Breast cancer risk factors according to joint estrogen receptor and progesterone receptor status

BACKGROUND: We investigated risk factor patterns for subtypes of breast cancer characterized by joint estrogen receptor (ER) and progesterone receptor (PR) status in a hospital-based case-control study. METHODS: ER and PR tumor status were determined immunohisotchemically. Risk factors of interest were entered into a multiple polychotomous logistic regression model simultaneously; odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Using this model, cases in the four tumor subtypes (ER+PR+, ER-PR-, ER+PR-, ER-PR+) were compared simultaneously to controls. A Wald test for heterogeneity across the four subtypes was conducted, as well as a case-case comparison between the two most biologically disparate subtypes, ER+PR+ and ER-PR-. RESULTS: The receptor status distribution was as follows: 33% ER+PR+, 34% ER-PR-, 20% ER+PR-, and 13% ER-PR+. Among 317 cases and 401 controls, we found significant heterogeneity across the four tumor subtypes for older age at first full-term pregnancy (p=0.04) and post-menopausal status (p=0.04). For older age at first full-term pregnancy, an elevated risk was found for the ER+PR- subtype (OR=2.5; 95% CI: 1.2-5.1). For post-menopausal status, elevated risks were found for both the ER+PR+ (OR=2.4; 95% CI: 1.1-4.9) and ER+PR- (OR=7.2; 95% CI: 2.4-21.7) subtypes. From the case-case comparisons, we found that cases, who had consumed alcohol for more than 1 year were 3.4 times more likely to have ER+PR+ tumors than ER-PR- tumors (95% CI: 1.4-8.4). CONCLUSIONS: Certain breast cancer risk factors may vary by ER and PR status, and joint ER/PR status should be taken into account in future studies of risk factor estimates.     

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.     

Hormonal factors and the risk of breast cancer according to estrogen- and progesterone-receptor subgroup.

Evidence suggests hormonal factors may be more strongly associated with estrogen receptor+progesterone receptor+ (ER+PR+) than ER-PR- breast cancer risk. This study evaluated risk factors according to ERPR tumor status among pre- and postmenopausal women participating in two recent population-based case-control studies. Breast cancer cases, ages 25-74 years, and diagnosed 1995-1998 were sampled from the Ontario Cancer Registry. Controls were a random sample of women identified using the Ontario Ministry of Finance rolls and were frequency-matched to cases within 5-year age groups. Epidemiological data were collected from breast cancer cases and controls using two self-administered questionnaires. ERPR data were obtained for 87% of the breast cancer cases (3,276 of 3,748). Multivariate polytomous logistic regression was used to obtain odds ratios estimates and 95% confidence intervals. The following significant differences were observed in the risk factor profiles for ER+PR+ and ER-PR- breast cancer: among premenopausal women, late age at menarche was only associated with a reduction in ER+PR+ breast cancer risk; obesity was associated with an increased ER-PR- and decreased ER+PR+ cancer risk; and the association between alcohol intake and breast cancer risk was heterogeneous across ERPR subgroups, although the direction varied across the levels of alcohol intake. Among postmenopausal women, there were no statistically significant differences observed in the risk factor profiles for ER+PR+ and ER-PR- breast cancer. Some heterogeneity exists in the risk factor profiles of ER+PR+ and ER-PR- premenopausal breast cancer; however, risk factor profiles did not differ markedly for postmenopausal breast cancer.     

The relationship between alcohol use and risk of breast cancer by histology and hormone receptor status among women 65-79 years of age.

