Summary of findings
The present systematic literature review and meta-analysis demonstrates the complex associations between adulthood energy balance-related factors and breast cancer risk in pre- and postmenopausal women.
Higher physical activity, in particular recreational physical activity, was associated with reduced risk of pre- and postmenopausal breast cancer, although there were less data on premenopausal women. The risk reduction was observed at high levels similar to the prolonged moderate physical activity of 45 to 60 min daily suggested for weight maintenance [
184]. Physical activity may operate through obesity-related biological pathways or mechanisms that involve immunity and defense [
7,
185], which could explain the observed inverse associations for both postmenopausal ER+ and ER− breast cancers. Strenuous physical activity before menarche may delay the onset of menstruation and increase anovulatory cycles in young women [
186]. In the present meta-analysis, significant inverse association was observed among normal weight women. It is unclear if the lack of association in overweight or obese women is due to low number of women with the required physical activity level or if any independent effect of physical activity is masked by excessive body adiposity. Previously, the National Cancer Institute Cohort Consortium (35,178 breast cancer cases overall) reported inverse associations in women of BMI < 25 and ≥ 25 kg/m
2, with no effect modification [
187]. Confirmation is needed in pre- and postmenopausal women. Sedentary behavior, represented by sitting time, was associated with an increased risk of postmenopausal breast cancer. Excessive sitting reduces overall energy expenditure and contributes to obesity [
188,
189], but could also be an independent risk factor for breast cancer [
190].
Higher early adult BMI (ages 18–30 years) was inversely associated with both pre- and postmenopausal breast cancers. The results corroborate with the inverse association published recently by the Premenopausal Breast Cancer Collaborative Group of 19 cohort studies [
191] (5 studies are in common with the present meta-analysis [
56,
113,
136,
175,
180]). The study also reported risk reductions for ER+ and ER− breast cancers in premenopausal women [
191], which are potentially driven by estrogen-induced early breast differentiation [
192] and slower pubertal growth [
193] that may reduce the susceptibility to carcinogens in the breast tissue of young girls with higher adiposity.
Weight loss was inversely associated with pre- and postmenopausal breast cancer. The results were not robust, and the intentionality of weight loss and potential weight regain were largely not known in the studies. The present findings require further confirmations, although studies of stable weight loss and bariatric surgery have shown postmenopausal breast cancer risk reduction [
70,
194,
195], and participants who lost weight or body fat in randomized controlled trials have demonstrated favorable changes in hormonal and metabolic profiles [
196‐
198].
Weight gain (from aged 18 years to study baseline) and subsequent excessive body adiposity (total adiposity, assessed by BMI at study baseline; abdominal adiposity, assessed by waist circumference, and waist-to-hip ratio; and gluteo-femoral adiposity, assessed by hip circumference) consistently increased the risk of breast cancer in postmenopausal women. Non-linear analyses did not reveal any threshold, indicating any weight gain after early adult years may lead to increased risk. The associations were more evident for HR+ but not HR- postmenopausal breast cancers; and among never but not current users of postmenopausal hormones, probably because exogenous estrogens, a strong risk factor of postmenopausal breast cancer [
199], have masked the effect of the hormones synthesized in adipose tissue. Recent publications reported largely supportive results. These included the different age-specific associations with baseline BMI for the risk of luminal-like and triple-negative breast cancers reported by the National Cancer Institute Cohort Consortium (9 cohorts) [
200], and the strong positive associations between different adiposity measures and breast cancer risk in long-term postmenopausal women reported by the UK Biobank Prospective Cohort Study [
201].
The evidence was less consistent in premenopausal women. In the present meta-analysis, we observed no association with adult weight gain, but weight gain between 40 and 50 years has been reported to increase premenopausal breast cancer risk [
72]. Since middle age is a period when more fat is deposited viscerally [
202], it is possible that timing, duration, as well as location of fat deposition are important factors for breast cancer development. Higher adult BMI (study baseline) was inversely associated with breast cancer risk in premenopausal women, although there was a lack of consistency across the study results. One possible explanation is the positive association observed in Asian studies [
112,
174]. Asian women tend to be more prone to visceral fat accumulation than their Western counterparts [
203], but further replication of the result is needed. In terms of abdominal obesity, we observed non-significant associations that were reverted to positive associations in studies accounting for total adiposity; since total and abdominal adiposity are highly correlated [
41,
145,
159,
165], the suggested independent effect requires confirmation. There were no significant associations for HR-defined premenopausal breast cancers, but the meta-analyses included few studies.
