Publications by authors named "Susan E Hankinson"

558 Publications

Cancer Progress and Priorities: Breast Cancer.

Cancer Epidemiol Biomarkers Prev 2021 May;30(5):822-844

Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, Massachusetts.

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http://dx.doi.org/10.1158/1055-9965.EPI-20-1193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104131PMC
May 2021

Biomarkers of phthalates and inflammation: Findings from a subgroup of Women's Health Initiative participants.

Int J Hyg Environ Health 2021 May 1;234:113743. Epub 2021 Apr 1.

Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, MA, USA. Electronic address:

Background: Recent experimental work has shown that phthalates may increase inflammation. Prior research has not examined the role of exposure to phthalates in relation to inflammatory status among postmenopausal women who are at higher risk of developing inflammation-related chronic disorders.

Objectives: We aimed to examine the associations of urinary phthalate biomarker concentrations with circulating levels of c-reactive protein [CRP] and interleukin-6 [IL-6] among 443 postmenopausal women selected into a breast cancer case-control study nested within the Women's Health Initiative (WHI).

Methods: A total of 13 phthalate metabolites were measured in urine samples provided at WHI enrollment from 1993 to 1998. We also measured baseline levels of CRP and IL-6 in these women's serum or plasma samples. Multivariable linear models were used to investigate the role of each phthalate biomarker in relation to CRP and IL-6, adjusting for potential confounding factors and specifically evaluating the role of BMI.

Results: In adjusted models we observed positive associations of monocarboxynonyl phthalate (MCNP) with CRP (β = 0.092; 95% CI 0.026, 0.158) and IL-6 (β = 0.108; 95% CI 0.013, 0.204). These positive associations were attenuated and non-significant, however, after further adjustment for body mass index (BMI). In contrast, we observed inverse associations of monoethyl phthalate (MEP) (β = -0.019; 95% CI -0.036, -0.001) and monobenzyl phthalate (MBzP) (β = -0.034; 95% CI -0.058, -0.010) with CRP levels only after adjustment for BMI. Other phthalate biomarkers examined were not significantly associated with either CRP or IL-6 levels.

Conclusions: Overall, these results do not suggest an important role for phthalates in promoting an inflammatory response. Future prospective studies are warranted to improve understanding of these associations, particularly in clarifying the role of BMI.
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http://dx.doi.org/10.1016/j.ijheh.2021.113743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096686PMC
May 2021

Urinary Phthalate Biomarkers and Bone Mineral Density in Postmenopausal Women.

J Clin Endocrinol Metab 2021 Jun;106(7):e2567-e2579

Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia 30341, USA.

Context: Phthalates are endocrine-disrupting chemicals that could disrupt normal physiologic function, triggering detrimental impacts on bone.

Objective: We evaluated associations between urinary phthalate biomarkers and BMD in postmenopausal women participating in the prospective Women's Health Initiative (WHI).

Methods: We included WHI participants enrolled in the BMD substudy and selected for a nested case-control study of phthalates and breast cancer (N = 1255). We measured 13 phthalate biomarkers and creatinine in 2 to 3 urine samples per participant collected over 3 years, when all participants were cancer free. Total hip and femoral neck BMD were measured at baseline and year 3, concurrent with urine collection, via dual-energy x-ray absorptiometry. We fit multivariable generalized estimating equation models and linear mixed-effects models to estimate cross-sectional and longitudinal associations, respectively, with stratification on postmenopausal hormone therapy (HT) use.

Results: In cross-sectional analyses, mono-3-carboxypropyl phthalate and the sum of di-isobutyl phthalate metabolites were inversely associated with total hip BMD among HT nonusers, but not among HT users. Longitudinal analyses showed greater declines in total hip BMD among HT nonusers and with highest concentrations of mono-3-carboxyoctyl phthalate (-1.80%; 95% CI, -2.81% to -0.78%) or monocarboxynonyl phthalate (-1.84%; 95% CI, -2.80% to -0.89%); similar associations were observed with femoral neck BMD. Among HT users, phthalate biomarkers were not associated with total hip or femoral neck BMD change.

Conclusion: Certain phthalate biomarkers are associated with greater percentage decreases in total hip and femoral neck BMD. These findings suggest that phthalate exposure may have clinically important effects on BMD, and potentially fracture risk.
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http://dx.doi.org/10.1210/clinem/dgab189DOI Listing
June 2021

Central adiposity and subsequent risk of breast cancer by menopause status.

J Natl Cancer Inst 2020 Dec 26. Epub 2020 Dec 26.

Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, MA, USA.

Background: Increased body mass index (BMI) is associated with higher postmenopausal breast cancer risk and lower premenopausal breast cancer risk. Less is known about the central adiposity-breast cancer risk association, particularly for tumor subtypes.

Methods: We used prospective waist (WC) and hip circumference (HC) measures in the Nurses' Health Studies. We examined associations of WC, HC and waist-to-hip ratio (WHR) with breast cancer independent of BMI, by menopausal status. Cox proportional hazards models estimated the hazard ratio (HR) and 95% confidence intervals (CI) adjusting for breast cancer risk factors, with and without BMI.

Results: Adjusting for BMI, WC, and HC were not associated and WHR was positively associated with premenopausal breast cancer risk (WHR, quintile 5 vs. 1: HRQ5vQ1, BMI-adjusted=1.27, 95%CI = 1.04-1.54, p-trend = 0.01); particularly for, estrogen receptor-negative (ER-)/ progesterone receptor-negative (PR-) and basal-like breast cancers. Premenopausal WC, HC, and WHR were not associated with postmenopausal breast cancer risk, with or without BMI adjustment. Postmenopausal WC, HC, and WHR were each positively associated with postmenopausal breast cancer (eg, WC HRQ5vsQ1=1.59, 95%CI = 1.36-1.86); after adjustment for BMI, only WC remained statistically significant (HRQ5vsQ1, BMI-adjusted=1.38, 95%CI = 1.15-1.64, p-trend = 0.002). In postmenopausal women, associations were stronger among never users of hormone therapy and for ER+/PR+ breast cancers.

Conclusions: Central adiposity was positively associated with pre- and postmenopausal breast cancers independent of BMI. This suggests that mechanisms other than estrogen may also play a role in the relationship between central adiposity and breast cancer. Maintaining a healthy waist circumference may decrease pre- and postmenopausal breast cancer risk.
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http://dx.doi.org/10.1093/jnci/djaa197DOI Listing
December 2020

Circulating carotenoids and breast cancer among high-risk individuals.

Am J Clin Nutr 2021 03;113(3):525-533

Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.

Background: Carotenoids represent 1 of few modifiable factors to reduce breast cancer risk. Elucidation of interactions between circulating carotenoids and genetic predispositions or mammographic density (MD) may help inform more effective primary preventive strategies in high-risk populations.

Objectives: We tested whether women at high risk for breast cancer due to genetic predispositions or high MD would experience meaningful and greater risk reduction from higher circulating levels of carotenoids in a nested case-control study in the Nurses' Health Studies (NHS and NHSII).

