Body size, body composition, and physical activity in relation to breast cancer risk

Accurately characterising the associations between adiposity, physical activity, and breast cancer risk has been limited by measurement error and confounding. This thesis investigates risk factors for breast cancer, with a focus on body size, body composition, and physical activity, within the UK Biobank, a new prospective cohort with comprehensive assessment of baseline characteristics, direct measures of body fat, and objectively-measured physical activity, which has the potential to address and overcome major limitations of prior studies.
To characterise the patterns of association for breast cancer risk factors in UK Biobank, prospective analyses were conducted in up to 255,083 women. A total of 4,522 women were diagnosed with breast cancer during a mean 5.8 years follow-up. Associations between established risk factors and breast cancer incidence were consistent with prior studies.
All measures of adiposity showed similar cross-sectional associations with self-reported physical activity, which were further investigated using objective, accelerometer measures of physical activity that were available on a subset of 42,992 women in the analyses, 3-5 years after end of recruitment. Compared to the non-linear associations seen with self-reported physical activity, accelerometer-measured physical activity showed nearly twofold larger, inverse, linear dose-response relationships with adiposity.
To investigate whether the effect of genetic susceptibility, as measured by a genetic risk score (GRS) of 70 body mass index (BMI)-associated single nucleotide polymorphisms, on objectively measured BMI was modified by physical activity, cross-sectional analyses of GRS and BMI were performed by physical activity level. Comparing the top to bottom fifth of GRS, the most inactive participants had a 2.23 kg/m2 higher BMI while the most active participants had only a 1.33 kg/m2 higher BMI. The results using accelerometer rather than self-reported physical activity provided stronger evidence that genetic predisposition to adiposity can be largely overcome by greater physical activity.
Prospective analyses of various indices of adiposity and breast cancer risk were performed to assess whether any were better predictors of risk, among women who were not current users of hormone replacement therapy. Women in the top compared to bottom quartile of body fat mass were at a 70% increased risk of breast cancer (relative risk (RR) 1.70; 95% confidence interval (CI) 1.52-1.90). All measures of body size and composition showed similar associations with breast cancer risk, suggesting impedance measures of fat were not substantially better indicators of risk than anthropometric measures. After adjusting for body fat mass, central adiposity was no longer associated with breast cancer risk.
Physical activity was inversely associated with risk in both pre- and postmenopausal women. Adjusting for body fat mass slightly strengthened the inverse association in premenopausal women (RR 0.79; 95% CI 0.65-0.95) and attenuated the association in postmenopausal women (RR 0.84; 95% CI 0.72-0.97), per 5 milli-gravity of accelerometer-based physical activity, suggesting that the remaining protective association may be mediated by non-adiposity related factors.
In conclusion, all indices of adiposity were similarly associated with physical activity, and associations were stronger with physical activity measured by accelerometer compared to questionnaire. Physical activity was an effect modifier of genetic susceptibility to adiposity. Adiposity was associated with increased breast cancer risk in postmenopausal women and physical activity was associated with reduced breast cancer risk in both pre- and postmenopausal women. The mechanisms underlying the protective association between physical activity and breast cancer risk are not entirely explained by adiposity and remain unclear.

Advisor: Key, T
Reeves, G