable breastcancer on day before the tumour excision andin 20 hospitalised control who were before anoperation from other cause than cancer. Serum dehydroepiandrosterone-sulphat(DHEAS) and testosterone (T) level were measured byradioimmunassay in the same groups and same time.There was no significant difference in the levelof urinary androgen metabolites. Pregnanediol level was significantlylower (P < 0.05) in cancer patients. Inthe 5 patients with positive axillary nodes thetetrahydrocortisol and -cortolone levels were significantly (P <0.05) higher than in node negative ones. Therewas no significant differences in the serum DHEASand T levels. These results indicate that metabolicchanges are existing in postmenopausal patients which maybe a cause or a consequence of thedisease.     

Birth weight is associated with postmenopausal breast cancer risk in Swedish women

There is some evidence that birth weight is associated with breast cancer. Whether this association differs between premenopausal and postmenopausal ages is still unclear. The results from this study suggest that higher birth weight is a risk factor for postmenopausal breast cancer (OR 1.06, CI 1.00-1.12, per 100 g), independent of selected early-life and adult factors.     

Whole and refined grain intake and risk of incident postmenopausal breast cancer (United States)

Objective: To assess the relation between whole and refined grain intake and risk of incident postmenopausal breast cancer. Findings from case–control studies of whole and refined grain intake and risk of postmenopausal breast cancer have been inconclusive. Methods: The Iowa Women's Health Study is a prospective cohort study of women initially 55–69 years old that relates diet and other lifestyle factors to cancer risk. After exclusions a total of 29,119 menopausal women who answered a 1986 baseline and a 1989 follow-up questionnaire were followed for 9 years for incident breast cancer. Results: Compared to women who at baseline rarely ate whole grain foods, women who habitually ate whole grain had a healthier lifestyle, including a higher likelihood of prior screening mammography. The multivariate-adjusted risk of incident breast cancer was 20% higher in women in the highest quintile of whole grain intake, compared to women in the lowest quintile of whole grain intake (95% confidence interval 0.95–1.5; p-value for trend = 0.03). No increase in breast cancer risk was found in women who had not undergone screening mammography before 1989; the apparent increase in risk was therefore likely due to increased use of screening mammography. Refined grain intake was not associated with breast cancer risk. Conclusion: Consistent with inverse but not statistically significant associations between whole grain intake and breast cancer in case–control studies, both whole and refined grain intakes are unrelated to risk of postmenopausal breast cancer in these Iowa women.     

Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis

One hundred fiftyone postmenopausal women with progressive metastatic breast cancer and no prior hormonal therapy were treated with either diethylstilbestrol (DES) or tamoxifen (TAM). One hundred fortythree eligible patients were followed until death or for a minimum of 14.1 years on the DES arm or 16.7 years on the TAM arm. The overall objective response was 42% for DES and 33% for TAM (p=0.31) and the median duration of response was 11.8 months for DES and 9.9 months for TAM (p=0.38). Duration of response and progressionfree survival were not found to be significantly different between DES and TAM (p=0.32 and 0.65, respectively). The median survival was 3.0 years for DES vs. 2.4 years for TAM. The 5year survival was 35% for the DES arm and 16% for the TAM arm. Survival was significantly better for women on DES than for women on TAM (adjusted p=0.039). Review of records did not show any difference in pattern of treatment failure or subsequent treatments in the DES and TAM arms.Treatment with DES was more commonly associated with toxicity such as nausea, edema, vaginal bleeding, and cardiac problems, whereas hot flashes were commonly seen with TAM therapy.The initial treatment with DES is associated with increased survival. The basis of this survival advantage is not known. TAM still is the preferred agent in the treatment of metastatic breast cancer, but this trial underscores the fact that estrogens have activity and remain in the armamentarium for treatment of selected patients with metastatic breast cancer.     

Obesity and subcutaneous fat patterning in relation to survival of postmenopausal breast cancer patients participating in the DOM-project

Summary The effect of obesity and fat distribution on survival of breast cancer patients was studied prospectively in 241 women with a natural menopause who participated in a breast cancer screening project, the DOM-project in Utrecht, The Netherlands. Mean follow-up time was 9.1 years and endpoint of interest was death from breast cancer. Fat distribution was assessed by contrasting groups of subscapular and triceps skinfold thickness.No significant differences in survival time between more obese (Quetelet's index 26 kg/m²) and leaner (Quetelet's index < 26 kg/m²) patients or between patients with central fat distribution and patients with peripheral fat distribution were observed. Analyses were stratified by axillary node status, estrogen receptor status, and way of detection (by first screening or afterwards). Results of the stratified analyses were suggestive of a modifying effect of these factors.The absence of an association between obesity and survival time might be explained by two counteracting mechanisms. On the one hand obesity might be related to impaired survival, due to a tumor growth promoting effect of extra-ovarian estrogens. On the other hand obesity might be related to improved survival in a screened population, because obese patients profit more from screening by earlier detection of tumors than leaner counterparts.     