Methods: This study included 1919 cases and 1695 controls in a nested case-control study in the NHS and NHSII. We assessed both multiplicative and additive interactions. RR reductions and 95% CIs were calculated using unconditional logistic regressions, adjusting for matching factors and breast cancer risk factors. Absolute risk reductions (ARR) were calculated based on Surveillance, Epidemiology, and End Results incidence rates.

Results: We showed that compared with women at low genetic risk or low MD, those with higher genetic risk scores or high MD had greater ARRs for breast cancer as circulating carotenoid levels increase (additive P-interaction = 0.05). Among women with a high polygenic risk score, those in the highest quartile of circulating carotenoids had a significant ARR (28.6%; 95% CI, 14.8-42.1%) compared to those in the lowest quartile of carotenoids. For women with a high percentage MD (≥50%), circulating carotenoids were associated with a 37.1% ARR (95% CI, 21.7-52.1%) when comparing the highest to the lowest quartiles of circulating carotenoids.

Conclusions: The inverse associations between circulating carotenoids and breast cancer risk appeared to be more pronounced in high-risk women, as defined by germline genetic makeup or MD.
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http://dx.doi.org/10.1093/ajcn/nqaa316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948839PMC
March 2021

Automated Quantitative Measures of Terminal Duct Lobular Unit Involution and Breast Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 11 11;29(11):2358-2368. Epub 2020 Sep 11.

Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Background: Manual qualitative and quantitative measures of terminal duct lobular unit (TDLU) involution were previously reported to be inversely associated with breast cancer risk. We developed and applied a deep learning method to yield quantitative measures of TDLU involution in normal breast tissue. We assessed the associations of these automated measures with breast cancer risk factors and risk.

Methods: We obtained eight quantitative measures from whole slide images from a benign breast disease (BBD) nested case-control study within the Nurses' Health Studies (287 breast cancer cases and 1,083 controls). Qualitative assessments of TDLU involution were available for 177 cases and 857 controls. The associations between risk factors and quantitative measures among controls were assessed using analysis of covariance adjusting for age. The relationship between each measure and risk was evaluated using unconditional logistic regression, adjusting for the matching factors, BBD subtypes, parity, and menopausal status. Qualitative measures and breast cancer risk were evaluated accounting for matching factors and BBD subtypes.

Results: Menopausal status and parity were significantly associated with all eight measures; select TDLU measures were associated with BBD histologic subtype, body mass index, and birth index ( < 0.05). No measure was correlated with body size at ages 5-10 years, age at menarche, age at first birth, or breastfeeding history ( > 0.05). Neither quantitative nor qualitative measures were associated with breast cancer risk.

Conclusions: Among Nurses' Health Studies women diagnosed with BBD, TDLU involution is not a biomarker of subsequent breast cancer.

Impact: TDLU involution may not impact breast cancer risk as previously thought.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642012PMC
November 2020

Olive oil and risk of breast cancer: a systematic review and dose-response meta-analysis of observational studies.

Br J Nutr 2021 May 4;125(10):1148-1156. Epub 2020 Sep 4.

Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, MA01003, USA.

Olive oil consumption has been suggested to be inversely associated with breast cancer risk, probably due to its high MUFA and polyphenol content. The purpose of this meta-analysis was to assess the association between olive oil and breast cancer risk, including assessing the potential for a dose-response association. We performed a systematic search of PubMed, Web of Science, CINAHL and Cochrane Central Register of Controlled Trials through June 2020, identifying ten observational studies (two prospective studies and eight case-control studies) for meta-analysis. We estimated summary OR and 95 % CI for the highest v. lowest olive oil intake category across studies using random effect models and assessed the dose-response relationship between olive oil and breast cancer risk using restricted cubic splines. The summary OR comparing women with the highest intake to those with the lowest category of olive oil intake was 0·48 (95 % CI 0·09, 2·70) in prospective studies and 0·76 (95 % CI 0·54, 1·06) in case-control studies, with evidence of substantial study heterogeneity (prospective I2 = 89 %, case-control I2 = 82 %). There was no significant dose-response relationship for olive oil and breast cancer risk; the OR for a 14 g/d increment was 0·93 (95 % CI 0·83, 1·04). There may be a potential inverse association between olive oil intake and breast cancer; however, since the estimates are non-significant and the certainty level is very low, additional prospective studies with better assessment of olive oil intake are needed.
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http://dx.doi.org/10.1017/S0007114520003499DOI Listing
May 2021

Associations of depression status with plasma levels of candidate lipid and amino acid metabolites: a meta-analysis of individual data from three independent samples of US postmenopausal women.

Mol Psychiatry 2020 Aug 28. Epub 2020 Aug 28.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.

Recent animal and small clinical studies have suggested depression is related to altered lipid and amino acid profiles. However, this has not been examined in a population-based sample, particularly in women. We identified multiple metabolites associated with depression as potential candidates from prior studies. Cross-sectional data from three independent samples of postmenopausal women were analyzed, including women from the Women's Health Initiative-Observational Study (WHI-OS, n = 926), the WHI-Hormone Trials (WHI-HT; n = 1,325), and the Nurses' Health Study II Mind-Body Study (NHSII-MBS; n = 218). Positive depression status was defined as having any of the following: elevated depressive symptoms, antidepressant use, or depression history. Plasma metabolites were measured using liquid chromatography-tandem mass spectrometry (21 phosphatidylcholines (PCs), 7 lysophosphatidylethanolamines, 5 ceramides, 3 branched chain amino acids, and 9 neurotransmitters). Associations between depression status and metabolites were evaluated using multivariable linear regression; results were pooled by random-effects meta-analysis with multiple testing adjustment using the false discovery rate (FDR). Prevalence rates of positive depression status were 24.4% (WHI-OS), 25.7% (WHI-HT), and 44.7% (NHSII-MBS). After multivariable adjustment, positive depression status was associated with higher levels of glutamate and PC 36 : 1/38 : 3, and lower levels of tryptophan and GABA-to-glutamate and GABA-to-glutamine ratio (FDR-p < 0.05). Positive associations with LPE 18 : 0/18 : 1 and inverse associations with valine and serotonin were also observed, although these associations did not survive FDR adjustment. Associations of positive depression status with several candidate metabolites including PC 36 : 1/38 : 3 and amino acids involved in neurotransmission suggest potential depression-related metabolic alterations in postmenopausal women, with possible implications for later chronic disease.
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http://dx.doi.org/10.1038/s41380-020-00870-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914294PMC
August 2020

Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Int J Cancer 2021 01 7;148(2):307-319. Epub 2020 Aug 7.

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia, USA.

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.
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http://dx.doi.org/10.1002/ijc.33206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757859PMC
January 2021

Low dose environmental radon exposure and breast tumor gene expression.