Alcohol consumption is associated with a moderate increase in breast cancer risk, possibly because alcohol increases estrogen levels in blood. Certain types of breast carcinomas are more hormonally responsive than others, including those that have a lobular histology or are hormone receptor positive, but few studies evaluating alcohol use and breast cancer risk have stratified results by histology or estrogen receptor (ER)/progesterone receptor (PR) status. We conducted a population-based case-control study of women 65-79 years of age in western Washington State. Women (975) diagnosed with invasive breast cancer during 1997-1999 were compared with 1007 controls. Ever-use of alcohol over the past 20 years was associated with a 1.3-fold [95% confidence interval (CI), 1.0-1.5] increased risk of breast cancer, although this increase was primarily limited to women who consumed > or =30.0 g/day of alcohol [odds ratio (OR), 1.7; 95% CI, 1.1-2.6]. Differences in risk by histology were observed: ever-use of alcohol was associated with a 1.8-fold (95% CI, 1.3-2.5) increased risk of lobular cancer but only a 1.2-fold (95% CI, 0.9-1.4) increased risk of ductal cancer. Ever-users of alcohol had an increase in risk of ER+/PR+ tumors (OR, 1.3; 95% CI, 1.1-1.7), but no change in their risks of ER+/PR- or ER-/PR- tumors. Alcohol use appears to be more strongly associated with risk of lobular carcinomas and hormone receptor-positive tumors than it is with other types of breast cancer. These results are consistent with there being an underlying hormonal basis for the known association between alcohol use and breast cancer incidence.     

Elevated levels of circulating insulin-like growth factor-I, IGF-binding globulin-3 and testosterone predict hormone-dependent breast cancer in postmenopausal women: a case-control study

There is increasing evidence that different types of breast cancers are related to distinct risk factors. We analyzed the risk of breast cancer with respect to circulating insulin-like growth factor (IGF)-I, IGF-binding protein (IGFBP)-3, 17beta-estradiol, estrone, testosterone, androstenedione and sex hormone-binding globulin (SHBG), taking into consideration the characteristics of the tumors. Plasma hormone levels of 102 postmenopausal patients with breast cancer detected by mammography screening, and 102 matched controls were analyzed in relation to the histological type, the status of the estrogen receptor (ER), the progesterone receptor (PR) and the HER2 in the tumors. Significant positive associations were revealed between the IGF-I concentration and the overall risk of breast cancer (OR=3.1, 95% CI: 1.5-6.2), ER+PR+ breast cancer (OR=2.4, 95% CI: 1.1-5.4) and ER+PR- breast cancer (OR=4.3, 95% CI: 1.2-14.3) when the highest and the lowest ranges of IGF-I were compared. Significant associations were also found between the highest and the lowest quartiles of testosterone, resulting in OR=4.1 (95% CI: 1.8-9.4) for the risks of breast cancer and OR=5.8 (96% CI: 2.1-16.2) of ER+PR+ breast cancer. A synergy was seen between IGF-I and testosterone levels. When both plasma IGF-I and testosterone were in the highest quartile ranges, an OR=26.4 (95% CI: 1.6-426.5, p=0.021) was computed for breast cancer overall. No significant synergistic effects could be demonstrated with other parameters. There were significant, 2.5-fold (95% CI: 1.2-5.6), and 16-fold (95% CI: 2.0-133.5) increases in the overall risks of breast cancer and of ER+PR- breast cancer, respectively, when the highest and the lowest quartiles of IGFBP-3 were compared. No associations were found between any of the hormones and the risk of ER-PR- tumors. The increased prevalence of ER+ breast cancers in patients with higher levels of IGF-I, IGFBP-3 or testosterone implicate these hormones in the etiology of hormone-dependent breast cancer. Additional analyses specific for breast cancer subtypes may shed light on the value of hormone determinations for tailored chemoprevention.     

The estrogen receptor negative-progesterone receptor positive breast carcinoma is a biological entity and not a technical artifact

The ER-/PR+ breast tumor may be the result of a false ER negative result. The aim of this study was to investigate whether there is a difference in patient and tumor characteristics of the ER-/PR+ phenotype in an Asian setting. A total of 2629 breast cancer patients were categorized on the basis of their age, ethnicity, tumor hormonal receptor phenotype, grade and histological type. There were 1230 (46.8%) ER+/PR+, 306 (11.6%) ER+/PR-, 122 (4.6%) ER-/PR+ and 972 (37%) ER-/PR-. ER-/PR+ tumors were 2.5 times more likely to be younger than 50 years at diagnosis (OR: 2.52; 95% CI: 1.72-3.67). Compared to ER+/PR+ tumors, the ER-/ PR+ phenotype was twice more likely to be associated with grade 3 tumors (OR:2.02; 95%CI: 1.00-4.10). In contrast, compared to ER-/PR- tumors, the ER-/PR+ phenotype was 90% less likely to be associated with a grade 3 tumor (OR: 0.12; 95%CI:0.05-0.26), and more likely to have invasive lobular than invasive ductal histology (OR: 3.66; 95%CI: 1.47-9.11). These results show that the ER-/PR+ phenotype occurs in a younger age group and is associated with intermediate histopathological characteristics compared to ER+/PR+ and ER-/PR- tumors. This may imply that it is a distinct entity and not a technical artifact.     

