Sildenafil Use May Be Associated With Increased Risk of Melanoma
In a prospective cohort study reported in JAMA Internal Medicine, Li et al found that recent and ever use of sildenafil for erectile dysfunction was associated with increased risk of subsequent melanoma, but not squamous cell or basal cell carcinoma.
The RAS/RAF/MAPK and ERK kinase/ERK cascade is crucial to melanoma cell proliferation and survival. Sildenafil is a phosphodiesterase (PDE) 5A inhibitor, and recent data indicate that BRAF activation downregulates PDE5A; low PDE5A expression resulting from BRAF activation or sildenafil use increases melanoma invasiveness, raising the possibility of an effect of sildenafil on incident melanoma risk.
Study Details
The study involved 25,848 men in the Health Professionals’ Follow-up Study who were questioned regarding sildenafil use for erectile dysfunction in 2000. Participants who reported cancer at baseline were excluded. The incidences of melanoma, squamous cell carcinoma, and basal cell carcinoma were obtained biennially from self-reported questionnaires. Diagnosis of melanoma and squamous cell carcinoma were pathologically confirmed.
Risks were assessed by multivariate models adjusting for age, body mass index, smoking, physical activity, childhood reaction to sun, number of severe sunburns, mole count, hair color, family history of melanoma, sun exposure at high school age and age 25 to 35, 36 to 59, and 60 years or older, UV index at birth and age 15 and 30 years, and other treatments for erectile dysfunction.
Increased Risk With Recent and Ever Use
Overall, 142 melanoma, 580 squamous cell carcinomas, and 3,030 basal cell carcinomas were identified between 2000 and 2010. On multivariate analysis, recent sildenafil use at baseline was significantly associated with an increased risk of subsequent melanoma with a hazard ratio (HR) of 1.84 (95% confidence interval [CI] = 1.04–3.22), with no increased risk of squamous cell carcinoma (HR = 0.84, 95% CI = 0.59–1.20) or basal cell carcinoma (HR = 1.08, 95% CI = 0.93–1.25) being observed. Level of erectile function was not associated with altered risk of melanoma. Ever use of sildenafil was also associated with significantly increased risk of melanoma (HR = 1.92, 95% CI = 1.14–3.22).
The significant association between sildenafil use and melanoma remained after excluding outcomes occurring in the first 2 years of follow-up (HR = 2.19, 95% CI =1.18–4.07) and excluding all users of other erectile dysfunction treatments (HR = 2.18, 95% CI = 1.15–4.15). Analysis excluding patients reporting major chronic diseases at baseline showed no marked effect on increased melanoma risk with recent sildenafil use at baseline (HR = 2.24, 95% CI = 1.05–4.78) or ever use (HR = 2.77, 95% CI = 1.32–5.85).
The investigators concluded, “Sildenafil use may be associated with an increased risk of developing melanoma. Although this study is insufficient to alter clinical recommendations, we support a need for continued investigation of this association.”
Jiali Han, PhD, of Indiana University, is the corresponding author for the JAMA Internal Medicine article.
The Health Professionals’ Follow-up Study is partly supported by a grant from the National Institutes of Health. The study authors reported no potential conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
