The average age of participants was 62 years (range: 50–76), and slightly more than half of the participants were female (52%). Most individuals had some college or an advanced degree (80%), and were overweight or obese (63%). Cohort members that developed primary cutaneous melanoma during the follow-up period were more likely to be male, have attained higher education, and to have fair skin phenotype (childhood freckling, ≥ 3 severe sunburns, natural red or blond hair, and have a tendency to burn with exposure to sunlight) (). They were also more likely to have had a personal history of skin cancer, a family history of melanoma, and have had moles removed. Cases and non-cases did not significantly differ in risk of a common indication for vitamin A supplementation, namely history of macular degeneration.
Associations between baseline characteristics and melanoma risk among VITAL participants, (n = 69,635)
Of the 566 incident melanomas, there were 257 in-situ, and 309 invasive tumors. The break-down of histopathologic subtype of the invasive tumors was n= 144 melanoma not otherwise specified, n=88 superficial spreading, n= 38 lentigo maligna, n= 21 nodular, and n= 13 rare subtypes (including 5 melanomas arising in a junctional nevus, 4 spindle cell, 3 acral lentiginous and 1 desomplastic melanoma). There were 5 cases who had no information on subtype available. There were only 16 invasive melanomas that developed among supplement users, so our cell sizes for the subtype variable were too small to permit meaningful analysis of supplement use by melanoma histopathologic subtype.
The results of supplement and dietary intake of retinol, β-carotene, total vitamin, lutein and lycopene and associated melanoma risk are shown in . Relative to non-use, current (HR 0.60, 95% CI: 0.41–0.89) but not former (HR 0.90, 95% CI: 0.57–1.43) use of individual retinol supplements at baseline was associated with a decreased risk of melanoma. Intake of supplemental retinol greater than the amount that can be obtained from common multivitamin formulations (>1200 ug/d) was of borderline statistical significance (HR: 0.74, 95% CI: 0.55–1.00); however the association was not linear (P-trend=0.25). Retinol intake from food, and the combination of supplement and dietary intake were not associated with melanoma risk.
Associations between retinol and carotenoid intakes and melanoma risk among VITAL participants (n = 69,635)
β-carotene, whether from supplement use or dietary intake, was not associated with melanoma risk. Similarly, total vitamin A intake and intake of pro-vitamin A carotenoids was also not associated with melanoma risk. Among participants who used individual lutein or lycopene supplements, very few developed melanoma (n<10), so our cohort was underpowered to detect an association with regard to supplemental intake of the non-pro-vitamin A carotenoids. Although there was a trend for increased melanoma risk with dietary intake of lutein, the effect was no longer statistically significant in adjusted models of dietary intake of the non-proretinoid carotenoids.
In examining the associations between retinol use and melanoma risk stratified by gender (), the association of current use of retinol supplements was largely driven by a marked risk reduction in melanoma risk among women (HR: 0.27, 95% CI: 0.11–0.66) but not men (HR: 0.83, 95% CI: 0.54–1.27; P-interaction=0.64). Inverse associations for high doses of retinol supplements and melanoma were similar among men (HR 0.77, 95% CI: 0.53–1.12) and women (HR 0.71, 95% CI: 0.43–1.16), although neither achieved statistical significance. Similar to unstratified findings, there were no clear associations or differences by gender for retinol exposure from diet or total retinol, irrespective of source (data not shown).
Interaction between retinol supplement use and gender in relation to melanoma risk among VITAL participants, (n = 69,635)
shows the association of retinol supplement use with melanoma by anatomic site. In comparing current users to non-users, the reduction in melanoma risk with retinol use appeared to be stronger in sun-exposed areas such as the limbs (HR 0.44, 95% CI: 0.22–0.89), and the head and neck (HR 0.49, 95% CI: 0.21–1.10) as compared to the trunk (HR 0.94, 95% CI: 0.52–01.70).
Association of retinol supplement use with melanoma by anatomic site, among VITAL participants, (n = 69,635).
We examined the association between retinol (both current use and dose) and tumor invasiveness and Breslow depth as proxies for tumor progression (). In comparing insitu to invasive melanomas, or invasive melanomas with Breslow depth <1.0 mm to those >1.0 mm, there was no differential association with retinol use. With regard to dose, low-dose users appeared to have a slightly increased risk of thin (<1.0 mm) melanoma as compared to nonusers (HR 1.44, 95% CI: 1.04–2.00), but this mildly increased risk in low-dose retinol users did not manifest for thicker melanomas (>1.0 mm).
Association of retinol supplement use with melanoma aggressiveness, among VITAL participants, (n = 69,635).