Dietary fiber intake and risk of postmenopausal breast cancer defined by estrogen and progesterone receptor status--a prospective cohort study among Swedish women

There is few data on the association between dietary fiber intake and estrogen receptor (ER)/progesterone receptor (PR)-defined breast cancer risk. We evaluated the association between dietary fiber and ER/PR-defined breast cancer risk stratified by postmenopausal hormone use, alcohol intake, and family history of breast cancer in the population-based Swedish Mammography Screening Cohort comprising 51,823 postmenopausal women. Fiber intake was measured by food-frequency questionnaire collected in 1987 and 1997. Relative risks (RRs) were estimated by hazard ratio derived from Cox proportional hazard regression models. During an average of 8.3-year follow-up, 1,188 breast cancer cases with known ER/PR status were diagnosed. When comparing the highest to the lowest quintile, we observed non-significant inverse associations between total fiber intake and the risk of all tumor subtypes; the multivariate-adjusted RRs were 0.85 (95% CI: 0.69-1.05) for overall, 0.85 (0.64-1.13) for ER+PR+, 0.83 (0.52-1.31) for ER+PR- and 0.94 (0.49-1.80) for ER-PR-. For specific fiber, we observed statistically significant risk reductions for overall (34%) and for ER+PR+ (38%) for the highest versus lowest quintile of fruit fiber, and non-significant inverse associations for other subtypes of cancer and types of fiber. Among ever-users of postmenopausal hormone (PMH), total fiber intake and especially cereal fiber were statistically significantly associated with approximately 50% reduced risk for overall and ER+PR+ tumors when comparing the highest to the lowest quartile, but no association was observed among PMH never users. Our results suggest that dietary fiber intake from fruit and cereal may play a role in reducing breast cancer risk.     

Body weight and incidence of breast cancer defined by estrogen and progesterone receptor status--a meta-analysis

Epidemiological evidence indicates that the association between body weight and breast cancer risk may differ across menopausal status as well as the estrogen receptor (ER) and progesterone receptor (PR) tumor status. To date, no meta-analysis has been conducted to assess the association between body weight and ER/PR defined breast cancer risk, taking into account menopausal status and study design. We searched MEDLINE for relevant studies published from January 1, 1970 through December 31, 2007. Summarized risk estimates with 95% confidence intervals (CIs) were calculated using a random-effects model. The summarized results of 9 cohorts and 22 case-control studies comparing the highest versus the reference categories of relative body weight showed that the risk for ER+PR+ tumors was 20% lower (95% CI=-30% to -8%) among premenopausal (2,643 cases) and 82% higher (95% CI=55-114%) among postmenopausal (5,469 cases) women. The dose-response meta-analysis of ER+PR+ tumors showed that each 5-unit increase in body mass index (BMI, kg/m2) was associated with a 33% increased risk among postmenopausal women (95% CI=20-48%) and 10% decreased risk among premenopausal women (95% CI=-18% to -1%). No associations were observed for ER-PR- or ER+PR- tumors. For discordant tumors ER+PR- (pre) and ER-PR+ (pre/post) the number of cases were too small (<200) to interpret results. The relation between body weight and breast cancer risk is critically dependent on the tumor's ER/PR status and the woman's menopausal status. Body weight control is the effective strategy for preventing ER+PR+ tumors after menopause.     

Body weight at age 20 years, subsequent weight change and breast cancer risk defined by estrogen and progesterone receptor status--the Japan public health center-based prospective study