Relative weight at age 12 and risk of postmenopausal breast cancer

BACKGROUND: Early adolescent weight may affect the risk of postmenopausal breast cancer, and this association may be modified by a family history of breast or ovarian cancer in a first-degree relative, and/or estrogen (ER) and progesterone (PR) receptor status of the disease. METHODS: Relative weight at age 12 years (above, below, or average weight compared with peers) and family history were ascertained using a mailed questionnaire in 1986, in the Iowa Women's Health Study, a prospective cohort study of postmenopausal women. Incident breast cancer cases (including ER and PR status) were identified using the Iowa Surveillance, Epidemiology, and End Results Cancer Registry. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards regression, and were adjusted for breast cancer risk factors, including body mass index at age 18 years and body mass index at study baseline. RESULTS: Through 2003, 2,503 cases of postmenopausal breast cancer were identified among 35,941 women in the analytic cohort. Compared with women with average weight at age 12 years, there was no association of below average weight with risk of breast cancer (RR, 1.02; 95% CI, 0.92-1.13), whereas women with above average weight had a lower risk (RR, 0.85; 95% CI, 0.74-0.98). There was no evidence of an interaction between weight at age 12 years and family history (P = 0.44). The inverse association of above average weight with risk of breast cancer was strongest for PR- tumors (RR, 0.62; 95% CI, 0.43-0.89), intermediate for ER+ (RR, 0.80; 95% CI, 0.67-0.96) and ER- (RR, 0.77; 95% CI, 0.50-1.19) tumors, and weakest for PR+ tumors (RR, 0.90; 95% CI, 0.74-1.09). These associations were not modified by a family history (all P > 0.18). In a joint ER/PR analyses, the strongest inverse association with above average weight at age 12 years was seen for ER+/PR- (RR, 0.49; 95% CI, 0.29-0.85). CONCLUSION: Above average weight at age 12 years was inversely associated with risk of postmenopausal breast cancer, and was not modified by a family history of the disease. The inverse association was strongest for ER+/PR- tumors.     

Hormonal receptors in locally advanced breast cancer: Change with response to neoadjuvant chemotherapy?

Twenty-one cancers in 20 patients with locally advanced breast cancer were studied. Incisional biopsy was performed without using electrocautery. Tissue was obtained for histology and estrogen (ER) and progesterone (PR) receptors. Patients received chemotherapy after biopsy. All responded and had radical mastectomy performed. Tissue was removed from the mastectomy specimen to confirm residual tumor and for repeat receptor measurements. Initial receptor levels were negative in 13 cancers. Following chemotherapy, both ER and PR levels were unchanged in 11 cancers. Levels in one cancer changed from ER-PR- to ER+PR- and one changed from ER-PR- to ER+PR+. Six cancers were ER+PR+ at initial examination. Repeat receptor levels after chemotherapy were ER+PR+ in three. One ER+PR+ tumor became ER-PR+, one changed to ER+PR-, and one to ER-PR-. One ER+PR- cancer remained ER+PR- after treatment and an ER-PR+ cancer became ER-PR- after treatment. Chemotherapy dose not significantly alter hormonal levels in breast cancer tissue.     

