title: Can hair re-growth be considered an early clinical marker of treatment resistance to Hedgehog inhibitors in patients with advanced basal cell carcinoma? A report of two cases.
abstract: BACKGROUND
  Basal cell carcinomas (BCCs) are the most common skin cancers in the Caucasian population. BCCs are in the majority of cases adequately managed with surgical excision, however a small subset of these tumours exhibit resistance to conventional therapies and progress to become locally advanced or even metastatic. Although Hedgehog inhibitors have been successfully used during the last few years in the treatment of locally advanced or metastatic BCCs, resistance to treatment remains an issue. Until this point, no biomarkers or clinical markers of drug resistance for Hedgehog inhibitors have been identified.
  
  
  RESULTS
  We report two patients, a female patient with Gorlin syndrome and a male patient with locally advanced BCC, which received treatment with the Hedgehog inhibitor Vismodegib. These patients responded adequately to treatment and they both developed Hedgehog inhibitor-induced alopecia as an adverse event. However, after 2.5 and 1.5 years of treatment, respectively, the patients exhibited progressive disease that was accompanied by reversal of the Hedgehog inhibitor-induced alopecia, although still under treatment with Vismodegib.
  
  
  CONCLUSIONS
  Although alopecia is a well-known adverse event associated with the administration of Hh inhibitors, data associated with the appearance and/or clinical severity of alopecia and the treatment efficacy of Hedgehog inhibitors are limited. The Hedgehog pathway plays an important role in the normal cycling of the hair follicles in adults and, therefore, the pathomechanism of Hedgehog inhibitor-induced alopecia is considered unique for this drug class. Based on the fact that Hh inhibitor resistance is associated with partial reactivation of the Hh pathway, it would not be illogical to suggest that reversal of Hh inhibitor-induced alopecia in patients under treatment with Hh inhibitors could serve as a clinical marker of drug resistance. However, this observation, as reported in this paper, is only limited in two patients and therefore more information is needed in order to assess its actual clinical importance.
authors.affiliation: 1st Department of Dermatology, School of Medicine, "Andreas Sygros" Hospital, University of Athens, Athens, Greece. anonaki@hotmail.com.
authors.forename: E
authors.initials: E
authors.lastname: Soura
authors.affiliation: 1st Department of Dermatology, School of Medicine, "Andreas Sygros" Hospital, University of Athens, Athens, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Plaka
authors.affiliation: 1st Department of Dermatology, School of Medicine, "Andreas Sygros" Hospital, University of Athens, Athens, Greece.
authors.forename: C
authors.initials: C
authors.lastname: Dessinioti
authors.affiliation: 3rd Department of Medicine, School of Medicine, "Sotiria" General Hospital, University of Athens, Athens, Greece.
authors.forename: K
authors.initials: K
authors.lastname: Syrigos
authors.affiliation: 1st Department of Dermatology, School of Medicine, "Andreas Sygros" Hospital, University of Athens, Athens, Greece.
authors.forename: A J
authors.initials: AJ
authors.lastname: Stratigos
mesh_terms: D000505:Alopecia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000009:adverse effects; D002280:Basal Cell Carcinoma / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D012878:Skin Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins