Press for an Underestimated Nemesis

“Thank goodness it’s not amelanoma!”Manyof usmayhave said or thought that when explaining the diagnosis of a nonmelanoma skin cancer to a patient.Wewoulddowell to avoid the temptation tounderestimatecutaneoussquamouscell carcinoma (SCC). Dermatologists, head and neck surgeons, medical and surgical oncologists, and transplant physicians are aware that cutaneous SCC can and does behave aggressively and has the potential tometastasize.1-3 Recent studies have shown that the death rate for SCC approaches that formelanomainpartsof theUnitedStates.4Other studies have defined risk factors for especially aggressive behavior by SCC that include large size; deep invasion; and involvement of nerves, lymphatics, and blood vessels.5,6 Some groups, including our own, have set out to define SCC at the molecular level,with theaimof identifyingmechanismsofcancer development, progression, and immunity.7-14 The natural progression of this work would be to define and test novel therapies for advanced SCC. Currently, there is a relative paucity of studies concerning metastatic cutaneous SCC. Options for cutaneous SCC refractory to surgery and irradiation remain limited.Capecitabine15-17 andcetuximab18,19 offerhope for locally advancedandmetastaticdiseaseon thebasis of case reports and series.Data from large trials are lacking. In a search of “metastatic cutaneous SCC” on the www .clinicaltrials.gov website, only 2 trials are currently registered (one recruiting) vs 911 trials for metastatic melanoma. Reasons for thismay includeageneral lackof awarenessof the potential gravity of SCC for somepatients and a lack of enthusiasmonthepartof fundingorganizations,whichoverall show little interest in skin cancers other thanmelanoma.The search for better approaches to cutaneous SCC lead to the consideration of epidermal growth factor receptor (EGFR) inhibitors. Epidermal growth factor receptor inhibitors including cetuximab, panitumumab, lapatinib, and erlotinib hydrochloride have been tried for metastatic cutaneous SCC (www .clinicaltrials.gov). SuccessfulEGFR inhibitiondependson the presenceofwild-typeEGFRasopposed tomutantEGFR.20The most common mutant EGFRvIII has been described in head and neck cancer, and its presence is associated with resistance to EGFR inhibitors. In this issueof JAMADermatology, Dziunycz et al21 looked for EFGRmutations that would confer resistance to therapy; they foundonlywild-typeEGFR inprimaryandmetastatic cutaneous SCC. This indicates that advanced cutaneous SCC mightbe susceptible to treatmentbyEGFR inhibition. Itwould be optimal if these findings evolved into a clinical trial. This would create an opportunity to advance not only our understanding ofmetastatic cutaneous SCC, butmore importantly, an opportunity to providemore effective therapy for a subset of patients with an otherwise dismal prognosis. This is more easily said than done in the current climate of limited resources and is especially true for an underestimated disease. I hope thatDziunyczandcolleagues21 andother similar groups will be able to continue and see their work through to fruition.For this tohappen,weneedtocontinuetopromoteawareness of thedangers of high-risk cutaneous SCCbeyond the inner circle of specialists confronted by it and get it on the radar of generalists, policymakers, and thepublic at large.With that, we can continue to do the work we set out to do to advance the stateof theart ofpatient care for advancedcutaneousSCC.