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 postmenopausal breast cancer risk defined by estrogen and progesterone receptor status among Swedish women: A prospective cohort study

Although obesity is one of the established risk factors for postmenopausal breast cancer, it is not clear whether this positive association differs across estrogen receptor (ER) and progesterone receptor (PR) status of breast tumors. We evaluated the association between body weight and ER/PR defined breast cancer risk stratified by postmenopausal hormone (PMH) use and a family history of breast cancer in the population-based Swedish Mammography Screening Cohort comprising 51,823 postmenopausal women. Relative body weight was measured by body mass index (kg/m2) based on self-reported weight and height collected in 1987 and 1997. Relative risks (RRs) were estimated by hazard ratios derived from Cox proportional hazards regression models. During an average of 8.3-year follow-up, 1,188 invasive breast cancer cases with known ER and PR status were diagnosed. When comparing to normal weight group, we observed a positive association between obesity and risk for the development of ER+ PR+ tumors (RR = 1.67, 95% CI = 1.34-2.07) and an inverse association for the development of all PR- tumors (RR = 0.68, 95% CI = 0.47-0.98). Statistically significant heterogeneity was observed in the RRs between ER+ PR+ tumors and all PR- tumors (p(heterogeneity) < 0.0001). The positive association of obesity with the development of ER+ PR+ tumors was confined to never-users of PMHs (RR = 1.90 (CI 95%:1.38-2.61)) and to those without a family history of breast cancer (RR = 1.82 (CI 95%:1.45-2.29)). Our results support the hypothesis that excess endogenous estrogen due to obesity contributes to an increased risk of ER+ PR+ postmenopausal breast cancer.     

Postmenopausal serum sex steroids and risk of hormone receptor-positive and -negative breast cancer: a nested case-control study

Prediagnostic endogenous sex steroid hormone levels have well established associations with overall risk of breast cancer. While evidence toward the existence of distinct subtypes of breast cancer accumulates, few studies have investigated the associations of sex steroid hormone levels with risk of hormone receptor [estrogen receptor (ER) and/or progesterone receptor (PR)] defined breast cancer. In a case-control study nested within the EPIC cohort (European Prospective Investigation into Cancer and Nutrition), estradiol, testosterone, and sex hormone-binding globulin levels were measured in prediagnostic serum samples from postmenopausal women not using hormone replacement therapy at blood donation. A total of 554 women who developed invasive breast cancer with information on receptor status were matched with 821 control subjects. Conditional logistic regression models estimated breast cancer risk with hormone concentrations according to hormone receptor status of the tumor. Sex steroid hormones were associated with risks of not only ER+PR+ breast cancer [estradiol OR for highest vs. lowest tertile = 2.91 (95% CI: 1.62-5.23), P(trend) = 0.002; testosterone OR = 2.27 (95% CI: 1.35-3.81), P(trend) = 0.002] but also of ER-PR- breast cancer [estradiol OR = 2.11 (95% CI: 1.00-4.46), P(trend) = 0.05; testosterone OR = 2.06 (95% CI: 0.95-4.46), P(trend) = 0.03], with associations appearing somewhat stronger in the receptor-positive disease. Serum androgens and estrogens are associated with risks of both hormone receptor-negative as well as receptor-positive breast tumors. Further research is needed to establish through which molecular pathways, and during which evolutionary stages of development, androgens and estrogens can promote the occurrence of both receptor-positive and -negative clinical breast tumors.     

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.     

SSRI use and breast cancer risk by hormone receptor status

BACKGROUND: There is little evidence linking the use of selective serotonin reuptake inhibitors (SSRIs) with increased breast cancer risk, but one study has found an association with estrogen receptor negative (ER-) and progesterone receptor negative (PR-) tumors. METHODS: We used data collected on 820 invasive breast cancer cases and 2852 hospitalized controls collected from 1990 through 2006. Information on medication use and other variables was collected by nurse interviewers. We used unconditional logistic regression analyses to evaluate the association between regular SSRI use (use at least 4 times/week for at least 3 months) and breast cancer risk overall and by subtype defined by hormone receptor status. RESULTS: The odds ratio for all breast cancer was not elevated among regular users of SSRIs (OR = 0.89, 95% CI 0.62-1.29). None of the odds ratios varied from 1.0 in any category of hormone receptor status. Among women aged 55 and over, the odds ratios were increased for ER- (OR = 1.84, 95% CI 0.66-5.16), PR- (OR = 1.85, 95% CI 0.80-4.27), and ER-PR- (OR = 2.10, 95% CI 0.73-6.02) tumors, but these estimates were compatible with chance. CONCLUSION: We found no association between SSRI use and breast cancer risk, overall or by hormone receptor status. Odds ratios were elevated in older women, particularly for ER- and PR- tumors, but the confidence intervals were compatible with no association.     

