Systemic Medications Linked to an Increased Risk for Skin Malignancy

CLINICAL REVIEW Systemic Medications Linked to an Increased Risk for Skin Malignancy Nathan Merritt Johnson, MD; Kyle A. Prickett, MD; Mariana A. Phillips, MD ermatologists are increasingly called on to evaluate PRACTICE POINTS patients with complex medical problems who are • Patients should be educated about the increased Doften takingcopy many medications. Over the last several risk for skin malignancy while undergoing treatment decades, many new drugs that target molecular pathways with BRAF inhibitors, sonic hedgehog–inhibiting in carcinogenesis and the inflammatory immune system agents, Janus kinase (JAK) inhibitors, and phosphodi- have been developed. Increased skin cancer risk has esterase 5 (PDE-5) inhibitors. beennot reported in association with BRAF inhibitors, sonic • For BRAF inhibitors, sonic hedgehog–inhibiting hedgehog–inhibiting agents, Janus kinase (JAK) inhibitors, agents, and JAK inhibitors, the increased risk for skin and phosphodiesterase 5 (PDE-5) inhibitors. We review the cancer warrants regular surveillance; however, given literature and data regarding the significance and strength the indications for these medications, many patientsDo of these associations and the molecular pathways by which will already be receiving regular skin screenings. these medications promote cutaneous tumorigenesis. The • The association between PDE-5 inhibitors and mela- association of skin cancer with drugs that either induce noma as well as nonmelanoma skin cancer remains photosensitivity—nonsteroidal anti-inflammatory drugs, questionable, and increased skin surveillance is not antibiotics (eg, tetracyclines, fluoroquinolones, trimethoprim- recommended at this time, unless patients have other sulfamethoxazole), voriconazole, thiazides—or suppress risk factors for cutaneous malignancy. the immune system—certain biologics (eg, anti–tumor necrosis factor agents), calcineurin inhibitors, thiopurines, methotrexate, cyclosporine—is well known and is there- CUTIS fore not reviewed in this discussion. Over the last several decades, many new drugs that target molecular pathways in carcinogenesis and the inflammatory immune system BRAF Inhibitors have been developed, resulting in substantial improvements in the treatment of many malignancies and inflammatory conditions. How- The mitogen-activated protein kinase (MAPK) pathway ever, an increasingly widespread deployment of these new drugs (also known as the RAS/RAF/MAPK signaling pathway) has revealed an increased tendency for patients to develop skin is important in growth factor–receptor signaling and plays malignancy in some instances and questions of possible associa- a key role in cell differentiation, survival, and proliferation. tion between their use and skin cancer. Specifically, increased skin Activating mutations in this pathway allow cells to grow cancer risk has been reported in association with BRAF inhibitors, and proliferate in a growth factor–independent manner. sonic hedgehog–inhibiting agents, Janus kinase (JAK) inhibitors, and phosphodiesterase 5 (PDE-5) inhibitors. We review the literature on Twenty percent of human cancers harbor a mutation in 1 each drug class and its association with skin malignancy, as well as the RAS oncogene, an upstream mediator of the pathway. recommendations regarding drug use, surveillance, and treatment. Activating mutations in BRAF, a serine/threonine kinase, Cutis. 2019;104:E32-E36. predominate in cutaneous melanoma and also have been found in 40% to 70% of papillary thyroid malignancies, From Carilion Clinic Dermatology & Mohs Surgery and Virginia Tech Carilion School of Medicine, Roanoke. The authors report no conflict of interest. Correspondence: Nathan Merritt Johnson, MD, 1 Riverside Cir, Ste 300, Roanoke, VA 24016 ([email protected]). E32 I CUTIS® WWW.MDEDGE.COM/DERMATOLOGY Copyright Cutis 2019. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. SKIN CANCER RISK OF SYSTEMIC THERAPIES 10% to 20% of cholangiocarcinomas, and 5% to 20% of inhibitors. It has been shown that these melanomas colorectal carcinomas. The most common BRAF mutation in occur in melanocytes with wild-type BRAF. It has been cutaneous melanoma is V600E, which involves a glutamic postulated that some of these tumors occur in cells that acid for valine substitution at codon 600. This mutation acti- harbor upstream mutations in RAS, whereas others might vates BRAF 500-fold and is present in approximately 50% result from alternate signaling through non-RAF onco- of melanomas.1,2 genic pathways.9,12 Vemurafenib, a selective BRAF inhibitor, was approved Zimmer et al1 reported 12 SPMs in 11 patients treated by the US Food and Drug Administration (FDA) for the with BRAF inhibitor therapy. They reported a