Prospective study on the role of glucose metabolism in breast cancer occurrence

High circulating glucose, insulin resistance and obesity appear to be associated with increased risk of breast cancer (BC). We sought further insight into the relation of these variables to BC. We assessed associations of BC risk with serum fasting glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR) index and sex-binding hormone globulin (SHBG) in women recruited to the ORDET cohort who gave blood samples in 1987-1992. After a median 13.5 years of follow-up, 356 women developed BC. Four matched controls per case were selected by incidence density sampling, and rate ratios (RR) were estimated by conditional logistic regression. Women in the highest glucose quartile had a significantly greater risk of BC than those in the lowest glucose quartile (RR 1.63; 95% CI: 1.14-2.32; p for trend of 0.003). The association was significant in pre and post menopausal women separately and in women diagnosed after 55 years. Women in the highest HOMA-IR quartile had higher BC risk than the lowest quartile (RR 1.44; 95% CI: 1.03-2.02). Significantly increased BC risk in women diagnosed after 55 years was also present in the highest HOMA-IR quartile; in the same group decreased BC risk was significantly associated with high SHBG. The results of this study add to the existing epidemiological evidence that hyperglycemia and insulin resistance increase BC risk.     

Leptin and insulin growth factor I in relation to breast cancer (Greece)

Objectives: Because both breast cancer and the hormone leptin are associated with obesity and reproductive phenomena in women, we have examined whether there is a relationship between leptin and breast cancer among premenopausal and postmenopausal women. We have also evaluated in this dataset the association of IGF-I with breast cancer. Methods: Seventy-five cases, diagnosed during mammographic screening, with incident breast cancer were matched for age and type of permanent residence with seventy-five controls from those screened negative in the same study base. Results: There was no evidence for an association between IGF-I and either premenopausal or postmenopausal breast cancer risk or between leptin and postmenopausal breast cancer. Among premenopausal women, however, there was a strong and statistically significant inverse association of leptin with breast cancer. Conclusion: We did not confirm the positive association, reported from other investigations, of IGF-I with premenopausal breast cancer risk. We have found evidence, however, that leptin may be inversely related to breast cancer risk among premenopausal women. The latter finding is not biologically implausible and deserves to be examined in additional datasets.     

来曲唑治疗绝经后晚期乳腺癌临床观察

目的观察来曲唑治疗绝经后晚期乳腺癌的疗效和不良反应。方法42例雌激素或孕激素受体阳性或不明的绝经后晚期乳腺癌患者口服来曲唑每日一次,每次2.5mg,28天一周期,至少2周期。结果42例患者中,可评价疗效者42例。完全缓解(CR)0例;部分缓解(PR)5例,占11.9%;稳定(SD)23例,占54.8%,其中SD≥6个月14例,占33.3%;临床获益CBR(CR PR SD≥6个月)19例,占45.2%;进展14例,占33.3%。肿瘤进展时间2月~58月,中位进展时间(TTP)10月。未出现严重不良反应。结论来曲唑治疗绝经后晚期乳腺癌疗效确切,不良反应轻微,耐受性好。     

Previous oral contraceptive use and breast cancer risk according to hormone replacement therapy use among postmenopausal women

Objective To assess postmenopausal breast cancer risk in relation to particular patterns of oral contraceptive (OC) use according to hormone replacement therapy (HRT) exposure.Methods Time-dependent Cox regression models were used to analyse information on postmenopausal women from a large-scale French cohort. Among a total of 68,670 women born between 1925 and 1950, 1405 primary invasive postmenopausal breast cancer cases were identified from 1992 to 2000.Results A non-significant decrease in risk of around 10% was associated with ever OC use as compared to never OC use in postmenopausal women. No significant interaction was found between OC and HRT use on postmenopausal breast cancer risk. Breast cancer risk decreased significantly with increasing time since first OC use (test for trend: p=0.01); this was consistent after adjustment for duration of use or for time since last use.Conclusion No increase in breast cancer risk was associated with previous OC exposure among postmenopausal women, probably because the induction window had closed. Some women may develop breast cancer soon after exposure to OCs, leading to a deficit of cases of older women. Further investigation is therefore required to identify young women at high risk.* Address correspondence to: F. Clavel-Chapelon, Equipe E3N-EPIC, INSERM “Nutrition, Hormones, Cancer”, Institut Gustave-Roussy, 94805 – Villejuif, France.     

