Circulating carotenoids and breast cancer among high-risk individuals

Abstract

Background: Carotenoids represent 1 of few modifiable factors to reduce breast cancer risk. Elucidation of interactions between circulating carotenoids and genetic predispositions or mammographic density (MD) may help inform more effective primary preventive strategies in high-risk populations.

Objectives: We tested whether women at high risk for breast cancer due to genetic predispositions or high MD would experience meaningful and greater risk reduction from higher circulating levels of carotenoids in a nested case-control study in the Nurses' Health Studies (NHS and NHSII).

Methods: This study included 1919 cases and 1695 controls in a nested case-control study in the NHS and NHSII. We assessed both multiplicative and additive interactions. RR reductions and 95% CIs were calculated using unconditional logistic regressions, adjusting for matching factors and breast cancer risk factors. Absolute risk reductions (ARR) were calculated based on Surveillance, Epidemiology, and End Results incidence rates.

Results: We showed that compared with women at low genetic risk or low MD, those with higher genetic risk scores or high MD had greater ARRs for breast cancer as circulating carotenoid levels increase (additive P-interaction = 0.05). Among women with a high polygenic risk score, those in the highest quartile of circulating carotenoids had a significant ARR (28.6%; 95% CI, 14.8-42.1%) compared to those in the lowest quartile of carotenoids. For women with a high percentage MD (≥50%), circulating carotenoids were associated with a 37.1% ARR (95% CI, 21.7-52.1%) when comparing the highest to the lowest quartiles of circulating carotenoids.

Conclusions: The inverse associations between circulating carotenoids and breast cancer risk appeared to be more pronounced in high-risk women, as defined by germline genetic makeup or MD.

Keywords: absolute risk; breast cancer; carotenoids; genetic risk; mammography density.

FIGURE 1

Multivariable RRs (95% CI) of overall breast cancer by (A) quartiles of carotenoids and PRS (case n = 1919; control n = 1695) and (B) quartiles of carotenoids and predetermined cutoff of MD (case n = 1439; control n = 1344). Models adjusted for age at blood draw (continuous), BMI at blood draw (continuous), family history (yes vs. no), history of benign breast disease (yes vs. no), alcohol consumption (non-drinker, <5 g/day, 5–10 g/day, 10–15 g/day, or 15+ g/day), age at first birth/parity (nulliparous; 1 or 2 children and <25 years old; 1 or 2 children and 25–29 years old; 1 or 2 children 30+ years old; 3+ children and <25 years old; or 3+ children and 25+ years old), menopausal status (premenopausal, postmenopausal, or unknown), age at menarche (11 years or younger, 12 years, 13 years, or 14+ years), and smoking status (never, former, or current). Multiplicative interaction was tested with a likelihood ratio test through comparing 2 generalized linear models with and without the interaction term. Additive interaction was assessed with relative excess risk due to interaction, which measured the difference between the joint RR and the separate contributions by the 2 dichotomized exposures. Standard error for additive interaction was estimated with the delta method as described by Hosmer and Lemeshow (26). Abbreviations: MD, mammographic density; PRS, polygenic risk score.