Background:Cutaneous nevi are suggested to be hormone-related. We hypothesized that the number of cutaneous nevi might be a phenotypic marker of plasma hormone levels and predict subsequent breast cancer risk.Methods and Findings:We followed 74,523 female nurses for 24 y (1986-2010) in the Nurses' Health Study and estimate the relative risk of breast cancer according to the number of cutaneous nevi. We adjusted for the known breast cancer risk factors in the models. During follow-up, a total of 5,483 invasive breast cancer cases were diagnosed. Compared to women with no nevi, women with more cutaneous nevi had higher risks of breast cancer (multivariable-adjusted hazard ratio, 1.04, 95% confidence interval [CI], 0.98-1.10 for 1-5 nevi; 1.15, 95% CI, 1.00-1.31 for 6-14 nevi, and 1.35, 95% CI, 1.04-1.74 for 15 or more nevi; p for continuous trend = 0.003). Over 24 y of follow-up, the absolute risk of developing breast cancer increased from 8.48% for women without cutaneous nevi to 8.82% (95% CI, 8.31%-9.33%) for women with 1-5 nevi, 9.75% (95% CI, 8.48%-11.11%) for women with 6-14 nevi, and 11.4% (95% CI, 8.82%-14.76%) for women with 15 or more nevi. The number of cutaneous nevi was associated with increased risk of breast cancer only among estrogen receptor (ER)-positive tumors (multivariable-adjusted hazard ratio per five nevi, 1.09, 95% CI, 1.02-1.16 for ER+/progesterone receptor [PR]-positive tumors; 1.08, 95% CI, 0.94-1.24 for ER+/PR- tumors; and 0.99, 95% CI, 0.86-1.15 for ER-/PR- tumors). Additionally, we tested plasma hormone levels according to the number of cutaneous nevi among a subgroup of postmenopausal women without postmenopausal hormone use (n = 611). Postmenopausal women with six or more nevi had a 45.5% higher level of free estradiol and a 47.4% higher level of free testosterone compared to those with no nevi (p for trend = 0.001 for both). Among a subgroup of 362 breast cancer cases and 611 matched controls with plasma hormone measurements, the multivariable-adjusted odds ratio for every five nevi attenuated from 1.25 (95% CI, 0.89-1.74) to 1.16 (95% CI, 0.83-1.64) after adjusting for plasma hormone levels. Key limitations in this study are that cutaneous nevi were self-counted in our cohort and that the study was conducted in white individuals, and thus the findings do not necessarily apply to other populations.Conclusions:Our results suggest that the number of cutaneous nevi may reflect plasma hormone levels and predict breast cancer risk independently of previously known factors.Please see later in the article for the Editors' Summary.
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