Postmenopausal Invasive Breast Cancer Research Articles

Trajectories of body mass index in adulthood and risk of subtypes of postmenopausal breast cancer

BackgroundBody fatness is a dynamic exposure throughout life. To provide more insight into the association between body mass index (BMI) and postmenopausal breast cancer, we aimed to examine the age at onset, duration, intensity, and trajectories of body fatness in adulthood in relation to risk of breast cancer subtypes.MethodsBased on self-reported anthropometry in the prospective Norwegian Women and Cancer Study, we calculated the age at onset, duration, and intensity of overweight and obesity using linear mixed-effects models. BMI trajectories in adulthood were modeled using group-based trajectory modeling. We used Cox proportional hazards models to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the associations between BMI exposures and breast cancer subtypes in 148,866 postmenopausal women.ResultsA total of 7223 incident invasive postmenopausal breast cancer cases occurred during follow-up. Increased overweight duration and age at the onset of overweight or obesity were associated with luminal A-like breast cancer. Significant heterogeneity was observed in the association between age at overweight and overweight duration and the intrinsic-like subtypes (pheterogeneity 0.03). Compared with women who remained at normal weight throughout adulthood, women with a descending BMI trajectory had a reduced risk of luminal A-like breast cancer (HR 0.54, 95% CI 0.33–0.90), whereas women with ascending BMI trajectories were at increased risk (HR 1.09; 95% CI 1.01–1.17 for “Normal-overweight”; HR 1.20; 95% CI 1.07–1.33 for “Normal-obesity”). Overweight duration and weighted cumulative years of overweight and obesity were inversely associated with luminal B-like breast cancer.ConclusionsIn this exploratory analysis, decreasing body fatness from obesity in adulthood was inversely associated with overall, hormone receptor-positive and luminal A-like breast cancer in postmenopausal women. This study highlights the potential health benefits of reducing weight in adulthood and the health risks associated with increasing weight throughout adult life. Moreover, our data provide evidence of intrinsic-like tumor heterogeneity with regard to age at onset and duration of overweight.

The association between the incidence of post-menopausal breast cancer and residential greenness

BackgroundThere is little data as to whether exposure to residential greenness is associated with the incidence of breast cancer. Lack of physical activity and obesity are two of the accepted risk factors for postmenopausal breast cancer and living near green areas may contribute to an active lifestyle and maintaining a normal body mass index and, consequently, residential greenness may be associated with lower incidence rates. ObjectivesThe objective of this study was to determine whether there was an association between past exposure to residential greenness and the incidence of invasive postmenopausal breast cancer among Canadian women living in Montreal, Quebec, in the mid-2000s. MethodsWe conducted a population-based, case-control study of incident postmenopausal breast cancer in Montreal, Canada, and herein we show analyses by level of greenness surrounding participants’ homes. Incident cases were identified between 2008 and 2011 from all but one hospital that treated breast cancer in the Montreal area. Population controls were identified from provincial electoral lists of Montreal residents and frequency-matched to cases on age. Residential greenness was estimated using the maximum daily normalized difference vegetation index averaged over the growing season (“maximum NDVI”). Maximum NDVI was assigned at the home address of recruitment for the years 1992–1998 (about 15 years before diagnosis), and we measured subjects’ personal information, exposure to NO2 and ultrafine particles, and area-wide variables to control for potential confounding effects. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer associated with residential greenness were estimated using logistic regression models adjusting for various combinations of potential confounders. We assessed the functional form of maximum NDVI using natural cubic splines. ResultsWe found that the response functions between incident postmenopausal breast cancer and maximum NDVI were consistent with linearity. The age-adjusted and fully-adjusted ORs, per increase in the interquartile range (IQR=0.13) of maximum NDVI measured with a 250 m buffer around residences, were 0.95 (95%CI: 0.86–1.04) and 1.00 (95%CI: 0.84–1.11), respectively. For maximum NDVI measured using a 1000 m buffer (IQR=0.05), these were 0.98 (95%CI: 0.94–1.02) and 0.99 (95%CI: 0.95–1.03), respectively. ConclusionsOur findings suggest that exposure to NDVI evaluated where participants were interviewed is not associated with the risk of incident postmenopausal breast cancer.

The association of body fat composition with risk of breast, endometrial, ovarian and colorectal cancers among normal weight participants in the UK Biobank.

BackgroundThe association between body fat composition and risk of cancer in normal weight individuals (body mass index (BMI) 18.5–24.9 kg/m2) is unclear.MethodsWe examined the association of measures of adiposity with risk of incident cancers of the breast (postmenopausal), endometrium, ovary and colon/rectum among 149,928 normal weight individuals (40–70 years) who were enrolled in the UK Biobank cohort between 2006 and 2010.ResultsAll of the body fat measures were positively associated with invasive postmenopausal breast cancer risk (hazard ratios (HR) for the uppermost quintile (Q5) versus the lowest quintile (Q1) ranged from 1.32 (95% CI: 1.09–1.60) for waist circumference (WC) to 1.56 (1.28–1.90) for BMI). Trunk fat mass index (HRQ5 vs Q1: 1.72, 95% CI: 1.02–2.89) and WC (HRQ5 vs Q1: 1.65, 95% CI: 1.01–2.70)) were positively associated with risk of endometrial cancer. Among males, trunk fat:trunk fat free mass ratio, trunk fat:leg fat mass ratio and (HRQ5 vs Q1: 1.63, 95% CI: 1.02–2.60; 1.92, 1.20–3.07 and 1.68, 1.05–2.66, respectively) were positively associated with colon cancer risk. None of the body fat measures was associated with risk of ovarian cancer or colorectal cancer in women.ConclusionThe findings of this study suggest that the current normal weight category based on BMI includes individuals who are at increased risk of some obesity-related cancers.