Do Clinical Features and Survival of Single Hormone Receptor Positive Breast Cancers Differ from Double Hormone Receptor Positive Breast Cancers?

The significance of the single hormone receptor positive phenotype of breast cancer is still poorly understood.The use of hormone therapy has been found to be less effective for this type, which has a survival outcome midwaybetween double positive and double negative phenotypes. The aim of this study was to investigate differencesin patient and tumor characteristics and survival between double-receptor positive (ER+PR+), double receptornegative (ER-PR-) and single receptor positive (ER+PR- and ER-PR+) breast cancer in an Asian setting. Atotal of 1,992 patients with newly diagnosed stage I to IV breast cancer between 2003 and 2008, and whereinformation on ER and PR were available, were included in this study. The majority of patients had ER+PR+tumors (n=903: 45.3%), followed by 741 (37.2%) ER-PR-, 247 (12.4%) ER+PR-, and 101 (5.1%) ER-PR+ tumors.Using multivariate analysis, ER+PR- tumors were 2.4 times more likely to be grade 3 compared to ER+PR+tumors. ER+PR- and ER-PR+ tumors were 82% and 86% respectively less likely to be grade 3 compared withER-PR- tumors. ER-PR+ tumours were associated with younger age. There were no survival differences betweenpatients with ER+PR+ and ER-PR+ tumors. However, ER+PR- tumors have poorer survival compared withER+PR+ tumours. ER-PR- tumours had the worst survival. Adjuvant hormonal therapy with tamoxifen wasfound to have identical survival advantage in patients with ER+PR+ and ER-PR+ tumors whereas impact wasslightly lower in patients with ER+PR- tumors. In conclusion, we found ER+PR- tumors to be more aggressiveand have poorer survival when compared to ER+PR+ tumors, while patients with ER-PR+ tumours were younger,but had a similar survival to their counterparts with ER+PR+ tumours.     

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.     

Alcohol and breast cancer risk defined by estrogen and progesterone receptor status: a case-control study

BACKGROUND: Alcohol consumption increases breast cancer risk. Some studies suggested that this association is stronger or limited to tumors expressing estrogen receptors (ER). METHODS: We investigated the role of alcohol according to ER and progesterone receptor (PR) status in a case-control study on breast cancer conducted from 1991 to 1994 in three Italian areas. Cases were 989 women with incident, histologically confirmed breast cancer. Controls were 1,350 women admitted to hospitals in the same catchment areas for acute nonneoplastic diseases. A validated food-frequency questionnaire was used to collect information on dietary habits and lifetime consumption of various alcoholic beverages. Multiple logistic regression models were used to estimate odds ratios and 95% confidence interval (95% CI). RESULTS: Alcohol drinking was associated with ER+ tumors (odds ratio, 2.16; 95% CI, 1.68-2.76 for an intake of > or =13.8 g/d as compared with nondrinkers). The odds ratio was 1.13 (95% CI, 1.07-1.20) for a 10-g increase in daily intake. For ER- tumors, the relation with alcohol consumption was not significant (odds ratio, 1.36; 95% CI, 0.93-2.01). When breast cancers were further classified according to PR, the findings for ER+PR+ cancers were similar to those for all ER+ ones, with an odds ratio of 2.34 (95% CI, 1.81-3.04) for an intake of > or =13.8 g/d. No significant association emerged for ER-PR- tumors (odds ratio, 1.25; 95% CI, 0.81-1.94). CONCLUSION: This study supports the hypothesis that alcohol is more strongly related to ER+ than to ER- breast tumors.     

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.     

