Association of Body Mass Index and Age With Subsequent Breast Cancer Risk in Premenopausal Women

Abstract

Importance: The association between increasing body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and risk of breast cancer is unique in cancer epidemiology in that a crossover effect exists, with risk reduction before and risk increase after menopause. The inverse association with premenopausal breast cancer risk is poorly characterized but might be important in the understanding of breast cancer causation.

Objective: To investigate the association of BMI with premenopausal breast cancer risk, in particular by age at BMI, attained age, risk factors for breast cancer, and tumor characteristics.

Design, setting, and participants: This multicenter analysis used pooled individual-level data from 758 592 premenopausal women from 19 prospective cohorts to estimate hazard ratios (HRs) of premenopausal breast cancer in association with BMI from ages 18 through 54 years using Cox proportional hazards regression analysis. Median follow-up was 9.3 years (interquartile range, 4.9-13.5 years) per participant, with 13 082 incident cases of breast cancer. Participants were recruited from January 1, 1963, through December 31, 2013, and data were analyzed from September 1, 2013, through December 31, 2017.

Exposures: Body mass index at ages 18 to 24, 25 to 34, 35 to 44, and 45 to 54 years.

Main outcomes and measures: Invasive or in situ premenopausal breast cancer.

Results: Among the 758 592 premenopausal women (median age, 40.6 years; interquartile range, 35.2-45.5 years) included in the analysis, inverse linear associations of BMI with breast cancer risk were found that were stronger for BMI at ages 18 to 24 years (HR per 5 kg/m2 [5.0-U] difference, 0.77; 95% CI, 0.73-0.80) than for BMI at ages 45 to 54 years (HR per 5.0-U difference, 0.88; 95% CI, 0.86-0.91). The inverse associations were observed even among nonoverweight women. There was a 4.2-fold risk gradient between the highest and lowest BMI categories (BMI≥35.0 vs <17.0) at ages 18 to 24 years (HR, 0.24; 95% CI, 0.14-0.40). Hazard ratios did not appreciably vary by attained age or between strata of other breast cancer risk factors. Associations were stronger for estrogen receptor-positive and/or progesterone receptor-positive than for hormone receptor-negative breast cancer for BMI at every age group (eg, for BMI at age 18 to 24 years: HR per 5.0-U difference for estrogen receptor-positive and progesterone receptor-positive tumors, 0.76 [95% CI, 0.70-0.81] vs hormone receptor-negative tumors, 0.85 [95% CI: 0.76-0.95]); BMI at ages 25 to 54 years was not consistently associated with triple-negative or hormone receptor-negative breast cancer overall.

Conclusions and relevance: The results of this study suggest that increased adiposity is associated with a reduced risk of premenopausal breast cancer at a greater magnitude than previously shown and across the entire distribution of BMI. The strongest associations of risk were observed for BMI in early adulthood. Understanding the biological mechanisms underlying these associations could have important preventive potential.

Figure 1.. Relative Risk of Premenopausal Breast Cancer Associated With BMI Category, by Age at BMI

Body mass index (BMI) is calculated as weight in kilograms divided by height in meters squared. Hazard ratios (HRs) were adjusted for attained age, cohort, year of birth, age at menarche, age at first birth, number of births, time since last birth, and family history of breast cancer. ^aRepresents linear trend per 5 kg/m² (5.0-U) difference in BMI from 18.5 to 49.9.

Figure 2.. Relative Risk of Premenopausal Breast Cancer Associated With BMI and Adjusted for BMI at Ages 18 to 24 Years, by Age at BMI

Body mass index (BMI) is calculated as weight in kilograms divided by height in meters squared. Hazard ratios (HRs) were adjusted for attained age, cohort, year of birth, age at menarche, age at first birth, number of births, time since last birth, and family history of breast cancer as well as BMI at ages 18 to 24 years. ^aRepresents linear trend per 5 kg/m² (5.0-U) difference in BMI from 18.5 to 49.9.

Figure 3.. Relative Risk of Premenopausal Breast Cancer per 5 kg/m² (5.0-U) Difference in BMI by Age at BMI and Breast Cancer Intrinsic Tumor Subtype

Body mass index (BMI) is calculated as weight in kilograms divided by height in meters squared. The luminal A–like subtype includes estrogen receptor (ER)–positive, progesterone receptor (PR)–positive, and ERBB2/HER2-negative tumors; luminal B–subtype, all ER-positive and/or PR-positive tumors that are not luminal A–like (subtypes luminal B–like ERBB2/HER2-negative and luminal B–like ERBB2/HER2-positive); and nonluminal subtype, all ER-negative and PR-negative tumors, regardless of ERBB2/HER2 status (subtypes ERBB2/HER2 enriched: ER-negative, PR-negative, and ERBB2/HER2-positive; triple-negative: ER-negative, PR-negative, and ERBB2/HER2-negative). ^aRepresents linear trend per 5.0-U of difference in BMI from 18.5 to 49.9 and are adjusted for attained age, cohort, year of birth, age at menarche, age at first birth, number of births, time since last birth, and family history of breast cancer. Estimates were obtained from 2 augmentation models. The first model included luminal A–like, luminal B–like, and nonluminal breast cancer as end points with tests for heterogeneity in effect by tumor type (for BMI at ages 18-24 years, P = .07; at ages 25-34 years, P = .002; at ages 35-44 years, P < .001; at ages 45-54, P < .001). Estimates for subtypes of luminal B–like and nonluminal breast cancer were obtained from a second model fitting luminal A–like, luminal B–like ERBB2/HER2-positive, luminal B–like ERBB2/HER2-negative, ERBB2/HER2-enriched, and triple-negative breast cancer as end points.