Abstract PS7-28: Association between epigenetic age acceleration and postmenopausal breast cancer risk in the Women’s Health Initiative

Abstract Earlier age of menopause and bilateral oophorectomy are associated with accelerated biologic aging based on epigenetic clocks. While these relationships suggest women with greater epigenetic age acceleration (AgeAccel) might be at a reduced risk of postmenopausal breast cancer, prior studies conflict with this theory. We hypothesized this paradox may be attributable to an interaction between epigenetic and reproductive aging on cancer risk. We evaluated this premise among 5,044 postmenopausal women in the Women’s Health Initiative (WHI) Observational Study and Clinical Trial with AgeAccel estimated in whole blood. Among a subset of 1,135 of these women, estradiol (E2) and sex hormone-binding globulin were assayed in baseline serum samples. For WHI participants with DNA methylation assays, we modeled the log odds of incident postmenopausal breast cancer during follow-up as a function of AgeAccel, adjusting for age at menopause, race/ethnicity, age at WHI screening, bilateral oophorectomy, nulliparity, alcohol consumption, smoking, body mass index, duration of postmenopausal hormone therapy use, exercise, clinical trial arm, and hysterectomy status at baseline. We repeated this analysis among the subset of participants with DNA methylation and E2 assays, and appraised the degree to which bioavailable E2 levels contributed to the observed association between AgeAccel and incident postmenopausal breast cancer. Finally, we evaluated whether bioavailable E2 levels modified the relationship between AgeAccel and cancer risk. Generalized estimating equations were used to model associations with AgeAccel, integrating repeated measures among a subset of participants and using inverse probability weights to account for sample selection probabilities. Based on our fully adjusted models, increased extrinsic AgeAccel was associated with decreased odds of incident postmenopausal invasive breast cancer during follow-up. This association was consistent among the subset of participants with E2 assays, and robust to adjustment for bioavailable E2 concentration. We found the inverse relationship between extrinsic AgeAccel and incident breast cancer was strongest among white non-Hispanic women with low levels of bioavailable E2. This study represents the largest investigation of the association between AgeAccel and postmenopausal breast cancer risk, and the first evaluation of how bioavailable E2 levels may influence this relationship. Our analyses inform our understanding of the relationship between the epigenetic and reproductive aging process, and the potential implications for postmenopausal breast cancer risk. Citation Format: Alexandra M. Binder, Lesley Tinker, Robert Wallace, JoAnn E. Manson, Lihong Qi, Parveen Bhatti, Eric A. Whitsel, Andrea Z. LaCroix, Steve Horvath. Association between epigenetic age acceleration and postmenopausal breast cancer risk in the Women’s Health Initiative [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-28.

Coffee Consumption and Invasive Breast Cancer Incidence among Postmenopausal Women in the Cancer Prevention Study-II Nutrition Cohort

There is limited evidence of a potential inverse association between coffee, particularly caffeinated coffee, consumption and postmenopausal breast cancer risk, and few studies have examined this association by tumor hormone receptor status. To provide further evidence, we examined total, caffeinated, and decaffeinated coffee consumption in relation to postmenopausal invasive breast cancer incidence overall, and by tumor estrogen receptor (ER) and/or progesterone receptor (PR) subtype. Among 57,075 postmenopausal women in the Cancer Prevention Study-II Nutrition Cohort who were cancer free and reported coffee intake in 1999, we identified 2,980 women diagnosed with invasive breast cancer during follow-up through June 2015. Multivariable-adjusted Cox proportional hazards regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI). Neither total, caffeinated, nor decaffeinated coffee consumption was associated with invasive breast cancer risk; HRs (95% CIs) comparing consumption of ≥2 cups per day with <1 cup per month were 0.99 (0.89-1.11), 0.96 (0.87-1.06), and 1.06 (0.95-1.19), respectively. Similarly, coffee consumption was not associated with risk of hormone receptor-positive (ER+ or PR+) or hormone receptor-negative (ER- and PR-) breast tumors. These findings do not support an association between coffee consumption and invasive breast cancer risk among postmenopausal women. This large prospective study contributes to the limited evidence on coffee consumption and breast cancer risk, finding no association overall or by tumor receptor subtype.

