In 2015, Loeb et al39 also examined the potential association between PDE-5 inhibitors and melanoma. Review of several Swedish drug and cancer registries allowed for analysis of melanoma risk and PDE-5 inhibitor use, based on number of prescriptions filled and type of PDE-5 inhibitor prescribed. Their analysis showed that men developing melanoma were more likely than nonmelanoma controls to have taken a PDE-5 inhibitor (11% vs 8%). In a subgroup analysis, however, statistical significance was shown for men with only a single prescription filled (34% of cases; P<.05), whereas the difference for men with multiple filled prescriptions did not meet statistical significance. Furthermore, the study did not find increased risk with longer-acting tadalafil and vardenafil (odds ratio [OR]=1.16) compared to sildenafil (OR=1.14). Last, use of PDE-5 inhibitors was only associated with stage 0 (OR=1.49) and stage I (OR=1.21) tumors, not with stages II to IV (OR=0.83) tumors. Although there was a statistically significant association between PDE-5 inhibitors and malignant melanoma (P<.05), the subgroup analysis findings pointed away from a causal relationship and likely toward a confounding of variable(s).39
A 2016 study by Lian et al40 looked at the risk for melanoma in a cohort of patients diagnosed with erectile dysfunction. No association between PDE-5 inhibitors and melanoma risk was shown when comparing patients who received a PDE-5 inhibitor and those who did not receive a PDE-5 inhibitor. However, secondary analysis did show that melanoma risk was increased among patients receiving more pills (34%) and prescriptions (30%). The authors concluded that there was no association between PDE-5 inhibitor use and overall increased risk for melanoma, and the increased risk associated with a greater number of pills and prescriptions would require further study.40
In contrast, a 2017 meta-analysis by Tang et al41 of 5 studies (3 of which were the aforementioned trials38-40) concluded that use of PDE-5 inhibitors was associated with a small but significantly increased risk for melanoma (OR=1.12) and BCC (OR=1.14) but not SCC. Furthermore, the study found no evidence of dosage-dependent association between PDE-5 inhibitor use and melanoma risk.41
Overall, clinical studies have been inconclusive in determining the risk for melanoma in the setting of PDE-5 inhibitor use. Studies showing an increased rate of melanoma within patient cohorts receiving PDE-5 inhibitors are limited; results might be affected by confounding variables. However, given the similarity in mechanism between PDE-5 inhibitors and HRAS-activated melanomas, it is reasonable to continue research into this potential association.
Conclusion
Since the turn of the century, drugs targeting cell-signaling pathways have been developed to treat inflammatory, oncologic, and immune conditions. The role of immunosuppressants in promoting skin cancer is well established and supported by a vast literature base. However, associations are less clear with newer immunomodulatory and antineoplastic medications. Skin cancer has been reported in association with BRAF inhibitors, sonic hedgehog–inhibiting agents, JAK inhibitors, and PDE-5 inhibitors. In the case of JAK and PDE-5 inhibitors, the increased risk for melanoma and NMSC is somewhat inconclusive; risk is more firmly established for BRAF inhibitors and smoothened inhibitors. For the antineoplastic agents reviewed, the therapeutic effect of cancer regression is well documented, and benefits of continued therapy outweigh the increased risk for skin cancer promotion in nearly all cases. The value of early detection has been well documented for skin malignancy; therefore, increased skin surveillance and prompt management of suspicious lesions should be a priority for physicians treating patients undergoing therapy with these medications