BMC Cancer 2020 Jul 28;20(1):695. Epub 2020 Jul 28.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Background: The International Agency for Research on Cancer classified radon and its decay-products as Group-1-human-carcinogens, and with the current knowledge they are linked specifically to lung cancer. Biokinetic models predict that radon could deliver a carcinogenic dose to breast tissue. Our previous work suggested that low-dose radon was associated with estrogen-receptor (ER)-negative breast cancer risk. However, there is limited research to examine the role of radon in breast cancer biology at the tissue level. We aim to understand molecular pathways linking radon exposure with breast cancer biology using transcriptome-wide-gene-expression from breast tumor and normal-adjacent tissues.

Methods: Our study included 943 women diagnosed with breast cancer from the Nurses' Health Study (NHS) and NHSII. We estimated cumulative radon concentration for each participant up-to the year of breast cancer diagnosis by linking residential addresses with a radon exposure model. Transcriptome-wide-gene-expression was measured with the Affymetrix-Glue-Human-Transcriptome-Array-3.0 and Human-Transcriptome-Array-2.0. We performed covariate-adjusted linear-regression for individual genes and further employed pathway-analysis. All analyses were conducted separately for tumor and normal-adjacent samples and by ER-status.

Results: No individual gene was associated with cumulative radon exposure in ER-positive tumor, ER-negative tumor, or ER-negative normal-adjacent tissues at FDR < 5%. In ER-positive normal-adjacent samples, PLCH2-reached transcriptome-wide-significance (FDR < 5%). Gene-set-enrichment-analyses identified 2-upregulated pathways (MAPK signaling and phosphocholine biosynthesis) enriched at FDR < 25% in ER-negative tumors and normal-adjacent tissues, and both pathways have been previously reported to play key roles in ionizing radiation induced tumorigenesis in experimental settings.

Conclusion: Our findings provide insights into the molecular pathways of radon exposure that may influence breast cancer etiology.
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http://dx.doi.org/10.1186/s12885-020-07184-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385902PMC
July 2020

Involvement of fine particulate matter exposure with gene expression pathways in breast tumor and adjacent-normal breast tissue.

Environ Res 2020 07 15;186:109535. Epub 2020 Apr 15.

Channing Division of Network Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Fine particulate matter (PM) has been associated with breast cancer specific mortality, particularly for women with Stage I cancer. We examined the biological pathways that are perturbed by PM exposures by analyzing gene expression measurements from breast tissue specimens.

Methods: The Nurses' Health Studies (NHS and NHSII) are prospective cohorts with archival breast tissue specimens from breast cancer cases. Global gene expression data were ascertained with the Affymetrix Glue Human Transcriptome Array 3.0. PM was estimated using spatio-temporal models linked to participants' home addresses. All analyses were performed separately in tumor (n = 591) and adjacent-normal (n = 497) samples, and stratified by estrogen receptor (ER) status and stage. We used multivariable linear regression, gene-set enrichment analyses (GSEA), and the least squares kernel machine (LSKM) to assess whether 3-year cumulative average pre-diagnosis PM exposure was associated with breast-tissue gene expression pathways among predominately Stage I and II women (90.7%) and postmenopausal (81.2%) women. Replication samples (tumor, n = 245; adjacent-normal, n = 165) were measured on Affymetrix Human Transcriptome Array (HTA 2.0).

Results: Overall, no pathways in the tumor area were significantly associated with PM exposure. Among 272 adjacent-normal samples from Stage I ER-positive women, PM was associated with perturbations in the oxidative phosphorylation, protein secretion, and mTORC1 signaling pathways (GSEA and LSKM p-values <0.05); however, results were not replicated in a small set of replication samples (n = 80).

Conclusions: PM was generally not associated with breast tissue gene expression though was suggested to perturb oxidative phosphorylation and regulation of proteins and cellular signaling in adjacent-normal breast tissue. More research is needed on the biological role of PM that influences breast tumor progression.
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http://dx.doi.org/10.1016/j.envres.2020.109535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368092PMC
July 2020

Prediagnostic 25-Hydroxyvitamin D Concentrations in Relation to Tumor Molecular Alterations and Risk of Breast Cancer Recurrence.

Cancer Epidemiol Biomarkers Prev 2020 06 1;29(6):1253-1263. Epub 2020 Apr 1.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Background: Although vitamin D inhibits breast tumor growth in experimental settings, the findings from population-based studies remain inconclusive. Our goals were to investigate the association between prediagnostic plasma 25-hydroxyvitamin D [25(OH)D] concentration and breast cancer recurrence in prospective epidemiologic studies and to explore the molecular underpinnings linking 25(OH)D to slower progression of breast cancer in the Nurses' Health Studies (NHS, = 659).

Methods: Plasma 25(OH)D was measured with a high-affinity protein-binding assay and a radioimmunoassay. We profiled transcriptome-wide gene expression in breast tumors using microarrays. Hazard ratios (HR) of breast cancer recurrence were estimated from covariate-adjusted Cox regressions. We examined differential gene expression in association with 25(OH)D and employed pathway analysis. We derived a gene expression score for 25(OH)D, and assessed associations between the score and cancer recurrence.

Results: Although 25(OH)D was not associated with breast cancer recurrence overall [HR = 0.97; 95% confidence interval (CI), 0.88-1.08], the association varied by estrogen-receptor (ER) status ( = 0.005). Importantly, among ER-positive stage I to III cancers, every 5 ng/mL increase in 25(OH)D was associated with a 13% lower risk of recurrence (HR = 0.87; 95% CI, 0.76-0.99). A null association was observed for ER-negative cancers (HR = 1.07; 95% CI, 0.91-1.27). Pathway analysis identified multiple gene sets that were significantly (FDR < 5%) downregulated in ER-positive tumors of women with high 25(OH)D (≥30 ng/mL), compared with those with low levels (<30 ng/mL). These gene sets are primarily involved in tumor proliferation, migration, and inflammation. 25(OH)D score derived from these gene sets was marginally associated with reduced risk of recurrence in ER-positive diseases (HR = 0.77; 95% CI, 0.59-1.01) in the NHS studies; however no association was noted in METABRIC, suggesting that further refinement is need to improve the generalizability of the score.

Conclusions: Our findings support an intriguing line of research for studies to better understand the mechanisms underlying the role of vitamin D in breast tumor progression, particularly for the ER-positive subtype.

Impact: Vitamin D may present a personal-level secondary-prevention strategy for ER-positive breast cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284927PMC
June 2020

Plasma Estradiol and Testosterone Levels and Ischemic Stroke in Postmenopausal Women.

Stroke 2020 04 14;51(4):1297-1300. Epub 2020 Feb 14.

From the Division of Women's Health (J.H., M.C.J., K.M.R.), Department of Medicine, Brigham and Women's Hospital, Boston, MA.