Abstract 3483: Measures of overall and central adiposity in relation to risk of obesity-related cancers among normal weight men and women in the UK Biobank

Abstract Background: Within the normal BMI (body mass index (BMI) of 18.5-24.9kg/m2) category, some individuals may be at increased risk of developing obesity-related cancers. Towards this end, studies have shown positive associations between body fat, particularly in the abdominal region, and cancer-associated metabolic disturbances among normal weight individuals. However, little is known about the association between body fat distribution and risk of obesity-related cancers among normal weight individuals. Thus, in this study, we examined the association of overall and central adiposity, assessed using bioelectrical impedance (BIA)-derived and anthropometric measures, with risk of selected obesity-related cancers among normal weight persons. Methods: The study included normal weight individuals aged 40-70 years who were enrolled in the UK Biobank cohort between 2006 and 2010. BIA-derived and anthropometric body fat measures were taken at baseline by trained staff. Incident tumors were ascertained via linkage to UK cancer registries. Multivariable Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the associations of the body fat measures with risk of cancers of the breast, endometrium, ovary, colorectum, pancreas, and kidney, and with multiple myeloma. Results: The overall incidence of obesity-related cancers was 2.2 per 1000 person-years of follow-up (N= 2364 incident obesity-related cases among 152,489 subjects with a median follow-up time of 7 years). All measures of central and peripheral adiposity demonstrated linear positive dose-response relationships with risk of postmenopausal invasive breast cancer and with endometrial cancer. For all of the body fat measures, postmenopausal women in the highest quartile showed increased invasive breast cancer risk, after adjusting for potential confounders, compared to women in the lowest quartile, with hazard ratios ranging from 1.29 (95% CI: 1.11-1.50) for the ratio of trunk fat to leg fat mass to 1.59 (95% CI: 1.31-1.93) for trunk fat mass index (TFMI; calculated as trunk fat mass (kg)/height (m)2). For endometrial cancer, only the TFMI (HR: 1.80, 95% CI:1.12-2.88) and waist circumference (HR: 1.70, 95% CI: 1.04-2.80) were positively associated with risk. A waist-to-hip ratio in the highest quartile was also positively associated with colorectal cancer risk among males (HR: 1.56, 95% CI: 1.03-2.37). None of the body fat measures were associated with risk colorectal cancer risk among women or with risk of the remaining cancers. Conclusion: The findings of this study suggest that elevated levels of central and/or overall adiposity may be associated with increased risk of postmenopausal breast cancer, endometrial cancer and probably colorectal cancer (males), among normal weight individuals. Evaluating body composition in those with a normal BMI can potentially identify individuals at increased risk for cancer providing an opportunity for interventions to reduce risk. Citation Format: Rhonda S. Arthur, Mimi Kim, Andrew Dannenberg, Thomas Rohan. Measures of overall and central adiposity in relation to risk of obesity-related cancers among normal weight men and women in the UK Biobank [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3483.

Dietary advanced glycation end products and the risk of postmenopausal breast cancer in the National Institutes of Health-AARP Diet and Health Study.

Advanced glycation end products (AGEs) are reactive metabolites produced as a by-product of sugar metabolism and are consumed through the diet in high-fat and highly processed foods. They are associated with chronic inflammatory diseases, and evidence suggests that they play a role in carcinogenesis. The authors evaluated the association of dietary AGE intake and the risk of postmenopausal invasive breast cancer. This was a prospective cohort study of 183,548 postmenopausal women in the National Institutes of Health-AARP Diet and Health Study. The main outcome was incident invasive breast cancer. AGE intake was estimated from food-frequency questionnaires. Incident breast cancer cases were identified through state cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals for developing breast cancer according to AGE intake quintiles. Multivariable regression models were adjusted for breast cancer risk factors. The mean follow-up was 12.8years, and 9851 breast cancers (1978 advanced stage) were identified. The median AGE daily intake was 5932kilo units per 100kilocalories (KU/1000kcal). Women with higher intake tended to have lower education levels, higher body mass index, less physical activity, were current smokers, and had higher fat and meat intake. The highest quintile of AGE intake (compared with the lowest) was associated with an increased risk of breast cancer (HR, 1.09; 95% CI, 1.02-1.16; P=.03) after adjusting for breast cancer risk factors and particularly was associated with 37% of advanced-stage tumors (HR, 1.37; 95% CI, 1.09-1.74; P<.02) after adjusting for risk factors and fat and meat intake. Dietary AGEs may play a role in the development of postmenopausal breast cancer.

Abstract 966: Coffee consumption and invasive breast cancer incidence among postmenopausal women in the Cancer Prevention Study II Nutrition Cohort