Primary hormone treatment in postmenopausal women with breast cancer

Clinical benefits of hormone therapy in patients with hormone-sensitive tumors have been clearly established. Postmenopausal women with positive hormone receptors represent the largest group of patients in whom early stage breast cancer is diagnosed. Third-generation aromatase inhibitors (letrozole, anastrozole, and exemestane) are active and well tolerated in postmenopausal women with hormone-sensitive metastasic or locally advanced breast cancer as first or second line treatment. These are also valuable agents in the neoadjuvant setting in postmenopausal women, and even as single treatment in localized breast tumors in women not amenable to surgery.     

Incidence of breast cancer among postmenopausal, hypertensive women

Elevated blood pressure has been proposed to be a risk factor for breast cancer but the results remain controversial. In this study, the incidence of breast cancer among 9,112 postmenopausal, hypertensive women included in the community-based hypertension register of the North Karelia project was assessed through the Finnish Cancer Registry. The mean follow-up time was 27 years. The incidence of breast cancer in hypertensive women in our cohort was similar to the age and period specific population-based rates for Eastern Finland [the standardised incidence ratio 0.96 (95% confidence interval 0.86-1.05)]. In the Cox regression analysis, there was no association between blood pressure levels, or use of antihypertensive (AH) drugs, and breast cancer incidence, when all women were considered. There was a statistically significant interaction of the use of AH drugs at baseline and the diastolic blood pressure (DBP). Among women who were not using AH drugs at baseline, the DBP level was positively associated with the subsequent risk of breast cancer (hazard ratio 1.26/10 mm Hg, 95% confidence interval 1.06-1.46). In women with AH drugs at baseline, the DBP had an opposite effect of borderline significance (hazard ratio 0.90/10 mm Hg, 95% confidence interval 0.78-1.01). In conclusion, breast cancer incidence among postmenopausal hypertensive patients in general does not differ from that of general population. Elevated DBP levels may be associated with an increased breast cancer risk among nonpharmacologically treated women.     

Endogenous estrogen and postmenopausal breast cancer: a quantitative review

This paper systematically reviews the results from epidemiologic studies investigating the hypothesis that breast cancer risk inpostmenopausal women increases with increasing concentrations of estradiol in blood and with increasing urinary estrogen excretion rates. Data from 29epidemiologic studies of endogenous hormones and postmenopausal breast cancer were used. The ratio of the average estrogen concentration in the women with breast cancer to that in the women without breast cancer (and its 95 percent confidence interval [CI]) was calculated for each study, and the results were summarized by calculating weighted averages of the log ratios. In six prospective studies of serum estradiol concentration, 329 women who subsequently developed breast cancer had, overall, a 15 percent (CI = 6-24percent, P = 0.0003) higher mean concentration of estradiol in their blood than the 1,105 women who remained free of cancer. The results of these prospective studies did not differ significantly from each other(chi-squared for heterogeneity = 8.7; degrees of freedom = 5; P > 0.1).Similar differences in mean estrogen levels were seen in the case-control studies which reported either estradiol concentrations in the blood or urinary estrogen excretion. However, the case-control studies showed significant heterogeneity among their results. The data from the prospective studies strongly suggest that breast cancer risk in postmenopausal women is associated with relatively high concentrations of endogenous estradiol. This revised version was published online in July 2006 with corrections to the Cover Date.     

Adiposity and estrogen receptor-positive,postmenopausal breast cancer risk: Quantification of the mediating effects of fasting insulin and free estradiol

Adiposity increases estrogen receptor (ER)-positive postmenopausal breast cancer risk. While mechanisms underlying this relationship are uncertain, dysregulated sex-steroid hormone production and insulin signaling are likely pathways. Our aim was to quantify mediating effects of fasting insulin and free estradiol in the adiposity and ER-positive postmenopausal breast cancer association. We used data from a case–cohort study of sex hormones and insulin signaling nested within the Melbourne Collaborative Cohort Study. Eligible women, at baseline, were not diagnosed with cancer, were postmenopausal, did not use hormone therapy and had no history of diabetes or diabetes medication use. Women with ER-negative disease or breast cancer diagnosis within the first follow-up year were excluded. We analyzed the study as a cumulative sampling case–control study with 149 cases and 1,029 controls. Missing values for insulin and free estradiol were multiply imputed with chained equations. Interventional direct (IDE) and indirect (IIE) effects were estimated using regression-based multiple-mediator approach. For women with body mass index (BMI) >30 kg/m² compared to women with BMI 18.5–25 kg/m², the risk ratio (RR) of breast cancer was 1.75 (95% confidence interval [CI] 1.05–2.91). The estimated IDE (RR) not through the mediators was 1.03 (95% CI 0.43–2.48). Percentage mediated effect through free estradiol was 72% (IIE-RR 1.56; 95% CI 1.11–2.19). There was no evidence for an indirect effect through insulin (IIE-RR 1.12; 95% CI 0.68–1.84; 28% mediated). Our results suggest that circulating free estradiol plays an important mediating role in the adiposity–breast cancer relationship but does not explain all of the association.     