Few prospective studies have investigated the association between BMI at age 20 years (BMI20y) and breast cancer risk with consideration to estrogen/progesterone receptor status (ER/PR). We evaluated the association between BMI20y and ER/PR-defined breast cancer risk among 41,594 women in the population-based Japan Public Health Center-based Prospective Study. Anthropometric factors were assessed using self-reported questionnaires. Relative risks (RRs) were estimated by Cox proportional hazards regression models. Through to the end of 2006, 452 breast cancer cases were identified. We observed a statistically significant inverse association between BMI20y and breast cancer incidence [multivariable-adjusted RR for each 5-unit increment 0.75 (95%CI=0.61-0.92)], which was not modified by menopausal or recent BMI status. In contrast, recent BMI and subsequent BMI gain were not associated with increased risk among premenopausal women, but were substantially associated with increased risk among postmenopausal women [corresponding RR(recent BMI)=1.31 (95%CI=1.07-1.59); RR(subsequent BMI gain)=1.32 (95%CI=1.09-1.60)]. In subanalyses by receptor status (～50% of cases), the observed inverse association of BMI20y with risk was consistent with the result for ER-PR- [0.49 (95%CI=0.27-0.88)], while the observed positive associations of BMI gain with postmenopausal breast cancer risk appeared to be confined to ER+PR+ tumors [corresponding RR(for subsequent BMI gain)=2.24 (95%CI=1.50-3.34)]. Low BMI at age 20 years was substantially associated with an increased risk of breast cancer. In contrast, high recent BMI and subsequent BMI gain from age 20 were associated with increased risk of postmenopausal ER+PR+ tumors.     

Dietary lignans and postmenopausal breast cancer risk by oestrogen receptor status: a prospective cohort study of Swedish women

Among the 51,823 postmenopausal women in the Swedish Mammography Cohort, we investigated breast cancer risk in relation to the FFQ-based estimated lignan intake by oestrogen receptor (ER) and progesterone receptor (PR) subtypes. A significant 17% risk reduction for breast cancer overall in the high lignan quartile was observed, especially among PMH user (P interaction<0.010), but no heterogeneity across ER/PR subtypes.     

Dietary cadmium and risk of breast cancer subtypes defined by hormone receptor status: A prospective cohort study

Diet is the primary source of cadmium—a proven Group 1 human carcinogen—for non-smokers. Observational studies investigating the effect of cadmium from food sources on breast cancer risk have produced inconsistent results. We examined the association between dietary cadmium and risk of breast cancer defined by estrogen receptor (ER), progesterone receptor (PR) and HER2 status, in 8924 women recruited to a prospective study between 1987 and 1992. Dietary cadmium intake was estimated using a semi-quantitative food frequency questionnaire at baseline. During a median of 22 years of follow-up, 451 incident cases of breast cancer were identified through the Varese Cancer Registry. Multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for breast cancer and receptor-defined breast cancer subtypes were estimated for quintiles of dietary cadmium intake, adjusting for confounding factors. Mean dietary cadmium intake was 7.8 (standard deviation 1.4) μg/day. Women with highest quintile of cadmium intake had a greater risk of breast cancer (HR 1.54; 95% CI, 1.06–2.22; p trend = 0.028) than those with lowest quintile of intake. Women premenopausal at recruitment had HR = 1.73 (95% CI, 1.10–2.71, highest vs. lowest quintile); postmenopausal women had HR = 1.32 (95% CI, 1.05–1.66 for each standard deviation increase in cadmium). Cadmium-related risk of breast cancer did not vary with ER, PR or HER2 status (p-heterogeneity not significant). These findings support the hypothesis that dietary cadmium is a risk factor for breast cancer.     

Alcohol intake and risk of breast cancer defined by estrogen and progesterone receptor status--a meta-analysis of epidemiological studies

The association between alcohol consumption and an increased risk of breast cancer has been established. It is still unclear however, whether this relationship differs across the estrogen receptor (ER) and progesterone receptor (PR) tumors subtypes. To provide a quantitative assessment of the association between alcohol intake and the risk of ER-/PR-defined breast cancer, we conducted a meta-analysis of cohort and case-control studies. Studies were identified by a literature search of PubMed through April 20, 2007 and by searching the reference lists of relevant articles. Summarized risk estimates (REs) with 95% confidence intervals (CIs) were calculated using random-effects models. The summarized results of the meta-analysis comparing the highest versus the lowest consumption categories showed statistically significant higher risks of developing all ER+ (27%), all ER- (14%), ER+PR+ (22%) and ER+PR- (28%), but not ER-PR- tumors. The dose-response meta-analysis showed that an increase in alcohol consumption of 10 g of ethanol per day was associated with statistically significant increased risks for all ER+ (12%), all ER- (7%), ER+PR+ (11%) and ER+PR- (15%), but not ER-PR-. A statistically significant heterogeneity of the REs across all ER+ versus ER-PR- was observed (p(heterogeneity) = 0.02). The summarized results from studies with adjustment for postmenopausal hormone use, body mass index and family history of breast cancer were higher and statistically significantly different from those without. The observed positive associations with alcohol for ER+PR+ and ER+PR- tumors cannot be explained by estrogen-dependent pathway only. Further studies need to clarify the biological mechanisms.     