Abstract Accumulating evidence suggests that coffee consumption may be inversely associated with breast cancer risk among postmenopausal women, with growing evidence of a stronger association for caffeinated than for decaffeinated coffee. However, few studies have examined this association by hormone receptor status or minimized confounding due to cigarette smoking. Recently, we found that caffeinated, but not decaffeinated coffee consumption was inversely associated with breast cancer mortality among nonsmoking women enrolled in the Cancer Prevention Study-II (CPS-II). Subsequently, the 2018 WCRF/AICR Diet, Nutrition, Physical Activity and Cancer Third Expert Report drew no conclusion regarding the association between coffee consumption and breast cancer risk. To provide further evidence, we examined total, caffeinated and decaffeinated coffee consumption in relation to postmenopausal invasive breast cancer incidence, overall, among nonsmokers and by estrogen and/or progesterone receptor (ER/PR) status among women enrolled in the CPS-II Nutrition Cohort, a subcohort of CPS-II. This analysis included 57,120 postmenopausal women who were cancer-free and reported coffee intake in 1999, and who were followed for cancer incidence through June 2013. During follow-up, 2,848 (2,349 ER or PR positive, and 252 ER and PR negative) women with a verified invasive breast cancer were identified. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI). Neither total nor decaffeinated coffee consumption was associated with risk of invasive breast cancer among all women or in any subgroup. For caffeinated coffee consumption, the HR (95% CI) for consumption of 2 or more cups/day, compared to less than 1 cup/month, was 0.90 (0.82-1.00) among all women, and 0.88 (0.80-0.98) among nonsmokers. Similarly, caffeinated coffee consumption was associated with a statistically significantly lower risk of ER+ or PR+ breast cancer (HR=0.88, 95% CI 0.79-0.99) and a nonsignificant lower risk of ER- and PR- breast cancer (HR=0.83, 95% CI 0.59-1.16) among all women. These findings underscore the importance of stratifying on type of coffee in studies examining the association between coffee consumption and risk of invasive postmenopausal breast cancer. Additionally, to better understand the role of caffeinated vs. decaffeinated coffee in breast cancer etiology we will examine the potential mediating effects of coffee metabolites on this association. Citation Format: Susan M. Gapstur, Marjorie L. McCullough, Rebecca A. Hodge, Ying Wang, Caroline Y. Um, Terryl J. Hartman, Mia M. Gaudet. Coffee consumption and invasive breast cancer incidence among postmenopausal women in the Cancer Prevention Study II Nutrition Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 966.

Continuous tumour growth models, lead time estimation and length bias in breast cancer screening studies.

Comparisons of survival times between screen-detected and symptomatically detected breast cancer cases are subject to lead time and length biases. Whilst the existence of these biases is well known, correction procedures for these are not always clear, as are not the interpretation of these biases. In this paper we derive, based on a recently developed continuous tumour growth model, conditional lead time distributions, using information on each individual's tumour size, screening history and percent mammographic density. We show how these distributions can be used to obtain an individual-based (conditional) procedure for correcting survival comparisons. In stratified analyses, our correction procedure works markedly better than a previously used unconditional lead time correction, based on multi-state Markov modelling. In a study of postmenopausal invasive breast cancer patients, we estimate that, in large (>12 mm) tumours, the multi-state Markov model correction over-corrects five-year survival by 2-3 percentage points. The traditional view of length bias is that tumours being present in a woman's breast for a long time, due to being slow-growing, have a greater chance of being screen-detected. This gives a survival advantage for screening cases which is not due to the earlier detection by screening. We use simulated data to share the new insight that, not only the tumour growth rate but also the symptomatic tumour size will affect the sampling procedure, and thus be a part of the length bias through any link between tumour size and survival. We explain how this has a bearing on how observable breast cancer-specific survival curves should be interpreted. We also propose an approach for correcting survival comparisons for the length bias.

Abstract P1-08-02: Associations of epidemiologic and clinical features with intensity of immune infiltrates in postmenopausal breast cancer cases from the cancer prevention study-II cohort

Abstract Stromal tumor-infiltrating lymphocytes (sTILs) are often prominent in HER2-enriched and triple negative breast cancers and predict a favorable prognosis for these subtypes. Clinical and epidemiological determinants of sTILs have not been defined in large cohorts. Accordingly, we analyzed these associations for 702 eligible, postmenopausal invasive breast cancer cases from the Cancer Prevention Study (CPS)-II Nutrition cohort. CPS-II included 97,786 women who completed baseline and follow-up surveys since 1992. Women with self-reported breast cancer diagnoses were consented for medical record and tumor tissue retrieval. We analyzed pre-diagnostic data from the survey prior to diagnosis on personal history of benign breast disease (BBD), menopausal hormone use, alcohol intake, cigarette smoking status, waist circumference, body mass index, adult weight gain, nonsteroidal anti-inflammatory drugs, and physical activity. One pathologist (TG) evaluated sTILs using whole slide images of H&amp;E stained sections according to recommendations by the International TILs Working Group 2014. sTIL levels were dichotomized: none/minimal (0-10%) and moderate/high (&amp;gt;10%). We compared the sTIL levels by clinical and epidemiologic risk factors using chi-square statistics. Odds ratio (ORs) and 95% confidence intervals (CIs) for the associations of clinical and epidemiologic risk factors with sTILs were estimated with multivariable logistic regression. Mean age at diagnosis was 71.9 years; 44% of cancers were moderate grade, 74% were localized staged and 88% were luminal-like. Cancers with high/moderate sTIL levels (n=614), compared to none/minimal (n=88), were more likely to be high grade (54% vs. 20%; p-value &amp;lt;0.001), node-positive (41% vs. 22%; p-value &amp;lt;0.001), and non-luminal (36% vs. 8%; p-value &amp;lt;0.001). In a model mutually-adjusted for age at diagnosis and clinical factors, all clinical factors were associated with moderate/high sTIL levels: node-positive (OR=2.15, 95% CI 1.28 – 3.58), high grade (OR=3.98, 95% CI 1.88 – 9.06), and non-luminal subtype (OR=3.65, 95% CI 2.00 – 6.59). Age at diagnosis was not associated with sTIL levels (per year: OR=1.01, 95% CI 0.97 – 1.05). Women with BBD were less likely to have moderate/high sTIL levels than minimal/none sTIL levels (38% vs. 54%; age-adjusted OR=0.50, 95% CI 0.31 – 0.79). Ever smokers also were less likely to have moderate/high sTIL levels (38% vs. 49%) with an OR=0.61 (95% 0.38 – 0.97). Other risk factors were not significantly associated with sTIL levels. In this large epidemiologic cohort, non-luminal cancers had more sTILs than luminal cancers. Women with a personal history of BBD and ever cigarette smokers had significant lower levels of sTILs. Our study is among the first to examine pre-diagnostic risk factors in relation to sTILs and provides the impetus for larger, population-based studies with phenotypic characterization of immune cells. Citation Format: Gaudet MM, Mellow MM, Puvanesarajah S, Gapstur SM, Sherman ME, Gansler T. Associations of epidemiologic and clinical features with intensity of immune infiltrates in postmenopausal breast cancer cases from the cancer prevention study-II cohort [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-02.