Background and Purpose- Although exogenous hormone therapy (HT) use has been associated with increased risk of ischemic stroke in postmenopausal women, it remains unknown whether sex hormone levels contribute to ischemic stroke risk. We aimed to estimate associations between plasma sex hormone levels and ischemic stroke risk, by HT status, in a nested case-control study of postmenopausal women from the NHS (Nurses' Health Study). Methods- Women with confirmed incident ischemic stroke (n=419) were matched with controls (n=419) by age, HT use, and other factors. Plasma estradiol and testosterone levels were measured using liquid chromatography tandem mass spectrometry; SHBG (sex hormone-binding globulin) was assayed by electrochemiluminescence immunoassay. Associations of total and free estradiol and testosterone, the estradiol/testosterone ratio, and SHBG with ischemic stroke were estimated using conditional logistic regressions stratified by HT status with adjustment for matching and cardiovascular risk factors. Results- Current HT users had different hormone profiles from never/past users. No clear linear trends were observed between estradiol (total or free) levels or the estradiol/testosterone ratio and ischemic stroke risk among either current users (>0.1) or never/past users (>0.6). For both current and never/past users, the associations between some of the sex hormones and ischemic stroke differed by body mass index categories (≤0.04). For women with a body mass index <25 kg/m, a higher estradiol/testosterone ratio was associated with significantly elevated ischemic stroke risk among current users (=0.01), and higher levels of total and free estradiol were significantly associated with higher ischemic stroke risk among never/past users (≤0.04). Testosterone and SHBG were not associated with ischemic stroke in either current or never/past users. Conclusions- Our findings do not support a role of sex hormone levels in mediating ischemic stroke risk among postmenopausal women. Replications in additional larger studies are required.
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http://dx.doi.org/10.1161/STROKEAHA.119.028588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159036PMC
April 2020

Adult weight change and premenopausal breast cancer risk: A prospective pooled analysis of data from 628,463 women.

Int J Cancer 2020 09 15;147(5):1306-1314. Epub 2020 Feb 15.

Albert Einstein College of Medicine, Bronx, NY.

Early-adulthood body size is strongly inversely associated with risk of premenopausal breast cancer. It is unclear whether subsequent changes in weight affect risk. We pooled individual-level data from 17 prospective studies to investigate the association of weight change with premenopausal breast cancer risk, considering strata of initial weight, timing of weight change, other breast cancer risk factors and breast cancer subtype. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained using Cox regression. Among 628,463 women, 10,886 were diagnosed with breast cancer before menopause. Models adjusted for initial weight at ages 18-24 years and other breast cancer risk factors showed that weight gain from ages 18-24 to 35-44 or to 45-54 years was inversely associated with breast cancer overall (e.g., HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.95-0.98) and with oestrogen-receptor(ER)-positive breast cancer (HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.94-0.98). Weight gain from ages 25-34 was inversely associated with ER-positive breast cancer only and weight gain from ages 35-44 was not associated with risk. None of these weight gains were associated with ER-negative breast cancer. Weight loss was not consistently associated with overall or ER-specific risk after adjusting for initial weight. Weight increase from early-adulthood to ages 45-54 years is associated with a reduced premenopausal breast cancer risk independently of early-adulthood weight. Biological explanations are needed to account for these two separate factors.
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http://dx.doi.org/10.1002/ijc.32892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365745PMC
September 2020

Association of Parity and Breastfeeding With Risk of Early Natural Menopause.

JAMA Netw Open 2020 01 3;3(1):e1919615. Epub 2020 Jan 3.

School of Public Health and Health Sciences, Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst.

Importance: Pregnancy and breastfeeding prevent ovulation and may slow the depletion of the ovarian follicle pool. These factors may lower the risk of early menopause, a condition associated with increased risk of cardiovascular disease and other adverse health outcomes.

Objective: To examine the association of parity and breastfeeding with the risk of early menopause.

Design, Setting, And Participants: This population-based cohort study within the Nurses' Health Study II cohort (1989-2015) included premenopausal participants who were aged 25 to 42 years at baseline. Response rates were 85% to 90% for each cycle, and follow-up continued until menopause, age 45 years, hysterectomy, oophorectomy, death, cancer diagnosis, loss to follow-up, or end of follow-up in May 2015. Hypotheses were formulated after data collection. Data analysis took place from February to July 2019.

Exposures: Parity (ie, number of pregnancies lasting ≥6 months) was measured at baseline and every 2 years. History and duration of total and exclusive breastfeeding were assessed 3 times during follow-up. Menopause status and age were assessed every 2 years.

Main Outcomes And Measures: Risk of natural menopause before age 45 years.

Results: At baseline, 108 887 premenopausal women aged 25 to 42 years (mean [SD] age, 34.1 [4.6] years; 102 246 [93.9%] non-Hispanic white) were included in the study. In multivariable models, higher parity was associated with lower risk of early menopause. Hazard ratios were attenuated with adjustment for breastfeeding but remained significant. Compared with nulliparous women, those reporting 1, 2, 3, and 4 or more pregnancies lasting at least 6 months had hazard ratios for early menopause of 0.92 (95% CI, 0.79-1.06), 0.84 (95% CI, 0.73-0.96), 0.78 (95% CI, 0.67-0.92), and 0.81 (95% CI, 0.66-1.01), respectively (P for trend = .006). In multivariable models also adjusted for parity, hazard ratios for duration of exclusive breastfeeding of 1 to 6, 7 to 12, 13 to 18, and 19 or more months were 0.95 (95% CI, 0.85-1.07), 0.72 (95% CI, 0.62-0.83), 0.80 (95% CI, 0.66-0.97), and 0.89 (95% CI, 0.69-1.16), respectively, compared with less than 1 month of exclusive breastfeeding (P for trend = .001). Despite the significant test for trend, estimates were not observed to be lower as duration of exclusive breastfeeding increased. In a stratified analysis of parous women, risk of early menopause was lowest among those reporting exclusive breastfeeding for 7 to 12 months in each level of parity (women with 2 pregnancies and 7-12 months of breastfeeding: HR, 0.79; 95% CI, 0.66-0.96; ≥3 pregnancies and 7-12 months of breastfeeding: HR, 0.68; 95% CI, 0.52-0.88; 2 pregnancies and ≥13 months of breastfeeding: HR, 0.87; 95% CI, 0.66-1.15; ≥3 pregnancies and 13-18 months of breastfeeding: HR, 0.86; 95% CI, 0.66-1.13; and ≥3 pregnancies and ≥19 months of breastfeeding: HR, 0.98; 95% CI, 0.72-1.32).

Conclusions And Relevance: In this study, an inverse association of parity with risk of early menopause was observed. Breastfeeding was associated with significantly lower risk, even after accounting for parity. Breastfeeding at levels consistent with current recommendations may confer an additional benefit of lower risk of early menopause.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.19615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991272PMC
January 2020

The Association of Modifiable Breast Cancer Risk Factors and Somatic Genomic Alterations in Breast Tumors: The Cancer Genome Atlas Network.

Cancer Epidemiol Biomarkers Prev 2020 03 13;29(3):599-605. Epub 2020 Jan 13.

Channing Division of Network Medicine, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts.