median treatment of metastatic melanoma in the United States in delay of 8 weeks (range, 4–27 weeks) for SPM develop- 2011. Phase 3 trial data demonstrated that vemurafenib ment. Tumors were detected in early stages; 1 tumor har- resulted in improved survival and decreased risk for bored an NRAS mutation.1 disease progression compared to dacarbazine, the for- Dalle et al13 reported 25 SPMs in 120 vemurafenib- mer best treatment.3 During phase 1 testing, it became treated patients. Median delay in SPM development was apparent that vemurafenib treatment was associated 14 weeks (range, 4–42 weeks). All tumors were thin, rang- with a 31% increased risk for squamous cell carcinoma ing from in situ to 0.45-mm thick. Wild-type BRAF was (SCC), most commonly well-differentiated SCC, and ker- detected in the 21 melanomas sampled; 1 lesion showed atoacanthomas (KAs).4 This association was confirmed mutated NRAS.13 in phase 2 and 3 studies, though the incidence was The exact incidence of SPM in the setting of BRAF lower. McArthur et al5 reported a 19% incidence of inhibition is thought to be at least 10-fold less than SCC cutaneous SCC with extended follow-up analysis of the and KA.2 Patients on BRAF inhibitor therapy should have phase 3 trial. Dabrafenib, another BRAF inhibitor, has routine full-body skin examinations, given the increased been similarly associated with increasing the risk for risk for SPM and SCC. SCC and KA. Another drugcopy belonging to the tyrosine kinase inhibi- In one study, the mean time to development of SCC tor family, sorafenib, is used in the treatment of solid after initiating vemurafenib therapy was 10 weeks, with tumors, particularly hepatocellular and renal cell carci- lesions reported as early as 3 weeks. Most patients had nomas, and also has been associated with development clinical signs of chronically sun damaged skin; however, of cutaneous SCC and KAs.14 Sorafenib is a multiple a history of SCC was present in only 17%. Most lesions tyrosinenot kinase inhibitor that also inhibits the RAF serine/ (63%) were characterized as KAs.6 threonine kinases. Similar to vemurafenib and dab- The mechanism for BRAF inhibitor–induced squamo- rafenib, SCCs and KAs associated with sorafenib tend proliferative growth is due to paradoxical activation ofDo the to arise in patients with chronic actinic damage during MAPK pathway in cells with wild-type BRAF that harbor the first 2 months of treatment. It has been hypothesized upstream-activating mutations in RAS or tyrosine kinase that inhibition of RAF kinases is pathogenic in inducing receptors.7 In the presence of a BRAF inhibitor, inacti- SCCs because these lesions have not been reported with vated BRAF forms heterodimers with wild-type CRAF sunitinib, another multiple tyrosine kinase inhibitor that (a BRAF-CRAF heterodimer). The heterodimer forms a lacks the ability to inhibit serine/threonine kinases.15,16 complex with the mutant RAS that leads to transactiva- Although SCCs and KAs associated with sorafenib tend tion of the CRAF molecule,8,9 resulting in a paradoxical to be low grade, it is reasonable to consider sunitinib or increase in MAPK signaling and consequent ERK phos- an alternative tyrosine kinase inhibitor in patients who phorylation and activation throughCUTIS CRAF signaling. RAS, develop multiple SCCs while taking sorafenib.16 particularly HRAS, mutations have been found in 60% of all vemurafenib-associated SCCs and KAs. For this reason, Sonic Hedgehog–Inhibiting Agents it is thought that vemurafenib potentiates tumorigenesis Vismodegib, the first small molecule inhibitor of the in subclinical lesions harboring upstream MAPK pathway signaling protein smoothened, gained FDA approval for mutations as opposed to inducing de novo lesions.6 the treatment of metastatic or locally advanced basal cell Because BRAF inhibitors are remarkably efficacious carcinoma (BCC) in 2012. A second agent with an identi- in the treatment of metastatic melanomas harboring the cal mechanism of action, sonidegib, was approved by the V600E BRAF mutation, there are no restrictions on their FDA for locally advanced BCC in 2015. Approximately use, despite the known increased risk for SCC. Squamous 90% of BCCs contain mutations in the sonic hedgehog cell carcinomas tend to be low grade, and all tumors that pathway, which lead to constitutive smoothened activation developed in phase 1 to 3 trials were treated with simple and uncontrolled cell proliferation.17 The development of excision. The development of SCC did not necessitate smoothened inhibitors introduced a much-needed treat- interruption of treatment. Furthermore, the addition of ment for inoperable or metastatic BCC,17,18 though long- MEK inhibition to BRAF inhibitor therapy reduces

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