Higher body fat link to lower breast cancer risk in pre-menopausal women

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While obesity has been shown to increase breast cancer risk in post-menopausal women, a large-scale study co-led by a University of North Carolina Lineberger Comprehensive Cancer Centre researcher found the opposite is true for pre-menopausal women: higher body fat was linked to lower breast cancer risk.

The findings show the need to better understand breast cancer risk factors in younger women before menopause, said UNC Lineberger’s Dr Hazel B Nichols.

“The drivers of breast cancer risk can be different for young women compared to older women, so we need to do a better job of understanding what contributes specifically to breast cancer risk in younger women so we can make appropriate recommendations for them,” said Nichols, who is an assistant professor in the UNC Gillings School of Global Public Health. “This study is not a reason to try to gain weight to prevent breast cancer. Heavier women have a lower overall risk of breast cancer before menopause, but there are a lot of other benefits to managing a healthy weight that should be considered. What it does do is help us to try to understand what contributes to breast cancer risk in younger women.”

Breast cancer is most common in older women, with a median age of diagnosis at 62 in the US. Obesity has been linked to higher risk for breast cancer in women after menopause, which occurs, on average, at age 51 in the US.

Since breast cancer is less common in younger women, researchers pooled data from 19 different studies to investigate breast cancer risk for a group of 758,592 women who were younger than 55 years. “Studies often have smaller numbers of premenopausal breast cancers since breast cancer is less common at younger ages, and the evidence was not as strong as for postmenopausal breast cancer,” Nichols said.

Their analysis linked a higher body mass index, or BMI, to lower breast cancer risk for younger women across this age group, even for women within a normal weight range. “We saw a trend where, as BMI went up, cancer risk went down,” Nichols said. “There was no threshold at which having a higher BMI was linked to lower cancer risk.”

The largest reductions in risk were for BMI between the ages of 18 and 24, with a 23% lower breast cancer risk linked to each five-unit increase in BMI during this time period. At ages 25 to 34, each five-unit increase in BMI was linked to 15% lower risk. There was a 13% lower risk for BMI at ages 35 to 44, and a 12% lower risk for BMI at ages 45 to 54 years.

They also saw the risk decreases linked to higher body mass index for oestrogen – or progesterone-receptor positive breast cancer, but they did not see a consistent relationship for BMI and triple negative breast cancer, or hormone-receptor negative breast cancer.

Nichols said multiple factors could be contributing to the link between higher BMI and lower breast cancer risk in younger women, such as differences in hormones, including oestrogen, growth factors, or breast density. Oestrogen can be a driver of breast cancer, but there are different levels and sources of oestrogen before and after menopause. Before menopause onset, the primary source of oestrogen comes from the ovaries, and oestrogen produced by fatty tissue may help to downregulate the amount of oestrogen produced by the ovaries.

“The amount of oestrogen produced by your ovaries is driven by feedback loops in your body,” Nichols said. “The small amount of oestrogen produced by fat tissue before menopause may help tell the ovaries that they can produce less oestrogen and also regulate other hormones or growth factors.” Nichols said that after menopause, women with higher adipose tissue have higher oestrogen levels.

“After menopause, the ovaries are no longer the primary source of oestrogen,” she said. “Instead, most oestrogens come from adipose, or fat, tissue,” she said. “Women who have more adipose tissue after menopause usually have higher levels of oestrogen which can contribute to higher breast cancer risk. In young women, oestrogen is one factor that contributes, but it’s not the whole story.”

To further their investigation of breast cancer risk factors, Nichols said the group will take a closer look at patterns of risk according to weight change in early-to-mid-adulthood and will also consider the role of pregnancy, and other factors that may be important to consider for breast cancer risk at younger ages.

“Although breast cancer is more common at older ages, it’s actually the most common type of cancer diagnosed among reproductive-aged women,” Nichols said.

“Understanding risk factors that may operate differently before menopause is critical to reducing breast cancer risk in young women, but these factors are hard to study in traditional settings where there are fewer young women in cancer research. The Premenopausal Breast Cancer Collaborative Group, which was founded by investigators at UNC, the National Institute of Environmental Health Sciences in North Carolina and the Institute of Cancer Research in London, gives us a way forward to investigate breast cancer in younger populations.”

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 Participant: 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.

Authors
The Premenopausal Breast Cancer Collaborative Group

UNC Lineberger Comprehensive Cancer Centre material
JAMA Oncology abstract


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