No Effect of β-Carotene Supplementation on Risk of Nonmelanoma Skin Cancer among Men with Low Baseline Plasma β-Carotene

Photooxidative stress may play a role in the etiology of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), collectively termed nonmelanoma skin cancer (NMSC). Antioxidant vitamins (e.g., β-carotene) might therefore offer some protection (1). β-carotene might also prevent UV-induced immunosuppression (2), enhance cell-to-cell communication (3), and affect cell proliferation and differentiation (4). Animal studies of UV-induced skin cancer have provided consistent evidence of an anticancer effect of carotenoids (5). In contrast, randomized trial data show no effect of β-carotene supplementation on NMSC (6–8), although the question of whether a benefit might be limited to subjects with low plasma β-carotene levels has not formerly been addressed. A previous report from the Physicians' Health Study documented no effect of β-carotene on incident NMSC (8). The present study was undertaken to test whether β-carotene supplementation reduced the risk of NMSC among subjects with low plasma β-carotene and/or vitamins E or A and to determine the risk of NMSC according to baseline plasma levels of these nutrients.

A nested case-control study was conducted within the Physicians' Health Study, a randomized, double-blind, placebo-controlled trial of 50 mg β-carotene supplementation on alternate days with 12 years of follow-up. Study subjects were 1,338 men ages 40 to 84 years at baseline who, during follow-up, developed a NMSC (including 1,156 with BCC and 166 with SCC) and an age and smoking–matched control group of 1,338 men who remained free of NMSC at the time of diagnosis of the case. Occurrence of BCC was assessed by self-report (8) and SCC by self-report followed up by review of pathology reports by an endpoints committee of physicians.

For each case and control, a frozen stored baseline plasma sample was thawed and assayed concurrently for β-carotene and vitamins E and A using reversed-phase high-performance liquid chromatography (9). Using conditional logistic regression models, we calculated the odds ratio (OR) and 95% confidence interval (CI) of a first NMSC, BCC, and SCC according to baseline levels of β-carotene and randomized β-carotene assignment. Our design provided >90% power to detect an OR of 0.60 for the effect of β-carotene in the lowest fourth of plasma levels.

Cases and controls had similar mean baseline plasma levels of β-carotene (mean ± SE 14.1 ± 1.0 μg/dL for cases vs. 13.4 ± 1.0 μg/dL for controls), α-tocopherol (9.5 ± 1.0 mg/L for cases vs. 9.4 ± 1.0 mg/L for controls), and vitamin A (61.8 ± 0.5 μg/dL for cases vs. 61.0 ± 0.5 μg/dL for controls), but cases were leaner (P < 0.001) and more likely to drink alcohol (P < 0.001).

We observed no significant effect of randomized β-carotene assignment in the lowest fourth of baseline β-carotene on risk of NMSC (OR 0.88, 95% CI 0.63-1.22; P for trend = 0.33), BCC (OR 0.87, 95% CI 0.61-1.24), or SCC (OR 0.81, 95% CI 0.30-2.23; Table 1). There was also no significant relationship between baseline plasma β-carotene level and risk of NMSC (OR 0.97, 95% CI 0.69-1.37 for top vs. bottom fourth among subjects assigned to placebo; P for trend = 0.84).

Similarly, among subjects in the lowest fourth of baseline plasma α-tocopherol, there was no effect of β-carotene supplementation on NMSC (OR 0.94, 95% CI 0.68-1.30; P for trend = 0.48), BCC (OR 0.90, 95% CI 0.65-1.25; P for trend = 0.65), or SCC (OR 1.24, 95% CI 0.53-2.91; P for trend = 0.53). Baseline plasma α-tocopherol levels were not associated with risk of NMSC (OR 1.04, 95% CI 0.75-1.43 for top vs. bottom fourth among subjects assigned to placebo; P for trend = 0.65). Among subjects with baseline plasma levels of vitamin A in the lowest fourth, β-carotene also had no significant effect on risks of NMSC (OR 0.86, 95% CI 0.61-1.23; P for trend = 0.55), BCC (OR 0.86, 95% CI 0.61-1.23; P for trend = 0.64), or SCC (OR 1.36, 95% CI 0.52-3.58; P for trend = 0.55). Risk of NMSC also did not vary significantly by baseline plasma vitamin A levels (OR 0.99, 95% CI 0.70-1.39 for top vs. bottom fourth among subjects assigned to placebo; P for trend = 0.80).

Our findings could theoretically be confounded by unmeasured risk factors including skin type, history of sun exposure, or sunburns. Because we relied on self-reported diagnoses, some controls may have had NMSC. If this bias were substantial, it could explain the null findings we observed. It is unclear whether a single measure of serum micronutrients provides an accurate estimate of the exposure levels that are most relevant to the disease process. Finally, participants were a well-nourished group of physicians not a random sample of U.S. men.

Despite plausible biological mechanisms and convincing animal data, this study provides substantial evidence that there is no beneficial effect of 12 years of β-carotene supplementation on the risk of NMSC, including BCC and SCC, among subjects with the lowest baseline plasma levels of β-carotene, α-tocopherol, or vitamin A. Furthermore, there is no association between plasma levels of β-carotene, α-tocopherol, or vitamin A and risk of NMSC. Until further evidence emerges, risk reduction through limiting exposure to UV light remains the best available strategy for prevention of NMSC.