Background: The link between modifiable breast cancer risk factors and tumor genomic alterations remains largely unexplored. We evaluated the association of prediagnostic body mass index (BMI), cigarette smoking, and alcohol consumption with somatic copy number variation (SCNV), total somatic mutation burden (TSMB), seven single base substitution (SBS) signatures (SBS1, SBS2, SBS3, SBS5, SBS13, SBS29, and SBS30), and nine driver mutations (, and ) in a subset of The Cancer Genome Atlas (TCGA).

Methods: Clinical and genomic data were retrieved from the TCGA database. Risk factor information was collected from four TCGA sites ( = 219 women), including BMI (1 year before diagnosis), cigarette smoking (smokers/nonsmokers), and alcohol consumption (current drinkers/nondrinkers). Multivariable regression analyses were conducted in all tumors and stratified according to estrogen receptor (ER) status.

Results: Increasing BMI was associated with increasing SCNV in all women ( = 0.039) and among women with ER tumors ( = 0.031). Smokers had higher SCNV and TSMB versus nonsmokers ( < 0.05 all women). Alcohol drinkers had higher SCNV versus nondrinkers ( < 0.05 all women and among women with ER tumors). SBS3 (defective homologous recombination-based repair) was exclusively found in alcohol drinkers with ER disease. mutation was more likely to occur in women with higher BMI. No association was significant after multiple testing correction.

Conclusions: This study provides preliminary evidence that BMI, cigarette smoking, and alcohol consumption can influence breast tumor biology, in particular, DNA alterations.

Impact: This study demonstrates a link between modifiable breast cancer risk factors and tumor genomic alterations.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060119PMC
March 2020

Endogenous sex hormones and colorectal cancer survival among men and women.

Int J Cancer 2020 08 11;147(4):920-930. Epub 2020 Jan 11.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Although previous studies have suggested a potential role of sex hormones in the etiology of colorectal cancer (CRC), no study has yet examined the associations between circulating sex hormones and survival among CRC patients. We prospectively assessed the associations of prediagnostic plasma concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone and sex hormone-binding globulin (SHBG) with CRC-specific and overall mortality among 609 CRC patients (370 men and 239 postmenopausal women not taking hormone therapy at blood collection) from four U.S. cohorts. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression. We identified 174 deaths (83 CRC-specific deaths) in men and 106 deaths (70 CRC-specific deaths) in women. In men, higher circulating level of free testosterone was associated with lower risk of overall (the highest vs. lowest tertiles, HR = 0.66, 95% CI, 0.45-0.99, p = 0.04) and possibly CRC-specific mortality (HR = 0.73, 95% CI, 0.41-1.29, p = 0.27). We generally observed nonsignificant inverse associations for other sex steroids, and a positive association for SHBG with CRC-specific mortality among male patients. In women, however, we found a suggestive positive association of estrone with overall (HR = 1.54, 95% CI, 0.92-2.60, p = 0.11) and CRC-specific mortality (HR = 1.96, 95% CI, 1.01-3.84, p = 0.06). Total estradiol, free estradiol and free testosterone were generally suggestively associated with higher risk of mortality among female patients, although not statistically significant. These findings implicated a potential role of endogenous sex hormones in CRC prognosis, which warrant further investigation.
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http://dx.doi.org/10.1002/ijc.32844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895324PMC
August 2020

Metrics of Diabetes Risk Are Only Minimally Improved by Exercise Training in Postmenopausal Breast Cancer Survivors.

J Clin Endocrinol Metab 2020 05;105(5)

Department of Kinesiology, University of Massachusetts, Amherst, MA, US.

Context: Insulin resistance is a risk factor for breast cancer recurrence. How exercise training changes fasting and postglucose insulin resistance in breast cancer survivors is unknown.

Objective: To evaluate exercise-induced changes in postglucose ingestion insulin concentrations, insulin resistance, and their associations with cancer-relevant biomarkers in breast cancer survivors.

Setting: The University of Massachusetts Kinesiology Department.

Participants: 15 postmenopausal breast cancer survivors not meeting the physical activity guidelines (150 min/week of exercise).

Intervention: A supervised 12-week aerobic exercise program (60 min/day, 3-4 days/week).

Main Outcome Measures: Postglucose ingestion insulin was determined by peak insulin and area under the insulin curve (iAUC) during a 5-sample oral glucose tolerance test. Insulin sensitivity was estimated from the Matsuda composite insulin sensitivity index (C-ISI). Changes in fitness and body composition were determined from submaximal VO2peak and dual energy X-ray absorptiometry.

Results: Participants averaged 156.8 ± 16.6 min/week of supervised exercise. Estimated VO2peak significantly increased (+2.8 ± 1.4 mL/kg/min, P < .05) and body weight significantly decreased (-1.1 ± 0.8 kg, P < .05) following the intervention. There were no differences in fasting insulin, iAUC, C-ISI, or peak insulin following the intervention. Insulin was only significantly lower 120 min following glucose consumption (68.8 ± 34.5 vs 56.2 ± 31.9 uU/mL, P < .05), and there was a significant interaction with past/present aromatase inhibitor (AI) use for peak insulin (-11.99 non-AI vs +13.91 AI uU/mL) and iAUC (-24.03 non-AI vs +32.73 AI uU/mL).

Conclusions: Exercise training had limited overall benefits on insulin concentrations following glucose ingestion in breast cancer survivors but was strongly influenced by AI use.
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http://dx.doi.org/10.1210/clinem/dgz213DOI Listing
May 2020

Flavonoid Intake and Plasma Sex Steroid Hormones, Prolactin, and Sex Hormone-Binding Globulin in Premenopausal Women.

Nutrients 2019 Nov 5;11(11). Epub 2019 Nov 5.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

Background: Flavonoids potentially exert anti-cancer effects, as suggested by their chemical structures and supported by animal studies. In observational studies, however, the association between flavonoids and breast cancer, and potential underlying mechanisms, remain unclear.

Objective: To examine the relationship between flavonoid intake and sex hormone levels using timed blood samples in follicular and luteal phases in the Nurses' Health Study II among premenopausal women.

Methods: Plasma concentrations of estrogens, androgens, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), prolactin, and sex hormone-binding globulin (SHBG) were measured in samples collected between 1996 and 1999. Average flavonoid were calculated from semiquantitative food frequency questionnaires collected in 1995 and 1999. We used generalized linear models to calculate geometric mean hormone concentrations across categories of the intake of flavonoids and the subclasses.

Results: Total flavonoid intake generally was not associated with the hormones of interest. The only significant association was with DHEAS (-trend = 0.02), which was 11.1% (95% confidence interval (CI): -18.6%, -3.0%) lower comparing the highest vs. lowest quartile of flavonoid intake. In subclass analyses, the highest (vs. lowest) quartile of flavan-3-ol intake was associated with significantly lower DHEAS concentrations (-11.3% with 95% CI: -18.3%, -3.7%, -trend = 0.01), and anthocyanin intake was associated with a significant inverse trend for DHEA (-18.0% with 95% CI: -27.9%, -6.7%, -trend = 0.003).