Letrozole and anastrozole in early breast cancer postmenopausal patients in oncology department at Suez Canal University Hospital

Background: There are limited data in the literature comparing the efficacy of aromatase inhibitors in postmenopausal hormonal receptor positive early breast cancer patients.Aim of study: To compare the efficacy of letrozole and anastrozole in hormone-receptor positive postmenopausal breast cancer patients.Methods: A retrospective study with a mean follow-up period of 64 months (about 5 years) for 74 files of early invasive postmenopausal breast cancer hormonal receptor positive patients; 39 received letrozole and 35 received anastrozole, considering TTP as primary end point, and OS as second end points.Results: Letrozole is not superior to anastrozole during the first 55 months of treatment (80% PFS at 5th year), and 80% OS benefit at 6th year. Overweight patients had better (90% PFS at 5th year) than obese patients (60% PFS at 5th year).Conclusion: Letrozole is not superior to anastrozole in efficacy in early invasive hormonal receptor positive breast cancer postmenopausal patients during the first 5 years of treatment; however, Letrozole 2nd line after tamoxifen is superior to anastrozole 2nd line after tamoxifen in treating obese patients with early invasive hormone receptor positive breast cancer.

Letrozole and Anastrozole in Early Breast Cancer Post-menopausal Patients in Oncology Department at Suez Canal University Hospital

Background:There are limited data in the literature comparing the efficacy of aromatase inhibitors in postmenopausal hormonal receptor positive early breast cancer patients. Aim: To compare the efficacy of letrozole and anastrozole in hormone-receptor positive postmenopausal breast cancer patients. Patients and Methods: A retrospective study with a mean follow-up period of 64 months (about 5 years) for 74 files of early invasive postmenopausal breast cancer hormonal receptor positive patients; 39 received letrozole and 35 received anastrozole, considering TTP as primary end point, and OS as second end points. Results: Letrozole is not superior to anastrozole during the first 55 months of treatment (80% PFS at 5th year), and 80% OS benefit at 6th year.. Overweight patients had better (90% PFS at 5th year) than obese patients (60% PFS at 5th year). Conclusion: Letrozole is not superior to anastrozole in efficacy in early invasive hormonal receptor positive breast cancer postmenopausal patients during the first 5 years of treatment; however, Letrozole 2nd line after tamoxifen is superior to anastrozole 2nd line after tamoxifen in treating obese patients with early invasive hormone receptor positive breast cancer.

Nutritional metabolomics and breast cancer risk in a prospective study

Background: The epidemiologic evidence for associations between dietary factors and breast cancer is weak and etiologic mechanisms are often unclear. Exploring the role of dietary biomarkers with metabolomics can potentially facilitate objective dietary characterization, mitigate errors related to self-reported diet, agnostically test metabolic pathways, and identify mechanistic mediators.Objective: The aim of this study was to evaluate associations of diet-related metabolites with the risk of breast cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.Design: We examined prediagnostic serum concentrations of diet-related metabolites in a nested case-control study in 621 postmenopausal invasive breast cancer cases and 621 matched controls in the multicenter PLCO cohort. We calculated partial Pearson correlations between 617 metabolites and 55 foods, food groups, and vitamin supplements on the basis of the 2015 Dietary Guidelines for Americans and derived from a 137-item self-administered food-frequency questionnaire. Diet-related metabolites (P-correlation < 1.47 × 10-6) were evaluated in breast cancer analyses. ORs for the 90th compared with the 10th percentile were calculated by using conditional logistic regression, with body mass index, physical inactivity, other breast cancer risk factors, and caloric intake controlled for (false discovery rate <0.2).Results: Of 113 diet-related metabolites, 3 were associated with overall breast cancer risk (621 cases): caprate (10:0), a saturated fatty acid (OR: 1.77; 95% CI = 1.28, 2.43); γ-carboxyethyl hydrochroman (γ-CEHC), a vitamin E (γ-tocopherol) derivative (OR: 1.64; 95% CI: 1.18, 2.28); and 4-androsten-3β,17β-diol-monosulfate (1), an androgen (OR: 1.61; 95% CI: 1.20, 2.16). Nineteen metabolites were significantly associated with estrogen receptor (ER)-positive (ER+) breast cancer (418 cases): 12 alcohol-associated metabolites, including 7 androgens and α-hydroxyisovalerate (OR: 2.23; 95% CI: 1.50, 3.32); 3 vitamin E (tocopherol) derivatives (e.g., γ-CEHC; OR: 1.80; 95% CI: 1.20, 2.70); butter-associated caprate (10:0) (OR: 1.81; 95% CI: 1.23, 2.67); and fried food-associated 2-hydroxyoctanoate (OR: 1.46; 95% CI: 1.03, 2.07). No metabolites were significantly associated with ER-negative breast cancer (144 cases).Conclusions: Prediagnostic serum concentrations of metabolites related to alcohol, vitamin E, and animal fats were moderately strongly associated with ER+ breast cancer risk. Our findings show how nutritional metabolomics might identify diet-related exposures that modulate cancer risk. This trial was registered at clinicaltrials.gov as NCT00339495.

