Genetic Factors, Adherence to Healthy Lifestyle Behavior, and Risk of Invasive Breast Cancer Among Women in the UK Biobank

Abstract

Background: Breast cancer is considered to result from a combination of genetic and lifestyle-related factors, but the degree to which an overall healthy lifestyle may attenuate the impact of multiple genetic variants on invasive breast cancer risk remains equivocal.

Methods: Using Cox proportional hazards regression models, we examined the association of a modified healthy lifestyle index (HLI) with risk of invasive breast cancer by genetic risk group among 146 326 women from the UK Biobank. We generated an HLI score based on a combination of diet, physical activity, smoking, alcohol consumption and anthropometry, and a polygenic risk score (PRS) using 304 breast cancer-associated genetic loci.

Results: Among premenopausal and postmenopausal women, a favorable lifestyle (highest tertile) was associated with 22% and 31% reductions in invasive breast cancer risk, respectively (hazard ratio [HR]high vs low = 0.78, 95% confidence interval [CI] = 0.64 to 0.94; HRhigh vs low = 0.69, 95% CI = 0.63 to 0.77, respectively), whereas a high PRS (highest tertile) was associated with more than a doubling in the risk in both groups. For premenopausal women, the greatest risk reduction in association with the HLI was seen among those with a high PRS (HRhigh vs low = 0.73, 95% CI = 0.75 to 0.95). In postmenopausal women, those with a favorable lifestyle had 30%, 29%, and 32% reductions in risk of invasive breast cancer in the low, intermediate, and high PRS groups, respectively (HRhigh vs low = 0.70, 95% CI = 0.56 to 0.88; HRhigh vs low = 0.71, 95% CI = 0.59 to 0.84; and HRhigh vs low = 0.68, 95% CI = 0.59 to 0.78, respectively). There was an additive but not multiplicative interaction between the HLI score and PRS for postmenopausal and, to a lesser extent, premenopausal women.

Conclusion: Our findings support the view that an overall healthy lifestyle may attenuate the impact of genetic factors on invasive breast cancer risk among women of European ancestry.

Figure 1.

Risk of breastAQ30 cancer by modified healthy lifestyle index (HLI) and polygenic risk score (PRS) among women from the UK Biobank. Adjusted for age at recruitment, socioeconomic status, age at menarche, parity and age at first pregnancy (combined), family history of breast cancer, history of mammograms, oral contraceptive use, age at menopause (postmenopausal women), hormone replacement therapy use (postmenopausal women), body mass index (premenopausal women), first five principal components of ancestry and genotyping batch, lifestyle score, and genetic score, unless included as main exposure, in Cox proportional hazards regression models. Cutpoints: HLI score: less than or equal to 2.5, greater than 2.5 to 3, greater than 3 and less than or equal to 3, greater than 3 to 3.75, greater than 3.75, for premenopausal and postmenopausal women, respectively; PRS score: less than or equal to −0.5008, −0.5007 to 0.0072, greater than 0.0072 and less than or equal to −0.5191, −0.5190 to −0.0097, greater than −0.0096 for premenopausal and postmenopausal women, respectively. All tests were two-sided. CI = confidence interval; HR = hazard ratio.

Figure 2.

Risk of breast cancer accordingto modified healthy lifestyle index (HLI) and polygenetic risk score (PRS) among women from the UK Biobank. Adjusted for age at recruitment, socioeconomic status, age at menarche, parity and age at first pregnancy (combined), family history of breast cancer, history of mammograms, oral contraceptive use, body mass index (premenopausal women), first five principal components of ancestry and genotyping batch, age at menopause (postmenopausal women only), and hormone replacement therapy use in Cox proportional hazards regression models. Cut points: HLI score: less than or equal to 2.5, greater than 2.5 to 3, greater than 3 and less than or equal to 3, greater than 3 to 3.75, greater than 3.75, for premenopausal and postmenopausal women, respectively; PRS score: less than or equal to −0.5008, −0.5007 to 0.0072, greater than 0.0072 and less than or equal to −0.5191, −0.5190 to −0.0097, greater than −0.0096 for premenopausal and postmenopausal women, respectively. All tests were two-sided. CI = confidence interval; HR = hazard ratio.