Autoimmune diseases and breast cancer risk by tumor hormone‐receptor status among elderly women

The female preponderance of many autoimmune diseases suggests a possible hormonal etiology. Little research exists on systemic and organ‐specific autoimmune diseases and risk of breast cancer by tumor estrogen receptor (ER)‐ and progesterone receptor (PR)‐ status. Here, we evaluate associations between selected systemic and organ‐specific autoimmune diseases and breast cancer risk overall and by tumor ER‐ and PR‐status. We used linked Surveillance, Epidemiology and End Results (SEER)‐Medicare data, with first female breast cancer cases ages ≥66 years identified by SEER registries (years 1992–2011; N = 209,929). We selected female controls (N = 200,000) from a stratified 5% random sample of Medicare recipients who were alive and breast cancer‐free. We assessed exposures until 12 months before breast cancer diagnosis/selection using Medicare claims data. We estimated odds ratios (OR) and 99.9% confidence intervals (CI) using unconditional and multinomial logistic regression. We found reduced breast cancer risk among those with rheumatoid arthritis (OR = 0.84; 99.9% CI 0.79–0.89), systemic lupus erythematosus (OR = 0.82; 99.9% CI 0.70–0.97) and pernicious anemia (OR = 0.90; 99.9% CI 0.83–0.97) and increased risk among those with psoriasis (OR = 1.16; 99.9% CI 1.06–1.27). Statistically significant alterations in risk for rheumatoid arthritis were limited to ER‐positive (+) breast cancer, whereas those for the other three conditions were further limited to ER+/PR+ breast cancer. However, only differences for rheumatoid arthritis by ER‐status were statistically significant (p‐heterogeneity = 0.0001). The reasons for these associations need to be investigated in future studies accounting for host characteristics and autoimmune disease treatment.     

Associations of adult-attained height and early life energy restriction with postmenopausal breast cancer risk according to estrogen and progesterone receptor status

Adult-attained height is a marker for underlying mechanisms, such as cell growth, that may also influence postmenopausal breast cancer (BC) risk, perhaps specifically hormone-sensitive BC subtypes. Early life energy restriction may inhibit these mechanisms, resulting in shorter height and a reduced postmenopausal BC risk. Women (62,573) from the Netherlands Cohort Study completed a self-administered questionnaire in 1986 when 55–69 years old, and were followed-up for 20.3 years (case–cohort: N_subcohort = 2,438; N_cases = 3,354). Cox multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated for BC risk overall and by estrogen and progesterone receptor subtypes in relation to height and early life energy restriction during the Hunger Winter, War Years, and Economic Depression. Although energy restriction can only influence longitudinal growth in women exposed before and/or during the growth spurt, it may also influence BC risk when occurring after the growth spurt, possibly through different growth processes. Therefore, Cox analyses were additionally conducted according to timing of energy restriction in relation to the growth spurt. Height was associated with an increased BC risk (HR_{per 5cm} = 1.07, 95%CI:1.01–1.13), particularly hormone receptor-positive BC. Energy restriction before and/or during the growth spurt was associated with a decreased hormone receptor-positive BC risk. Energy restriction during the Hunger Winter increased the estrogen receptor-negative BC risk regardless of the timing of energy restriction. In conclusion, height and energy restriction before and/or during the growth spurt were both associated with hormone receptor-positive BC risk, in the direction as expected, indicating critical exposure windows for hormonal growth-related mechanisms.     