绝经后乳腺癌雌、孕激素受体状态与血清性激素水平的关系

目的探讨绝经后乳腺癌雌激素受体(ER)、孕激素受体(PR)状态与患者血清性激素水平的关系及意义。方法使用全自动免疫分析仪化学发光分析法检测41例乳腺癌患者血清性激素六项(LH、FSH、PRL、E2、P、T)水平,免疫组化EnVision二步法检测乳腺癌ER、PR表达状态。结果绝经后乳腺癌PR阴性组与PR阳性组比较,患者血清LH、FSH水平显著增高(P值分别为0.005和0.031),PRL、E2、P、T水平在二组间差异无统计学意义;在ER阴性组与ER阳性组之间所测性激素水平差异无统计学意义。结论绝经后乳腺癌PR表达状态可能与垂体激素LH、FSH水平有关。     

Neoadjuvant tamoxifen for hormone-sensitive non-metastatic breast carcinomas in early postmenopausal women.

BACKGROUND: From 1984 to 1996, 1581 postmenopausal women aged 50-70 years old were treated at Institut Bergonié for an infiltrative non-metastatic breast carcinoma with a positive estrogen and/or progesterone receptor determination. PATIENTS AND METHODS: Among them, 199 were treated with first line tamoxifen. Ninety-seven had operable disease (T2 >30 mm, T3, N0/1) and 102 had T4 tumours. RESULTS: After a mean treatment duration of 5.3 months, 89 T2 and T3 (92%) and 93 T4 (91%) were treated by surgery (conservative or not) with or without irradiation, or by irradiation alone. Conserving treatment levels were 53.6% and 44%, respectively. The other women were treated with either second-line chemotherapy or another hormonotherapy; the remaining patients continued regularly with tamoxifen. Overall survival is analysed with a 83 month median follow-up. CONCLUSIONS: A comparison between neoadjuvant endocrine therapy and surgery seems feasible to assess the concept of neoadjuvant hormonotherapy.     

Dietary intake and risk of postmenopausal breast cancer (United States)

Objectives: While there is good evidence from cell-culture and animal studies to indicate that dietary intake impacts breast cancer risk, results of epidemiologic studies have been inconsistent. Additionally, while the etiology of breast cancer in premenopausal versus postmenopausal women may be quite different, most studies have not chosen to focus solely on one group or the other. In this case–control study, we evaluate the associations between red meat, fish, dairy products, and fruits and vegetables, and risk of breast cancer in postmenopausal women. Methods: A food-frequency questionnaire was completed by 441 women with in-situ or invasive breast cancer and 370 population controls. Cases were identified from the population-based Cancer Surveillance System (CSS) of western Washington and frequency age-matched controls identified by random-digit dialing (RDD). Unconditional logistic regression was used to model the association between each food grouping and breast cancer risk adjusting for age, number of pregnancies, and education. Results: Red meat intake was significantly associated with an increased breast cancer risk (p for trend = 0.002) and fish (including fried fish) and dairy product intake was inversely associated with breast cancer risk (p for trend = 0.04 and 0.05, respectively). No significant associations were noted between fruit or vegetable intake and breast cancer risk. Conclusions: The findings from this study support the results of several larger cohort studies and contribute to the evidence for the development of dietary recommendations for breast cancer risk reduction specific to postmenopausal women.     

Recreational physical activity and risk of postmenopausal breast cancer in a large cohort of US women

Due to its potential effects on ovarian hormone production, physical activity has been proposed as a modifiable risk factor for breast cancer. The authors analyzed data from the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort to examine the association between various measures of physical activity and postmenopausal breast cancer risk. Information on physical activity was obtained in 1992 via a self-administered questionnaire for 72,608 postmenopausal female participants who were cancer-free. During the five year prospective follow-up, 1520 incident breast cancer cases were identified among these women. Cox proportional hazards modeling was used to compute hazard rate ratios (RR) and to adjust for potential confounding factors including mammography. Women who were most physically active (>42.0 MET-h/week) at baseline had 29% lower incidence rates than active women with the least activity (>0–7.0 MET-h/week) (95% CI, 0.49–1.02). The difference in risk was largest for localized breast cancer, and for women who did not use hormone replacement therapy (HRT) at enrollment. Our findings are consistent with other studies that show lower risk of postmenopausal breast cancer associated with regular physical activity.