Expression Quantitative Trait loci (QTL) in tumor adjacent normal breast tissue and breast tumor tissue.

We investigate 71 single nucleotide polymorphisms (SNPs) identified in meta-analytic studies of genome-wide association studies (GWAS) of breast cancer, the majority of which are located in intergenic or intronic regions. To explore regulatory impacts of these variants we conducted expression quantitative loci (eQTL) analyses on tissue samples from 376 invasive postmenopausal breast cancer cases in the Nurses’ Health Study (NHS) diagnosed from 1990–2004. Expression analysis was conducted on all formalin-fixed paraffin-embedded (FFPE) tissue samples (and on 264 adjacent normal samples) using the Affymetrix Human Transcriptome Array. Significance and ranking of associations between tumor receptor status and expression variation was preserved between NHS FFPE and TCGA fresh-frozen sample sets (Spearman r = 0.85, p<10^-10 for 17 of the 21 Oncotype DX recurrence signature genes). At an FDR threshold of 10%, we identified 27 trans-eQTLs associated with expression variation in 217 distinct genes. SNP-gene associations can be explored using an open-source interactive browser distributed in a Bioconductor package. Using a new a procedure for testing hypotheses relating SNP content to expression patterns in gene sets, defined as molecular function pathways, we find that loci on 6q14 and 6q25 affect various gene sets and molecular pathways (FDR < 10%). Although the ultimate biological interpretation of the GWAS-identified variants remains to be uncovered, this study validates the utility of expression analysis of this FFPE expression set for more detailed integrative analyses.

Evaluation of Local CYP17A1 and CYP19A1 Expression Levels as Prognostic Factors in Postmenopausal Invasive Ductal Breast Cancer Cases.

There is growing attention focused on local estrogen production in the breast tissue and its possible role in breast cancer initiation and progression. Understanding the underlying mechanisms for estrogen synthesis and the microenvironment consisting of tumor and its surrounding adipose tissue might open new avenues in breast cancer prevention, prognosis and treatment. In order to obtain insight, we compared peritumoral and tumor tissue expressions of CYP17A1 and CYP19A1 genes, which play an important role in estrogen biosynthesis. The paired tissue samples of 20 postmenopausal ER+/PR+ patients diagnosed with invasive ductal breast cancer were studied. In addition, 12 breast tissue samples obtained from premenopausal women without a history of breast cancer were also investigated as representative of normal conditions. Peritumoral adipose tissues expressed CYP19A1 approximately threefold higher than tumor itself (p=0.001). A nonsignificant trend toward low expression of CYP17A1 was observed in peritumoral compared to tumor tissue (p=0.687). Clinicopathological parameters and patient characteristics which are accepted as risk factors for breast cancer were also associated with individual and combined expressions of CYP17A1 and CYP19A1. This study offers that evaluation of CYP17A1 and CYP19A1 local expression levels might be useful for deciding on personalized treatment approaches and more accurate diagnosis, when evaluated together with several clinicopathological and disease risk factors. Considering the key role of these CYPs in estrogen synthesis, determining their expression levels may be useful as a postdiagnostic marker and for choosing the right treatment method in addition to the conventional approach.

Endogenous Estrogens, Estrogen Metabolites, and Breast Cancer Risk in Postmenopausal Chinese Women

The role of estrogen metabolism in determining breast cancer risk and differences in breast cancer rates between high-incidence and low-incidence nations is poorly understood. We measured urinary concentrations of estradiol and estrone (parent estrogens) and 13 estrogen metabolites formed by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring in a nested case-control study of 399 postmenopausal invasive breast cancer case participants and 399 matched control participants from the population-based Shanghai Women's Health Study cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer by quartiles of metabolic pathway groups, pathway ratios, and individual estrogens/estrogen metabolites were estimated by multivariable conditional logistic regression. Urinary estrogen/estrogen metabolite measures were compared with those of postmenopausal non-hormone-using Asian Americans, a population with three-fold higher breast cancer incidence rates. All statistical tests were two-sided. Urinary concentrations of parent estrogens were strongly associated with breast cancer risk (ORQ4vsQ1 = 1.94, 95% CI = 1.21 to 3.12, Ptrend = .01). Of the pathway ratios, the 2-pathway:total estrogens/estrogen metabolites and 2-pathway:parent estrogens were inversely associated with risk (ORQ4vsQ1 = 0.57, 95% CI = 0.35 to 0.91, Ptrend = .03, and ORQ4vsQ1 = 0.61, 95% CI = 0.37 to 0.99, Ptrend = .04, respectively). After adjusting for parent estrogens, these associations remained clearly inverse but lost statistical significance (ORQ4vsQ1 = 0.65, 95% CI = 0.39 to 1.06, Ptrend = .12 and ORQ4vsQ1 = 0.76, 95% CI = 0.44 to 1.32, Ptrend = .28). The urinary concentration of all estrogens/estrogen metabolites combined in Asian American women was triple that in Shanghai women. Lower urinary parent estrogen concentrations and more extensive 2-hydroxylation were each associated with reduced postmenopausal breast cancer risk in a low-risk nation. Markedly higher total estrogen/estrogen metabolite concentrations in postmenopausal United States women (Asian Americans) than in Shanghai women may partly explain higher breast cancer rates in the United States.