Rates for breast cancer characteristics by estrogen and progesterone receptor status in the major racial/ethnic groups

It has been reported that age-specific breast cancer rates vary by estrogen receptor and progesterone receptor status. We report breast cancer rates for age-at-diagnosis, stage-at-diagnosis, histological grade and type by estrogen (ER) and progesterone (PgR) receptor status in six major racial/ethnic groups. The average annual age-adjusted rates for breast cancers with estrogen receptor positive (ER⁺), ER^–, progesterone receptor positive (PgR⁺), PgR^–, ER⁺PgR⁺, ER⁺PgR^–, ER^–PgR⁺ and ER^–PgR^– are determined from 123,732 breast cancers with known ER status, diagnosed from 1992 to 1998 from 11 Surveillance, Epidemiology, and End Results (SEER) cancer registries. For each racial/ethnic group, their ER⁺ (ER⁺PgR⁺ and ER⁺PgR^–) age-specific rates increased with age (but at a slower pace after ages 50–54) while their ER^– (ER^– PgR⁺ and ER^–PgR^–) age-specific rates did not increase after ages 50–54. The rank orders of the rates among the racial/ethnic groups varied by ER/PgR status. The stage I rates were greater than the stage II rates for the ER/PgR groups except for ER^– and ER^–PgR^– cancers. The grade 2 (moderately differentiated) rates were greater than the grades 3 and 4 (poorly differentiated and undifferentiated cancers) rates for ER⁺ cancers, but not for ER^– cancers. These results suggest that although breast cancer is a disease with enormous heterogeneity, the multiple types of breast cancer can be separated into distinct subgroups by their ER status, and perhaps by their ER/PgR status, and their cancer characteristics may be important in understanding the multiple nature of breast cancer.     

Influence of endocrine status on biochemical and immunocytochemical estrogen and progesterone receptor assays in breast cancer patients

Summary Breast cancer tissue from 190 patients was studied for immunocytochemically reactive estrogen and progesterone receptors (ER, PR). Parallel cytosol ER and PR assays were performed on 159 of these patients using the dextran-coated charcoal (DCC) method. For the immunocytochemical determination, monoclonal antibodies to ER (ER-ICA kit) and PR were used in an immunoperoxidase procedure. Agreement between the two techniques in postmenopausal patients was better than in the premenopausal group (ER, kappa = 0.597 vs. 0.398; PR, kappa = 0.460 vs. 0.329). The median ER cytosol concentration in receptor-positive postmenopausal patients was significantly higher than in receptor-positive premenopausal patients (87 vs. 31 fmol/mg cytosol protein, p<0.001). A similar trend was also found in the immunocytochemical ER assay (270 vs. 207 histoscore units, p>0.05). Significantly higher cytosol ER contents were found in patients with low serum estradiol concentration. The proportion of ER-negative tumors was slightly higher in the premenopausal patients by both methods. In the PR assays (biochemical or immunocytochemical) there were no significant differences between the two patient groups in the proportion of PR-negative tumors or in the median PR content in PR-positive tumors.     

Body mass index,height, and postmenopausal breast cancer mortality in a prospective cohort of US women

Objective: Epidemiologic evidence suggests a positive association between body mass, adult height, and postmenopausal breast cancer. However, most studies have not been large enough to examine the association across a very wide range of body mass or height, and few studies have assessed the relationship between body mass or height and postmenopausal breast cancer mortality. Methods: The relation between body mass index (BMI) and height and postmenopausal breast cancer mortality was examined in the American Cancer Society's Cancer Prevention Study II (CPS-II), a large prospective mortality study of US adults enrolled in 1982. After 14 years of follow-up, 2852 breast cancer deaths were observed among 424,168 postmenopausal women who were cancer-free at interview. Cox proportional hazards modeling was used to estimate relative risks and to control for potential confounding. Results: Breast cancer mortality rates increased continually and substantially with increasing BMI (rate ratio (RR) = 3.08, 95% confidence interval (CI) = 2.09–4.51 for BMI 40.0 compared to BMI 18.5–20.49). If causal, the multivariate-adjusted RR estimates in this study correspond to approximately 30–50% of breast cancer deaths among postmenopausal women in the US population being attributable to overweight. Breast cancer mortality also increased with increasing height up to 66 inches with RR = 1.64, (95% CI = 1.23–2.18) in women 66 inches tall compared to those < 60 inches. Conclusions: Postmenopausal obesity is an important and potentially avoidable predictor of fatal breast cancer in this study. These results underscore the importance of maintaining moderate weight throughout adult life.     