Postmenopausal hormone therapy and breast cancer risk: the Multiethnic Cohort

Epidemiological studies indicate that menopausal estrogen-progestin therapy (EPT) use is associated with an increase in breast cancer risk. Further data are needed on whether this association varies by specific prognostic factors and ethnicity. We conducted a cohort study among 55,371 African-American, Native Hawaiian, Japanese-American, Latina and White postmenopausal women aged 45-75 years old in the Multiethnic Cohort Study (MEC). A total of 1,615 incident invasive breast cancer cases were identified over an average of 7.3 years. Adjusted relative risks (RRs) were computed for the various forms of hormone therapy (HT). Assuming current users continued HT use to the end of follow-up, current EPT use was associated with a 29% increased risk of breast cancer per 5 years of use (95% confidence interval (CI) = 23-35%), and current estrogen therapy (ET) use with a 10% increase in risk per 5 years of use (95% CI = 5-16%). These figures increased to only a very small extent when we adjusted for the estimated 3% of such women who stop HT use per year of follow-up. EPT and ET use were associated with greater risk among leaner women, but the increase in risk with EPT use was still very evident in women with BMI > or =30 kg/m(2). Current EPT use was associated with increased risk for ER+/PR+, ER+/PR- and ER-/PR- tumors. There was little difference in risk by stage of disease or histologic subtype. The increase with EPT use was clearly seen in all 5 ethnic groups; and the increase with ET in 4 of the 5 groups.     

A case–control study of reproductive factors associated with subtypes of breast cancer in Northeast China

Based on the expression of estrogen receptor (ER), progesterone receptor (PR) and HER2/neu (HER2), breast cancer is classified into several subtypes: luminal A (ER+ and/or PR+, HER2?), luminal B (ER+ and/or PR+, HER2+), HER2-overexpressing (ER?, PR?, and HER2+) and triple-negative (ER?, PR?, and HER2?). The aim of this case–control study is to determine reproductive factors associated with breast cancer subtypes in Chinese women. A total of 1,417 patients diagnosed with breast cancer in the First Affiliated Hospital, China Medical University, Shenyang, China between 2001 and 2009 and 1,587 matched controls without a prior breast cancer were enrolled. Personal interviews were conducted to obtain information on reproductive characteristics and clinical history. Relationships between the factors and the subtypes of breast cancer were examined using logistic regression to compute odds ratios (OR) and 95% confidence intervals (CI). Notably, luminal A (50.0%) was the most prevalent subtype relative to luminal B (15.10%), HER2-overexpressing (10.87%) and triple-negative (23.08%). Menarche at an early age was associated with a reduced risk of luminal A (OR, 2.35; 95% CI, 1.45–3.81). Breastfeeding protected parous women from any subtype of breast cancer. Postmenopause and spontaneous abortion were inversely associated with the risk of luminal tumors. By contrast, multiparity, family history of breast cancer and induced abortion increased the risk of breast cancer. Collectively, our findings suggest that reproductive factors such as age at menarche, parity, breastfeeding, menopausal status and abortion history have different effects on the subtypes of breast cancer in Chinese women.     

Tumor variants by hormone receptor expression in white patients with node-negative breast cancer from the surveillance, epidemiology, and end results database.

PURPOSE: Hormone receptor expression (presence-positive or absence-negative) may reflect different stages of one disease or different breast cancer types. Determining whether hormone receptor expression represents one or more breast cancer phenotypes would have important paradigmatic and practical implications. METHODS: Breast cancer records were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. The study included 19,541 non-Hispanic white women with node-negative breast cancer. Standard tumor cell characteristics and breast cancer-specific survival were analyzed by independent estrogen receptor (ER+ and ER-), independent progesterone receptor (PR+ and PR-), and joint ERPR expression (ER+PR+, ER+PR-, ER-PR+, and ER-PR-). RESULTS: Age frequency density plots by hormone receptor expression showed two overlapping breast cancer populations with early-onset and/or late-onset etiologies. Independent ER+ and PR+ phenotype were associated with smaller tumor sizes, better grade, and better cancer-specific survival than ER- and PR- breast cancer types. Joint ERPR phenotype exhibited biologic gradients for tumor size, grade, and cancer-specific survival, which ranked from good to worse for ER+PR+ to ER+PR- to ER-PR+ to ER-PR-. CONCLUSION: Variations of standard tumor cell characteristics and breast cancer-specific survival by hormone receptor expression in white patients with node-negative breast cancer suggested two breast cancer phenotypes with overlapping etiologies and distinct clinical features.