Proportion of premenopausal and postmenopausal breast cancers attributable to known risk factors: Estimates from the E3N-EPIC cohort.

Breast cancer is the most frequently diagnosed cancer among women worldwide. Breast cancer risk factors have been widely explored individually; however, little is known about their combined impact. We included 67,634 women from the French E3N prospective cohort, aged 42-72 at baseline. During a 15-year follow-up period, 497 premenopausal and 3,138 postmenopausal invasive breast cancer cases were diagnosed. Population-attributable fractions (PAFs) were used to estimate cases proportions attributable to risk factors under hypothetical scenarios of lowest exposure. We examined overall premenopausal and postmenopausal invasive breast cancers and tumour subtypes (ER status and HER2 expression). Premenopausal breast cancer was not significantly attributable to non-behavioral (61.2%, -15.5 to 91.88%) nor to behavioral (39.9%, -71.0 to 93.9%) factors, contrary to postmenopausal breast cancer (41.9%, 4.5 to 68.7% and 53.5%, 12.8 to 78.7%, respectively). Individually, the highest statistically significant PAFs were obtained in premenopause for birth weight (33.6%, 5.7 to 56.6%) and age at menarche (19.8%, 5.2 to 33.6%) for non-behavioral factors and in postmenopause for history of benign breast diseases (14.9%, 11.6 to 18.0%) and age at menarche (9.7%, 3.9 to 15.5%) for non-behavioral factors and for body shape at menarche (17.1%, 9.7 to 24.3%), use of hormone replacement therapy (14.5%, 9.2 to 19.6%), dietary pattern (10.1%, 2.6 to 17.4%) and alcohol consumption (5.6%, 1.9 to 9.3%) for behavioral factors. These proportions were higher for ER+, HER2- and ER+/HER2- postmenopausal breast cancers. Our data support the hypothesis that in postmenopause, never starting unhealthy behaviors can reduce the number of diagnosed breast cancers.

Abstract A43: Population attributable risk of postmenopausal breast cancer according to known and modifiable breast cancer risk factors

Abstract Introduction: Multiple risk factors for postmenopausal breast cancer are well established. We aimed to determine the proportion of breast cancers in the population that are attributable to established risk factors, and to different combinations of risk factors, to better understand the proportion of breast cancer which could be prevented by changes in modifiable risk factors. Methods: We used data from the Nurses' Health Study (NHS), an ongoing prospective study of 121,700 US nurses initiated in 1976. Information on breast cancer risk factors and breast cancer diagnosis is collected every two years through mailed questionnaires. Follow-up for this cohort of women through 2008 has been greater than 90%. The analysis was restricted to postmenopausal women. Relative risks and their 95% confidence intervals were estimated by Cox models stratified by calendar year and age in months at the time of each questionnaire return using the counting process data structure to facilitate the incorporation of time-varying covariates. We included the following established breast cancer risk factors in the analyses: age, age at menarche, height, age at first birth/parity, current adult BMI/weight change since age 18, alcohol consumption, physical activity, breast feeding, menopausal hormone therapy, family history of breast cancer, and prior benign breast disease. Full and partial population attributable risk percents (PARs) were calculated. We conducted analyses for total invasive breast cancer, estrogen receptor (ER)+, and ER- breast cancer. Results: Over the course of follow-up, 8,421 postmenopausal invasive breast cancer cases developed over 2,424,778 person years between 1980 and 2008. As expected, earlier age at menarche, increasing weight gain since age 18, increasing alcohol consumption, current use of menopausal hormones, and being tall were all significantly positively associated with risk of breast cancer in multivariate models. Because age has a large influence on the risk of breast cancer we estimated the PAR both with and without age. When all of the risk factor variables except for age were include in the model the PAR for all invasive breast cancers was 0.62 (95% CI 0.46-0.75). Thus, if women could change to the lowest risk category for all of the variables considered, the number of invasive breast cancers would be reduced by 62%. In models that additionally included age, the PAR was 0.92 (95%CI 0.76-0.97) for total invasive and 0.95 (95%CI 0.75-0.99) for ER+ breast cancer and 0.86 (95%CI 0.21-0.98) for ER- breast cancer. However, because many of the risk factors considered are not easily modifiable, we also examined more readily modifiable risk factors singly and in combinations. The risk factor with the largest PAR, was BMI/weight gain since age 18 (PAR=0.24(95%CI 0.13-0.34)). Reproductive risk factors such as age at first birth/parity (PAR=0.10 (95%CI 0.07-0.14)) and age at menarche (PAR=0.08 (95%CI 0.03-0.12)) also had modest impact on the PAR, both of which were higher for ER+ breast cancer than ER- breast cancer. When considering all of the modifiable risk factors together we found that changing one's risk factor profile to have the lowest weight gain, no alcohol consumption, high physical activity, breast feeding and no hormone use was associated with a PAR of 0.38 (95%CI 0.23-0.52) for overall invasive breast cancer. Conclusion: The established breast cancer risk factors explain a large proportion of both ER+ and ER- postmenopausal breast cancers in the population. The most important modifiable risk factor for postmenopausal breast cancer prevention is maintaining a healthy weight. Citation Format: Rulla M. Tamimi, Molin Wang, Mathew Pazzaris, Stephanie A. Smith-Warner, Walter C. Willett, A. Heather Eliassen, Donna Spiegelman, David J. Hunter. Population attributable risk of postmenopausal breast cancer according to known and modifiable breast cancer risk factors. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A43.