Dietary lignan intakes and risk of breast cancer by tumor estrogen receptor status

We examined the association of dietary lignan intake with estrogen receptor negative (ER−) and ER positive (ER+) breast cancer risk in a breast cancer case–control study. Among premenopausal women only, there was a reduced risk of ER− breast cancer for those in the highest compared to the lowest quartile of lignan intake suggesting that the observed negative association of lignans with breast cancer may be limited to ER− tumors.     

Genetic evolution of breast cancer: II. relationship with estrogen and progesterone receptor expression

Summary The expression of estrogen (ER) and progesterone (PR) receptors was assayed by steroid binding in a series of 95 malignant breast tumors, for which the analysis of chromosome aberrations was performed and allowed the reconstruction of their chromosomal evolution. It was shown that breast tumors undergo a progressive loss of chromosomes, with occasionally one and rarely two endoreduplications. Chromosome losses were often the consequence of rearrangements, and the rate of rearranged chromosomes, which increases progressively, appeared as a possible indicator of tumor progression. The distribution of ER and PR values in the sample of 95 tumors was compared to that of a larger control series of consecutive cases: 598 for ER and 460 for PR. The similarities of the distributions indicated that the sample of 95 tumors was representative of the general population of breast cancers. The levels of ER and PR expression were very strongly and negatively correlated to the rate of rearranged chromosomes, but not to the modal number of chromosomes. However, when tumors having either undergone endoreduplication or not (>50 or <51 chromosomes, respectively) were considered separately, a significant correlation between ER and PR expression and chromosome number was found within each group. Finally, breast cancers were subdivided into 4 stages of cytogenetic evolution, from the least to the most evolved: stage 1: 50 chromosomes, <25% rearranged chromosomes; stage 2: >50 chromosomes, <25% rearranged chromosomes; stage 3: 50 chromosomes, >25% rearranged chromosomes; stage 4: >50 chromsomes, >25% rearranged chromosomes. The rate of negative or low ER values (<500 fmol/g tissue) was 10% in stage 1; 16% in stage 2; 45% in stage 3; 82% in stage 4. The corresponding rates for negative or low PR values (<500 fmol/g tissue) were 17%; 28%; 60%; and 91%. These data illuminate the probable role of genetic evolution in determining the variations of biological prognostic parameters of breast cancer, such as steroid hormone receptors.     

Risk factors for breast cancer in young women by oestrogen receptor and progesterone receptor status

We used data from 765 cases and 564 controls in the population-based Australian Breast Cancer Family Study to investigate whether, in women under the age of 40, the profile of risk factors differed between breast cancer subtypes defined by joint oestrogen and progesterone receptor status. As hypothesised, no significant differences were found.     

The effect of tumor size and axillary lymph node metastasis on estrogen and progesterone receptors in primary breast cancer

We evaluated the estrogen receptors (Er) and the progesterone receptors (Pr) in 209 female patients with primary breast cancer. There is statistically a very highly significant negative correlation between the size of the tumor and the Pr (p = 0.007); large tumor contains low Pr. The same correlation was found with Er, but it was not statistically significant (p = 0.40). There is also a negative correlation between the number of axillary metastatic lymph nodes and Er and Pr, but this was not statistically significant.     

A dietary pattern based on estrogen metabolism is associated with breast cancer risk in a prospective cohort of postmenopausal women

Increased exposure to estrogen is a risk factor for postmenopausal breast cancer, and dietary factors can influence estrogen metabolism. However, studies of diet and breast cancer have been inconclusive. We developed a dietary pattern associated with levels of unconjugated estradiol and the ratio of 2‐ and 16‐hydroxylated estrogen metabolites in a subsample of Prostate, Lung, Colorectal and Ovarian Screening Trial (PLCO) participants (n = 653) using reduced rank regression, and examined its association with postmenopausal breast cancer prospectively in the larger PLCO cohort (n = 27,488). The estrogen‐related dietary pattern (ERDP) was comprised of foods with positively‐weighted intakes (non‐whole/refined grains, tomatoes, cruciferous vegetables, cheese, fish/shellfish high in ω‐3 fatty acids, franks/luncheon meats) and negatively‐weighted intakes (nuts/seeds, other vegetables, fish/shellfish low in ω‐3 fatty acids, yogurt, coffee). A 1‐unit increase in the ERDP score was associated with an increase in total (HR: 1.09, 95% CI: 1.01–1.18), invasive (HR: 1.13; 95% CI: 1.04–1.24) and estrogen receptor (ER)‐positive (HR: 1.13, 95% CI: 1.02–1.24) breast cancer risk after adjustment for confounders. Associations were observed for the fourth quartile of ERDP compared with the first quartile for overall breast cancer (HR: 1.14; 95% CI: 0.98–1.32), invasive cases (HR: 1.20, 95% CI: 1.02–1.42) and ER‐positive cases (HR: 1.19; 95% CI: 0.99–1.41). The increased risk associated with increasing ERDP score was more apparent in strata of some effect modifiers (postmenopausal hormone therapy non‐users and non‐obese participants) where the relative estrogen exposure due to that factor was lowest, although the p values for interaction were not statistically significant. Results suggest a dietary pattern based on estrogen metabolism is positively associated with postmenopausal breast cancer risk, possibly through an estrogenic influence.     