Mechanistically, increased expression of aromatase in adipose tissue of postmenopausal women with obesity increases conversion of androgens to estrogens that induce tumor cell proliferation and inhibit apoptosis [
204,
205]; whereas lowered concentrations of progesterone in premenopausal women with obesity mitigate estrogen-induced proliferation in breast epithelial cells [
206], albeit inconsistent findings on progesterone and breast cancer [
207‐
209]. Studies on gene expression patterns in breast tissue have shown that as body weight increases, there is increased breast cancer cell proliferation in postmenopausal women but decreased proliferation in premenopausal women [
210]. Abdominal obesity is frequently associated with insulin resistance and hyperinsulinemia [
211,
212]. Insulin and insulin-like growth factor-I are mitogenic. Insulin also inhibits sex hormone-binding globulin synthesis, leading to higher concentrations of free oestradiol [
205]. Other proposed mechanisms that link obesity to breast cancer include increased concentrations of proinflammatory cytokines and leptin that induce aromatization and reduced concentrations of adiponectin that has anti-inflammatory and insulin-sensitizing ability [
205,
213‐
215].
Our findings are generally in agreement with those of published umbrella reviews of the literature evidence on physical activity and adiposity with cancer risk [
216‐
218], but are opposite to the results of Mendelian randomization (MR) studies. Recent publications from large-sized MR studies reported inverse associations with genetically predicted adiposity for the risk of breast cancer, overall [
219] and in premenopausal [
220‐
222] and postmenopausal women [
220,
222], which were not shown in an earlier small study [
47]. One possible explanation is that genetically predicted adiposity may be more closely related to early life adiposity than later life adiposity that is largely influenced by the environment. One MR study provided causal evidence that higher childhood adiposity reduces breast cancer risk [
219].
Study limitations
Several limitations in the present review require discussion. There may be some level of misclassification of cancer as pre- or postmenopausal depending on whether the required information was taken at study baseline or cancer diagnosis; however, subgroup meta-analyses by timing of classification mostly did not show significantly different associations. Premenopausal breast cancer studies that used baseline information on average found an inverse association with adult BMI, opposite to the positive association in postmenopausal studies.
The association with physical activity may have been underestimated due to measurement error, as frequency, intensity, and type of activity were poorly characterized in most studies. Attenuation of the associations due to regression dilution is possible as most studies had long follow-up (≥ 10 years) and collected information at baseline. Recall or other biases in weight change and weight at early age are also possible. While BMI—a practical measure of total adiposity—is predictive of health outcomes on a population level, it does not reflect fat distribution or differentiates lean from fat mass that varies across women of different age and ethnicity [
223].
Data on pre- and postmenopausal hormone receptor-defined breast cancers were limited. Information on type of postmenopausal hormone use was not available for meta-analysis. A few studies did not report data sufficient for the meta-analysis [
224‐
230]; nevertheless, most excluded studies reported concordant findings with the meta-analyses.
Strength of the study and future research
The present systematic literature review is extensive and comprehensive, in that all known existing scientific evidence from observational cohort studies—a design that is less prone to recall and selection biases than case–control studies [
9]—on different domains of physical activity, sedentary behavior, adiposity measures, and weight change in different periods of adulthood in relation to breast cancer risk by menopausal status and hormone receptor subtype were summarized. Most meta-analyses comprised more than 900 breast cancer cases from at least three cohort studies that were of average to good quality.
With the accumulated evidence, we were able to explore the magnitude and the shape of the associations. Nevertheless, more longitudinal studies with repeated exposure assessments along the life course are needed, in women across all age range, and from different ethnic/racial groups who may have different risk patterns. Improved assessments for better quantification and characterization of exposure factors are needed, to evaluate their independent and joint effects on breast cancer development. Also, more studies are needed to clarify the different associations in molecular and clinical breast cancer subgroups. Randomized controlled trials, in particular weight loss trials and physical activity trials, are needed to provide definitive evidence for effective interventions to prevent breast cancer.
In conclusion, physical activity reduces breast cancer risk in both pre- and postmenopausal women, whereas factors reflecting energy imbalance influence the risk differently along the life course of the women. Although higher adiposity at early adulthood may reduce pre- and postmenopausal breast cancer risk, weight gain and excessive adiposity later in life increase the risk, consistently in postmenopausal women and evidently for HR+ but not for HR− postmenopausal breast cancers. Under precautionary principle, women should aim to be physically active (at least 150 min/week) and follow a lifestyle that leads to healthy body weight (BMI 18.5–24.9 kg/m
2) for breast cancer prevention. Only about 25% of the public recognize the link between obesity and cancer [
231]. Therefore, collective effort—driven by public health policies [
232]—is needed to promote healthy lifestyles for cancer prevention.