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Shining a Light on the Link between PDE5-Inhibitors and Melanoma


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Christina Teeter Doligalski, PharmD, BCPS
Tampa General Hospital
Tampa, FL USA
cdoligalski@tgh.org



Breaking News
Practicing in Florida, I read with great interest the recent study potentially linking sildenafil and melanoma [1]. The evening news was awash with cautionary warnings for middle-aged men, while simultaneously ruining many 24 hour news channels' daytime advertising base.

Early Research
The first correlation between PDE5A and melanoma was reported in 2008 [2,3], following several years of groundbreaking research in which the cellular pathways of melanoma were being elucidated [4-7] This research identified two key regulatory melanoma pathways, both of which are effected by PDE5A expression. The most significant pre-clinical finding came in 2011, when Arozarena and colleagues [8] investigated the physiologic relevance of PDE5A to melanoma, and were able to find that PDE5A inhibition produced increased melanoma invasion, while PDE5A stimulation produced stable or decreased invasive potential. These findings led to the question: Is there a clinically-significant link between melanoma and sildenafil use? [9]

The Latest Data
In Li and colleagues' analysis, a cohort was followed from 2000 to 2010. At baseline, men in the United States reported their use, ever or current, of sildenafil (the only commercially available PDE5A inhibitor at the time) for erectile dysfunction. Additional information including other known risk factors for melanoma was also assessed. Participants then reported diagnoses of melanoma, squamous cell cancers (SCC), basal cell cancers (BCC), and other cancers on biennial surveys. Self-reported cancers were only included if they were pathologically confirmed via review of their medical record. Risk was then analyzed by assessing melanoma cases in those who were using sildenafil in 2000 compared to those who were not in 2000; those men who developed erectile dysfunction (ED) and began use of PDE5A inhibitors after 2000 were not identified and were therefore included in the "no sildenafil" group.

Of the 25,848 participants included in the analysis, there were 142 cases of melanoma: 128/193,935 (0.07%) in the "no sildenafil" arm, and 14/10,935 (0.13%) in the "sildenafil" arm. The average patient was, as expected, a 65 year old white male, with 68% having "burn or blistering skin reaction to the sun". After adjusting for multiple factors (including known risk factors for melanoma), the hazard ratio for incident of melanoma associated with use of sildenafil was 1.84 (1.04-2.33). This increased risk association was not seen with SCC (HR: 0.84 [0.59-1.20]) or BCC (HR: 1.08 [0.93-1.25]).

What the authors did not explicitly state, however, was that the absolute risk of development of melanoma in men receiving sildenafil was 0.128%, or 1 cancer case per 781 person-years. Additional limitations of this study included its lack of melanoma outcomes data (survival, treatment, etc), lack of dosing information for sildenafil, and potential for underestimation of risk given that new use of sildenafil was not captured in the "no sildenafil" group after 2000.

The Dilemma
PDE5A inhibitors are mainstays in the therapy of pulmonary arterial hypertension and PAH from left heart disease (PH-LHD). These recent data are especially concerning given the cumulative and persistent exposure to PDE5 inhibition in PAH/PH-LHD in the patients we serve compared with occasional use seen in ED. Unfortunately, alternative therapies for PAH or PH-LHD are not innocuous and carry much more concrete potential adverse events, inconvenient dosing, and extensive costs.

Additionally, early research pointed to an increased risk of melanoma's invasiveness, not in melanoma development. This point was raised by Li and colleagues, in which they suggested that perhaps those who received sildenafil had acceleration in development of melanoma through PDE5 inhibition; essentially that PDE5A inhibitors "may promote invasion of primary tumors". However, it is important to remember that retrospective cohorts can only suggest an association, not prove cause and effect relationships. Perhaps other pathways are responsible for the increased risk seen with sildenafil use, such as PDE5A inhibitor's promotion of melanin synthesis [10-11].

The Solution
Unfortunately, a definitive risk assessment in our patient population is unlikely to occur given the incredibly low absolute risk and large population that would be needed to properly assess this risk. In a commentary to Li's analysis [12], the point is made that the only known modifiable cause of melanoma is exposure to UV radiation. In patient's presenting with PAH or PH-LHD in which sildenafil (or any PDE5-inhibitor therapy) is being considered, a careful assessment of past UV exposure, frequent follow up with a dermatologist, and education on self-screening should be considered in light of available data until a more definitive cause/effect relationship can be determined. ■

Disclosure Statement: the author has no conflicts of interest to report.


References:

  1. Li WQ, Qureshi AA, Robinson KC, Han J. Sildenafil use and increased risk of incident melanoma in US men: a prospective cohort study. JAMA Intern Med. 2014 Jun;174(6):964-70.
  2. Pinner S, Jordan P, Sharrock K, et al. Intravital imaging reveals transient changes in pigment production and Brn2 expression during metastatic melanoma dissemination. Cancer Res.2009:69, 7969-77.
  3. Goodall J, Carreira S, Denat L, et al. Brn-2 represses microphthalmia-associated transcription factor expression and marks a distinct subpopulation of microphtalmia associated transcription factor-negative melanoma cells. Cancer Res. 2008:68, 7788-94.
  4. Goydos JS, Mann B, Kim HJ, et al. Detection of B-RAF and N-RAS mutations in human melanoma. J AmColl Surg. 2005;200(3):362-370.
  5. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417 (6892):949-954.
  6. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358-365.
  7. Bollag G, Tsai J, Zhang J, et al. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov. 2012;11(11):873-886.
  8. Arozarena I, Sanchez-Laorden B, Packer L, et al. Oncogenic BRAF induces melanoma cell invasion by downregulating the cGMP-specific phosphodiesterase PDE5A. Cancer Cell. 2011;19(1): 45-57.
  9. Mitra D, Robinson KC, Fisher DE. Melanoma and Viagra: an unexpected connection. Pigment Cell Melanoma Res. 2011;24:16-18.
  10. Zhang X, Yan G, Ji J, et al. PDE5 inhibitor promotes melanin synthesis through the PKG pathway in B16 melanoma cells. J Cell Biochem. 2012;113(8):2738-2743.
  11. Noonan FP, Zaidi MR, Wolnicka-Glubisz A, et al. Melanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment. Nat Commun. 2012;3:884.
  12. Robinson JK. Role of sildenafil in melanoma incidence and mortality. JAMA Intern Med. 2014 Jun;174(6):970-1.



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