Conclusion: Flavonoid intake in this population had limited impact on most plasma sex hormones in premenopausal women. Anthocyanins and flavan-3-ols were associated with lower levels of DHEA and DHEAS.
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http://dx.doi.org/10.3390/nu11112669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928816PMC
November 2019

Psychotropic Medication Use and Postmenopausal Breast Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 01 4;29(1):254-256. Epub 2019 Nov 4.

Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, Massachusetts.

Background: Prior studies evaluating psychotropic medications in relation to breast cancer risk are inconsistent and have not separately evaluated invasive and disease.

Methods: We estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association of psychotropic medication use (any, typical antipsychotics, atypical antipsychotics, and lithium) with invasive and breast cancer risk among Women's Health Initiative participants ( = 155,737).

Results: Prevalence of psychotropic medication use was low ( = 642; 0.4%). During an average 14.8 (SD, 6.5) years of follow-up, 10,067 invasive and 2,285 breast tissues were diagnosed. Any psychotropic medication use was not associated with invasive breast cancer risk compared with nonusers (HR, 0.82; 95% CI, 0.57-1.18). breast cancer risk was higher among "typical" antipsychotic medication users compared with nonusers (HR, 2.05; 95% CI, 0.97-4.30).

Conclusions: These findings do not support an association of psychotropic medication use with invasive breast cancer risk. The possible elevation in breast cancer risk associated with "typical" antipsychotics could not be explained by differences in screening mammography utilization and merits further study.

Impact: Our findings contribute to knowledge of the safety profile of psychotropic medications and may be useful to clinicians and patients considering use of these medications.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954318PMC
January 2020

Circulating lipids, mammographic density, and risk of breast cancer in the Nurses' Health Study and Nurses' Health Study II.

Cancer Causes Control 2019 Sep 1;30(9):943-953. Epub 2019 Jul 1.

Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.

Purpose: Epidemiologic evidence supports an association between high mammographic density and increased breast cancer risk yet etiologic mechanisms remain largely unknown. Mixed evidence exists as to whether circulating lipid levels influence mammographic density and breast cancer risk. Therefore, we examined these associations in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII), two large prospective cohorts with information on PMD and circulating lipid measures, long follow-up, and breast cancer risk factor and outcome data.

Methods: We conducted a nested case-control study among women in the NHS and NHSII. Percent mammographic density (PMD) was measured using Cumulus software, a computer-assisted method, on digitized film mammograms. Cross-sectional associations between circulating lipids [total cholesterol (n = 1,502), high-density lipoprotein (HDL-C; n = 579), and triglycerides (n = 655)] and PMD were evaluated among controls. All analyses were stratified by menopausal status at time of mammogram. Relative risks for breast cancer by lipid and PMD measures were estimated among postmenopausal women in the full nested case-control study (cases/controls for cholesterol, HDL-C, and triglycerides were 937/975, 416/449, and 506/537, respectively).

Results: There were no significant associations between circulating lipid levels and PMD among healthy women, irrespective of menopausal status. The association between PMD and breast cancer risk among postmenopausal women was not modified by circulating lipid levels (p interaction = 0.83, 0.80, and 0.34 for total cholesterol, HDL-C, and triglycerides, respectively).

Conclusion: Overall, no association was observed between lipid levels and PMD, and there was no evidence that lipid levels modified the association between PMD and breast cancer risk.
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http://dx.doi.org/10.1007/s10552-019-01201-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778452PMC
September 2019

Shift Work, Chronotype, and Melatonin Rhythm in Nurses.

Cancer Epidemiol Biomarkers Prev 2019 07 29;28(7):1177-1186. Epub 2019 May 29.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Background: Previous studies associated night-shift work with melatonin disruption, with mixed evidence regarding the modulating effects of chronotype (i.e., diurnal preference).

Methods: One hundred and thirty active nurses (84 rotating-shift and 46 day-shift workers) in the Nurses' Health Study II wore a head-mounted light meter and collected spontaneous urine voids over 3 days. 6-Sulfatoxymelatonin (aMT6s), the major urinary metabolite of melatonin, was assessed.

Results: Rotating-shift workers on night shifts had more light exposure and lower urinary melatonin levels during the night, and urinary melatonin rhythms with smaller peaks [11.81 ng/mg-creatinine/h, 95% confidence interval (CI), 9.49-14.71 vs. 14.83 ng/mg-creatinine/h, 95% CI, 11.72-18.75] and later peak onset (5.71 hours, 95% CI, 4.76-6.85 vs. 4.10 hours, 95% CI, 3.37-4.99), compared with day-shift workers. Furthermore, evening chronotypes' melatonin rhythms had later peak onset compared with morning types (4.90 hours, 95% CI, 3.94-6.09 vs. 3.64 hours, 95% CI, 2.99-4.43). However, among day-shift workers, morning chronotypes had melatonin rhythms with greater mean levels, larger peaks, and earlier peak onset compared with evening chronotypes; patterns were similar comparing evening versus morning chronotypes among rotating-shift workers on night shifts. The interaction of rotating-shift work and chronotype was significant across all parameters ( < 0.05).

Conclusions: As expected, rotating-shift workers on night shifts had greater light exposure and lower urinary melatonin levels during the night compared with day-shift workers. Intriguingly, melatonin rhythms were dependent on both chronotype and rotating-shift work type, and better alignment of rotating-shift work and chronotype appeared to produce less disrupted melatonin rhythms.

Impact: The joint effects of shift-work type and chronotype require attention in future studies.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750706PMC
July 2019

The Mind-Body Study: study design and reproducibility and interrelationships of psychosocial factors in the Nurses' Health Study II.

Cancer Causes Control 2019 Jul 2;30(7):779-790. Epub 2019 May 2.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Ave., Rm 432, Boston, MA, 02115, USA.

Purpose: Associations between psychosocial factors and biomarkers are increasingly investigated in studies of cancer incidence and mortality. Documenting optimal data/biospecimen collection protocols and scale properties are fundamental for elucidating the impact of psychosocial factors on biologic systems and ultimately cancer development/progression.

Methods: Between 2013 and 2014, 233 Nurses' Health Study II women (mean age: 60.6) participated in the Mind-Body Study. Participants completed a detailed online psychosocial assessment and provided hair, toenail, timed saliva over 1 day, urine and fasting blood twice, 1 year apart. Additionally, two separate microbiome collections for stool and saliva were conducted between the psychosocial assessments. We assessed correlations between various psychosocial measures and evaluated their 1-year reproducibility using intraclass correlations (ICC).

Results: Compliance with the protocols was high among participants. Psychosocial measures showed moderate-to-high reproducibility over 1 year (ICCs = 0.51-0.81). There was clear clustering of psychosocial factors according to whether they were querying positive (e.g., optimism, mastery, mindfulness) or negative (e.g., anxiety, depression, discrimination) emotion-related or social constructs.