Overweight, Obesity, and Postmenopausal Invasive Breast Cancer Risk

More than two-thirds of US women are overweight or obese, placing them at increased risk for postmenopausal breast cancer. To investigate in this secondary analysis the associations of overweight and obesity with risk of postmenopausal invasive breast cancer after extended follow-up in the Women's Health Initiative (WHI) clinical trials. The WHI clinical trial protocol incorporated measured height and weight, baseline and annual or biennial mammography, and adjudicated breast cancer end points in 67 142 postmenopausal women ages 50 to 79 years at 40 US clinical centers. The women were enrolled from 1993 to 1998 with a median of 13 years of follow-up through 2010; 3388 invasive breast cancers were observed. Height and weight were measured at baseline, and weight was measured annually thereafter. Data were collected on demographic characteristics, personal and family medical history, and personal habits (smoking, physical activity). Women underwent annual or biennial mammograms. Breast cancers were verified by medical records reviewed by physician adjudicators. Women who were overweight and obese had an increased invasive breast cancer risk vs women of normal weight. Risk was greatest for obesity grade 2 plus 3 (body mass index [BMI], calculated as weight in kilograms divided by height in meters squared, >35.0) (hazard ratio [HR] for invasive breast cancer, 1.58; 95% CI, 1.40-1.79). A BMI of 35.0 or higher was strongly associated with risk for estrogen receptor-positive and progesterone receptor-positive breast cancers (HR, 1.86; 95% CI, 1.60-2.17) but was not associated with estrogen receptor-negative cancers. Obesity grade 2 plus 3 was also associated with advanced disease, including larger tumor size (HR, 2.12; 95% CI, 1.67-2.69; P = .02), positive lymph nodes (HR, 1.89; 95% CI, 1.46-2.45; P = .06), regional and/or distant stage (HR, 1.94; 95% CI, 1.52-2.47; P = .05), and deaths after breast cancer (HR, 2.11; 95% CI, 1.57-2.84; P < .001). Women with a baseline BMI of less than 25.0 who gained more than 5% of body weight over the follow-up period had an increased breast cancer risk (HR, 1.36; 95% CI, 1.1-1.65), but among women already overweight or obese we found no association of weight change (gain or loss) with breast cancer during follow-up. There was no effect modification of the BMI-breast cancer relationship by postmenopausal hormone therapy, and the direction of association across BMI categories was similar for never, past, and current hormone therapy use. Obesity is associated with increased invasive breast cancer risk in postmenopausal women. These clinically meaningful findings should motivate programs for obesity prevention. clinicaltrials.gov Identifier: NCT00000611.

A prospective cohort study of the combined effects of physical activity and anthropometric measures on the risk of post-menopausal breast cancer.

Although keeping a healthy weight and being physically active are among the few modifiable risk factors for post-menopausal breast cancer, the possible interaction between these two risk factors remains to be established. We analyzed prospectively a cohort of 19,196 women who provided detailed self-report on anthropometric measures, physical activity and possible confounders at enrollment in 1997. We achieved complete follow-up through 2010 and ascertained 609 incident cases of post-menopausal invasive breast cancer. We calculated metabolic energy turnover (MET h/day) per day and fitted Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). The incidence of post-menopausal breast cancer among obese women (BMI≥30kg/m(2)) was 58% higher (HR 1.58, CI 1.16-2.16) than in women of normal weight (18.5≤BMI<25). Women in the lowest tertile of total physical activity (<31.2 MET h/day) had 40% higher incidence of post-menopausal breast cancer (HR 1.40, CI 1.11-1.75) than those in the highest tertile (≥38.2 METh/day). The excess incidence linked to these two factors seemed to combine in an approximately additive manner; the incidence among the most obese and sedentary women was doubled (HR 2.07, CI 1.31-3.25) compared with the most physically active women with normal weight. No heterogeneity of the physical activity-linked risk ratios across strata of BMI was detected (p value for interaction=0.98). This prospective study revealed dose-dependent, homogenous inverse associations between post-menopausal breast cancer incidence and physical activity across all strata of BMI, and between post-menopausal breast cancer incidence and BMI across all strata of physical activity, with no evidence of additive or multiplicative interaction between the two, suggesting independent effects.