Estrogen and progesterone receptor isoforms: clinical significance in breast cancer

The identification and exploitation of biomarkers that may predict response to anti-cancer treatments has the capacity to revolutionize the way that patients with cancer are treated. In breast cancer, the estrogen receptor (ER) and the progesterone receptor (PgR) are known to have a significant predictive value in determining sensitivity to endocrine therapies. Tumor expression of ER or PgR is known to affect clinical outcome and this information is often used to determine a patient's optimal treatment regimen. However, the measurement of ER and PgR alone is more complex than originally thought and the impact of the recently identified isoforms of ER (ERα and ERβ) and PgR (PgRA and PgRB), as well as several variant and mutant forms, upon the choice of treatment remains unclear. Therefore, ER and PgR expression alone are unlikely to determine a patient's optimal treatment regimen, particularly when the amount of ‘cross-talk’ between different pathways, such as the epidermal growth factor receptor pathway, is considered. In order to account for the complex cell-signaling environment that occurs in breast cancer, multifactorial techniques are needed to analyze tumor biomarker expression. The recent advances in genomic- or proteomic-based approaches has enabled molecular portraits of breast cancers to be painted, allowing biomarkers of response and prognosis to be identified and characterized more accurately than before. In the future, patients could be treated according to the molecular portrait of their tumor biomarker expression, maximizing the therapeutic benefit that each patient receives. This revised version was published online in August 2006 with corrections to the Cover Date.     

Adjuvant tamoxifen for pre- and postmenopausal women with estrogen receptor positive,node positive breast cancer: A randomized study

Summary 370 patients with operable, axillary node positive breast cancer, were randomized to receive tamoxifen (TAM) 20 mg/day for 2 years or no adjuvant hormone therapy. All patients had estrogen receptor (ER) positive (ER > 10 pmol/g) primary tumours. 350 patients, 93 younger than 50 years of age and 257 patients 50 years or older, were evaluable for the study. After a median follow up of 76 months, significantly (p = 0.0001) fewer loco-regional, but not distant (systemic), relapses have been recorded in the TAM group. Overall survival was also improved, but even though the study was designed to give maximum benefit from TAM statistically significant effect of TAM seemed to be limited to patients 50 years of age and older.     

Adiposity, adult weight change and breast cancer risk in postmenopausal Japanese women: the Miyagi Cohort Study

Background:

The role of adult weight change in breast cancer (BC) risk is unclear in Japanese women.

Methods:

A total of 10 106 postmenopausal women aged 40–64 years (the Miyagi Cohort) were followed from 1990 to 2003, and 108 BC cases were identified. Hazard ratios (HRs) were estimated according to body mass index (BMI) at the current age and at the of age 20 years, and weight change since age 20 years.

Results:

Higher current BMI was associated with an increased risk of BC (P for trend=0.02), whereas higher BMI at the age 20 years was inversely associated with this risk (P for trend=0.002). There was a significant association between weight change since age 20 years and BC risk (P for trend=0.0086). Compared with stable weight, HR was 0.35 for weight loss of 5 kg or more (P for weight loss trend=0.04) and 1.55 for weight gain of 12 kg or more (P for weight gain trend=0.05).

Conclusion:

Adiposity at younger and current age has differential effects on BC risk among postmenopausal women; weight gain in adulthood being associated with an increased, and weight loss with a decreased risk.