Conclusion: Results suggest feasibility for self-administered collection of various biospecimens and moderate-to-high reproducibility of psychosocial factors. The Mind-Body Study provides a unique resource for assessing inter-relationships between psychosocial factors and biological processes linked with long-term health outcomes, including carcinogenesis.
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http://dx.doi.org/10.1007/s10552-019-01176-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631300PMC
July 2019

Comparison of Questionnaire-Based Breast Cancer Prediction Models in the Nurses' Health Study.

Cancer Epidemiol Biomarkers Prev 2019 07 23;28(7):1187-1194. Epub 2019 Apr 23.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Background: The Gail model and the model developed by Tyrer and Cuzick are two questionnaire-based approaches with demonstrated ability to predict development of breast cancer in a general population.

Methods: We compared calibration, discrimination, and net reclassification of these models, using data from questionnaires sent every 2 years to 76,922 participants in the Nurses' Health Study between 1980 and 2006, with 4,384 incident invasive breast cancers identified by 2008 (median follow-up, 24 years; range, 1-28 years). In a random one third sample of women, we also compared the performance of these models with predictions from the Rosner-Colditz model estimated from the remaining participants.

Results: Both the Gail and Tyrer-Cuzick models showed evidence of miscalibration (Hosmer-Lemeshow < 0.001 for each) with notable ( < 0.01) overprediction in higher-risk women (2-year risk above about 1%) and underprediction in lower-risk women (risk below about 0.25%). The Tyrer-Cuzick model had slightly higher C-statistics both overall ( < 0.001) and in age-specific comparisons than the Gail model (overall C, 0.63 for Tyrer-Cuzick vs. 0.61 for the Gail model). Evaluation of net reclassification did not favor either model. In the one third sample, the Rosner-Colditz model had better calibration and discrimination than the other two models. All models had C-statistics <0.60 among women ages ≥70 years.

Conclusions: Both the Gail and Tyrer-Cuzick models had some ability to discriminate breast cancer cases and noncases, but have limitations in their model fit.

Impact: Refinements may be needed to questionnaire-based approaches to predict breast cancer in older and higher-risk women.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684099PMC
July 2019

Objective and Self-Reported Measures of Physical Activity and Sex Hormones: Women's Lifestyle Validation Study.

J Phys Act Health 2019 05 11;16(5):355-361. Epub 2019 Apr 11.

: The relationship between specific characteristics of physical activity (PA) (eg, intensity, type, frequency) with sex hormones is uncertain. The authors evaluated the association between characteristics of PA and circulating sex hormones. : This was a cross-sectional analysis of the Women's Lifestyle Validation Study (n = 493). Total PA, light-intensity PA (LPA), and moderate- to vigorous-intensity PA (MVPA) were assessed by accelerometry (a) and self-report (sr). Self-report was used to assess PA type (ie, aerobic, weight training) and exercise frequency. Dehydroepiandrosterone sulfate, testosterone, and sex hormone-binding globulin (SHBG) were assayed among all women; estradiol was assayed in postmenopausal women not currently on hormone therapy. : Estradiol was inversely associated and SHBG positively associated with MVPA and LPA (estradiol:  = -0.15 per SD increase,  ≤ .01 for a-MVPA and a-LPA; SHBG: a-MVPA  = 0.20 per SD increase,  ≤ .01, a-LPA  = 0.15,  < .01). By type, aerobic activity and weight training were each independently associated with estradiol and SHBG. Controlling for body mass index attenuated all associations for estradiol, and to a lesser extent SHBG. PA was not associated with testosterone levels. : Multiple aspects of PA were independently associated with sex hormones; associations varied some by activity intensity and type, and were attenuated after accounting for body mass index.
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http://dx.doi.org/10.1123/jpah.2018-0241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823841PMC
May 2019

Plasma B-vitamins and one-carbon metabolites and the risk of breast cancer in younger women.

Breast Cancer Res Treat 2019 Jul 6;176(1):191-203. Epub 2019 Apr 6.

Department of Biostatistics and Epidemiology, University of Massachusetts, 715 North Pleasant Street, Amherst, MA, 01003, USA.

Purpose: We examined the association of plasma B-vitamins and metabolites, and related genetic variants, with risk of breast cancer among predominantly premenopausal women.

Methods: We conducted a nested case-control study within the Nurses' Health Study II. From blood samples collected in 1996-1999 and follow-up through 2007, plasma measures were available for 610 cases and 1207 controls. Unconditional multivariable logistic regression was used to estimate relative risks (RR) of breast cancer and 95% confidence intervals (CIs). We examined whether associations varied by methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase polymorphisms, breast cancer risk factors, or tumor characteristics.

Results: Plasma vitamin B was associated with a 64% higher risk of breast cancer comparing the highest versus lowest quintile (95% CI 1.17-2.29, p-trend = 0.02). Plasma folate (comparable RR = 1.18, 95% CI 0.84-1.66), pyridoxal 5'-phosphate (RR = 1.18, 95% CI 0.85-1.64), homocysteine (RR = 0.93, 95% CI 0.67-1.28), cysteine (RR = 1.14, 95% CI 0.81-1.62), and cysteinylglycine (RR = 0.93, 95% CI 0.66-1.31) were not associated with overall breast cancer risk. Folate was significantly positively associated with invasive and estrogen receptor-positive/progesterone receptor-positive breast cancer, and this association was suggestively stronger for bloods collected post-fortification. Several nutrient/breast cancer associations varied across subgroups defined by age, smoking, alcohol, multivitamin use, and MTHFR status (p-interaction < 0.05).

Conclusions: Overall, plasma B-vitamins and metabolites were not associated with lower breast cancer risk. Plasma vitamin B-12 was positively associated with higher risk of overall breast cancer, and plasma folate was positively associated with risk of invasive breast cancer. Additionally, there may be associations in subgroups defined by related genetic variants, breast cancer risk factors, and tumor factors. Further studies in younger women and in the post-fortification era are needed to confirm these findings.
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http://dx.doi.org/10.1007/s10549-019-05223-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551273PMC
July 2019

Breast cancer risk prediction in women aged 35-50 years: impact of including sex hormone concentrations in the Gail model.

Breast Cancer Res 2019 03 19;21(1):42. Epub 2019 Mar 19.

Department of Population Health, New York University School of Medicine, 650 First Avenue, New York, NY, 10016, USA.

Background: Models that accurately predict risk of breast cancer are needed to help younger women make decisions about when to begin screening. Premenopausal concentrations of circulating anti-Müllerian hormone (AMH), a biomarker of ovarian reserve, and testosterone have been positively associated with breast cancer risk in prospective studies. We assessed whether adding AMH and/or testosterone to the Gail model improves its prediction performance for women aged 35-50.

Methods: In a nested case-control study including ten prospective cohorts (1762 invasive cases/1890 matched controls) with pre-diagnostic serum/plasma samples, we estimated relative risks (RR) for the biomarkers and Gail risk factors using conditional logistic regression and random-effects meta-analysis. Absolute risk models were developed using these RR estimates, attributable risk fractions calculated using the distributions of the risk factors in the cases from the consortium, and population-based incidence and mortality rates. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminatory accuracy of the models with and without biomarkers.

