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Body size, physical activity, and risk of triple-negative and estrogen receptor-positive breast cancer.

ABSTRACT: BACKGROUND:Triple-negative breast cancer, characterized by a lack of hormone receptor and HER2 expression, is associated with a particularly poor prognosis. Focusing on potentially modifiable breast cancer risk factors, we examined the relationship between body size, physical activity, and triple-negative disease risk. METHODS:Using data from 155,723 women enrolled in the Women's Health Initiative (median follow-up, 7.9 years), we assessed associations between baseline body mass index (BMI), BMI in earlier adulthood, waist and hip circumference, waist-hip ratio, recreational physical activity, and risk of triple-negative (n=307) and estrogen receptor-positive (ER+, n=2,610) breast cancers. RESULTS:Women in the highest versus lowest BMI quartile had 1.35-fold (95% CI, 0.92-1.99) and 1.39-fold (95% CI, 1.22-1.58) increased risks of triple-negative and ER+ breast cancers, respectively. Waist and hip circumferences were positively associated with risk of ER+ breast cancer (Ptrend=0.01 for both measures) but were not associated with triple-negative breast cancer. Compared with women who reported no recreational physical activity, women in the highest activity tertile had similarly lower risks of triple-negative and ER+ breast cancers (HR=0.77; 95% CI, 0.51-1.13; and HR=0.85; 95% CI, 0.74-0.98, respectively). CONCLUSIONS:Despite biological and clinical differences, triple-negative and ER+ breast cancers are similarly associated with BMI and recreational physical activity in postmenopausal women. The biological mechanisms underlying these similarities are uncertain and these modest associations require further investigation. IMPACT:If confirmed, these results suggest potential ways postmenopausal women might modify their risk of both ER+ and triple-negative breast cancers.

SUBMITTER: Phipps AI

PROVIDER: S-EPMC3064558 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Body size, physical activity, and risk of triple-negative and estrogen receptor-positive breast cancer.

Phipps Amanda I AI Chlebowski Rowan T RT Prentice Ross R McTiernan Anne A Stefanick Marcia L ML Wactawski-Wende Jean J Kuller Lewis H LH Adams-Campbell Lucile L LL Lane Dorothy D Vitolins Mara M Kabat Geoffrey C GC Rohan Thomas E TE Li Christopher I CI

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20110301 3

<h4>Background</h4>Triple-negative breast cancer, characterized by a lack of hormone receptor and HER2 expression, is associated with a particularly poor prognosis. Focusing on potentially modifiable breast cancer risk factors, we examined the relationship between body size, physical activity, and triple-negative disease risk.<h4>Methods</h4>Using data from 155,723 women enrolled in the Women's Health Initiative (median follow-up, 7.9 years), we assessed associations between baseline body mass i ...[more]

PMID: 21364029

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Project description:PURPOSE:A subset of estrogen receptor-positive (ER-positive) breast cancer (BC) contains high levels of tumor-infiltrating lymphocytes (TILs), similar to triple-negative BC (TNBC). The majority of immuno-oncology trials target TNBCs because of the greater proportion of TIL-rich TNBCs. The extent to which the immune microenvironments of immune-rich ER-positive BC and TNBC differ is unknown. PATIENTS AND METHODS:RNA sequencing data from The Cancer Genome Atlas (TCGA; n = 697 ER-positive BCs; n = 191 TNBCs) were used for discovery; microarray expression data from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n = 1,186 ER-positive BCs; n = 297 TNBCs) was used for validation. Patients in the top 25th percentile of a previously published total TIL metagene score distribution were considered immune rich. We compared expression of immune cell markers, immune function metagenes, and immuno-oncology therapeutic targets among immune-rich subtypes. RESULTS:Relative fractions of resting mast cells (TCGA P adj = .009; METABRIC P adj = 4.09E-15), CD8+ T cells (TCGA P adj = .015; METABRIC P adj = 0.390), and M2-like macrophages (TCGA P adj= 4.68E-05; METABRIC P adj = .435) were higher in immune-rich ER-positive BCs, but M0-like macrophages (TCGA P adj = 0.015; METABRIC P adj = .004) and M1-like macrophages (TCGA P adj = 9.39E-08; METABRIC P adj = 6.24E-11) were higher in immune-rich TNBCs. Ninety-one immune-related genes (eg, CXCL14, CSF3R, TGF-B3, LRRC32/GARP, TGFB-R2) and a transforming growth factor ? (TGF-?) response metagene were significantly overexpressed in immune-rich ER-positive BCs, whereas 41 immune-related genes (eg, IFNG, PD-L1, CTLA4, MAGEA4) were overexpressed in immune-rich TNBCs in both discovery and validation data sets. TGF-? pathway member genes correlated negatively with expression of immune activation markers (IFNG, granzyme-B, perforin) and positively with M2-like macrophages (IL4, IL10, and MMP9) and regulatory T-cell (FOXP3) markers in both subtypes. CONCLUSION:Different immunotherapy strategies may be optimal in immune-rich ER-positive BC and TNBC. Drugs targeting the TGF-? pathway and M2-like macrophages are promising strategies in immune-rich ER-positive BCs to augment antitumor immunity.

Project description:INTRODUCTION:Breast cancer, the leading cancer diagnosis among American women, is positively associated with postmenopausal obesity and little or no recreational physical activity (RPA). However, the underlying mechanisms of these associations remain unresolved. Aberrant changes in DNA methylation may represent an early event in carcinogenesis, but few studies have investigated associations between obesity/RPA and gene methylation, particularly in postmenopausal breast tumors where these lifestyle factors are most relevant. METHODS:We used case-case unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the associations between body mass index (BMI=weight [kg]/height [m2]) in the year prior to diagnosis, or RPA (average hours/week), and methylation status (methylated vs. unmethylated) of 13 breast cancer-related genes in 532 postmenopausal breast tumor samples from the Long Island Breast Cancer Study Project. We also explored whether the association between BMI/RPA and estrogen/progesterone-receptor status (ER+PR+ vs. all others) was differential with respect to gene methylation status. Methylation-specific PCR and the MethyLight assay were used to assess gene methylation. RESULTS:BMI 25-29.9kg/m2, and perhaps BMI?30kg/m2, was associated with methylated HIN1 in breast tumor tissue. Cases with BMI?30kg/m2 were more likely to have ER+PR+ breast tumors in the presence of unmethylated ESR1 (OR=2.63, 95% CI 1.32-5.25) and women with high RPA were more likely to have ER+PR+ breast tumors with methylated GSTP1 (OR=2.33, 95% CI 0.79-6.84). DISCUSSION:While biologically plausible, our findings that BMI is associated with methylated HIN1 and BMI/RPA are associated with ER+PR+ breast tumors in the presence of unmethylated ESR1 and methylated GSTP1, respectively, warrant further investigation. Future studies would benefit from enrolling greater numbers of postmenopausal women and examining a larger panel of breast cancer-related genes.

Dataset Information

Body size, physical activity, and risk of triple-negative and estrogen receptor-positive breast cancer.

Publications

Body size, physical activity, and risk of triple-negative and estrogen receptor-positive breast cancer.

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