Results: The AUC for invasive breast cancer including only the Gail risk factor variables was 55.3 (95% CI 53.4, 57.1). The AUC increased moderately with the addition of AMH (AUC 57.6, 95% CI 55.7, 59.5), testosterone (AUC 56.2, 95% CI 54.4, 58.1), or both (AUC 58.1, 95% CI 56.2, 59.9). The largest AUC improvement (4.0) was among women without a family history of breast cancer.

Conclusions: AMH and testosterone moderately increase the discriminatory accuracy of the Gail model among women aged 35-50. We observed the largest AUC increase for women without a family history of breast cancer, the group that would benefit most from improved risk prediction because early screening is already recommended for women with a family history.
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http://dx.doi.org/10.1186/s13058-019-1126-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425605PMC
March 2019

Parity, breastfeeding, and breast cancer risk by hormone receptor status and molecular phenotype: results from the Nurses' Health Studies.

Breast Cancer Res 2019 03 12;21(1):40. Epub 2019 Mar 12.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Ave, Boston, MA, 02115, USA.

Background: Epidemiologic data suggest that parity increases risk of hormone receptor-negative breast cancer and that breastfeeding attenuates this association. Prospective data, particularly on the joint effects of higher parity and breastfeeding, are limited.

Methods: We investigated parity, breastfeeding, and breast cancer risk by hormone-receptor (estrogen (ER) and progesterone receptor (PR)) and molecular subtypes (luminal A, luminal B, HER2-enriched, and basal-like) in the Nurses' Health Study (NHS; 1976-2012) and NHSII (1989-2013). A total of 12,452 (ER+ n = 8235; ER- n = 1978) breast cancers were diagnosed among 199,514 women. We used Cox proportional hazards models, adjusted for breast cancer risk factors, to calculate hazard ratios (HR) and 95% confidence intervals (CI).

Results: Parous women had lower risk of ER+ breast cancer (vs. nulliparous, HR = 0.82 [0.77-0.88]); no association was observed for ER- disease (0.98 [0.84-1.13]; P = 0.03). Among parous women, breastfeeding was associated with lower risk of ER- (vs. never 0.82 [0.74-0.91]), but not ER+, disease (0.99 [0.94-1.05]; P < 0.001). Compared to nulliparous women, higher parity was inversely associated with luminal B breast cancer regardless of breastfeeding (≥ 3 children: ever breastfed, 0.78 [0.62-0.98]; never breastfed, 0.76 [0.58-1.00]) and luminal A disease only among women who had breastfed (≥ 3 children, 0.84 [0.71-0.99]). Basal-like breast cancer risk was suggestively higher among women with higher parity who never breastfed; associations were null among those who ever breastfed.

Conclusions: This study provides evidence that breastfeeding is inversely associated with hormone receptor-negative breast cancers, representing an accessible and cost-effective risk-reduction strategy for aggressive disease subtypes.
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http://dx.doi.org/10.1186/s13058-019-1119-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416887PMC
March 2019

Urinary concentrations of phthalate biomarkers and weight change among postmenopausal women: a prospective cohort study.

Environ Health 2019 03 12;18(1):20. Epub 2019 Mar 12.

Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, 411 Arnold House, 715 North Pleasant Street, Amherst, MA, 01003, USA.

Background: Some phthalates are endocrine disrupting chemicals used as plasticizers in consumer products, and have been associated with obesity in cross-sectional studies, yet prospective evaluations of weight change are lacking. Our objective was to evaluate associations between phthalate biomarker concentrations and weight and weight change among postmenopausal women.

Methods: We performed cross-sectional (N = 997) and longitudinal analyses (N = 660) among postmenopausal Women's Health Initiative participants. We measured 13 phthalate metabolites and creatinine in spot urine samples provided at baseline. Participants' weight and height measured at in-person clinic visits at baseline, year 3, and year 6 were used to calculate body mass index (BMI). We fit multivariable multinomial logistic regression models to explore cross-sectional associations between each phthalate biomarker and baseline BMI category. We evaluated longitudinal associations between each biomarker and weight change using mixed effects linear regression models.

Results: In cross-sectional analyses, urinary concentrations of some biomarkers were positively associated with obesity prevalence (e.g. sum of di (2-ethylhexyl) phthalate metabolites [ΣDEHP] 4th vs 1st quartile OR = 3.29, 95% CI 1.80-6.03 [p trend< 0.001] vs normal). In longitudinal analyses, positive trends with weight gain between baseline and year 3 were observed for mono-(2-ethyl-5-oxohexyl) phthalate, monoethyl phthalate (MEP), mono-hydroxybutyl phthalate, and mono-hydroxyisobutyl phthalate (e.g. + 2.32 kg [95% CI 0.93-3.72] for 4th vs 1st quartile of MEP; p trend < 0.001). No statistically significant associations were observed between biomarkers and weight gain over 6 years.

Conclusions: Certain phthalates may contribute to short-term weight gain among postmenopausal women.
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http://dx.doi.org/10.1186/s12940-019-0458-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417117PMC
March 2019

Protein intake and the risk of premenstrual syndrome.

Public Health Nutr 2019 07 18;22(10):1762-1769. Epub 2019 Feb 18.

1Department of Biostatistics and Epidemiology,University of Massachusetts,715 North Pleasant Street,Arnold House 412,Amherst,MA01003,USA.

Objective: To examine the relationship between protein intake and the risk of incident premenstrual syndrome (PMS).

Design: Nested case-control study. FFQ were completed every 4 years during follow-up. Our main analysis assessed protein intake 2-4 years before PMS diagnosis (for cases) or reference year (for controls). Baseline (1991) protein intake was also assessed.

Setting: Nurses' Health Study II (NHS2), a large prospective cohort study of registered female nurses in the USA.ParticipantsParticipants were premenopausal women between the ages of 27 and 44 years (mean: 34 years), without diagnosis of PMS at baseline, without a history of cancer, endometriosis, infertility, irregular menstrual cycles or hysterectomy. Incident cases of PMS (n 1234) were identified by self-reported diagnosis during 14 years of follow-up and validated by questionnaire. Controls (n 2426) were women who did not report a diagnosis of PMS during follow-up and confirmed experiencing minimal premenstrual symptoms.

Results: In logistic regression models adjusting for smoking, BMI, B-vitamins and other factors, total protein intake was not associated with PMS development. For example, the OR for women with the highest intake of total protein 2-4 years before their reference year (median: 103·6 g/d) v. those with the lowest (median: 66·6 g/d) was 0·94 (95 % CI 0·70, 1·27). Additionally, intakes of specific protein sources and amino acids were not associated with PMS. Furthermore, results substituting carbohydrates and fats for protein were also null.

Conclusions: Overall, protein consumption was not associated with risk of developing PMS.
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http://dx.doi.org/10.1017/S1368980018004019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554041PMC
July 2019