Update on Hedgehog Pathway Inhibitor Therapy for Patients with Basal Cell Naevus Syndrome or High-frequency Basal Cell Carcinoma
Systematic review
DOI:
https://doi.org/10.2340/actadv.v102.980Keywords:
basal cell nevus syndrome, high-frequency, hedgehog pathway inhibitor, basal cell carcinoma, oral, topicalAbstract
Some patients with basal cell carcinoma develop a large number of basal cell carcinomas during their lives. The most common underlying genetic disease that causes multiple basal cell carcinomas is basal cell naevus syndrome. Basal cell naevus syndrome is caused by a germline mutation in patched-1 (PTCH1), a tumour suppressor gene of the hedgehog signalling pathway. However, in a significant portion of patients with multiple basal cell carcinomas, no underlying genetic cause is found. Nevertheless, these patients can experience a treatment burden comparable to that of patients with basal cell naevus syndrome. They are referred to as high-frequency basal cell carcinoma patients. Hedgehog pathway inhibitors were the first group of targeted therapy for basal cell carcinomas. This study reviews the literature on hedgehog pathway inhibitor therapy for patients with basal cell naevus syndrome or high-frequency basal cell carcinoma, to provide an overview on efficacy, safety, dosing regimens, tumour resistance and reoccurrence, and health-related quality of life.
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References
Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A 2010; 152A: 327-332.
https://doi.org/10.1002/ajmg.a.33139 DOI: https://doi.org/10.1002/ajmg.a.33139
Lo Muzio L, Nocini PF, Savoia A, Consolo U, Procaccini M, Zelante L, et al. Nevoid basal cell carcinoma syndrome. Clinical findings in 37 Italian affected individuals. Clin Genet 1999; 55: 34-40.
https://doi.org/10.1034/j.1399-0004.1999.550106.x DOI: https://doi.org/10.1034/j.1399-0004.1999.550106.x
Verkouteren BJA, Cosgun B, Reinders M, Kessler P, Vermeulen RJ, Klaassens M, et al. A guideline for the clinical management of basal cell nevus syndrome (Gorlin-Goltz syndrome). Br J Dermatol 2022; 186: 215-226.
https://doi.org/10.1111/bjd.20700 DOI: https://doi.org/10.1111/bjd.20700
Peris K, Fargnoli MC, Garbe C, Kaufmann R, Bastholt L, Seguin NB, et al. Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines. Eur J Cancer 2019; 118: 10-34.
https://doi.org/10.1016/j.ejca.2019.06.003 DOI: https://doi.org/10.1016/j.ejca.2019.06.003
Work G, Invited R, Kim JYS, Kozlow JH, Mittal B, Moyer J, et al. Guidelines of care for the management of basal cell carcinoma. J Am Acad Dermatol 2018; 78: 540-559.
https://doi.org/10.1016/j.jaad.2017.10.006 DOI: https://doi.org/10.1016/j.jaad.2017.10.006
Huq AJ, Bogwitz M, Gorelik A, Winship IM, White SM, Trainer AH. Cohort study of Gorlin syndrome with emphasis on standardised phenotyping and quality of life assessment. Intern Med J 2017; 47: 664-673.
https://doi.org/10.1111/imj.13429 DOI: https://doi.org/10.1111/imj.13429
Axelson M, Liu K, Jiang X, He K, Wang J, Zhao H, et al. U.S. Food and Drug Administration approval: vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma. Clin Cancer Res 2013; 19: 2289-2293.
https://doi.org/10.1158/1078-0432.CCR-12-1956 DOI: https://doi.org/10.1158/1078-0432.CCR-12-1956
Atwood SX, Sarin KY, Whitson RJ, Li JR, Kim G, Rezaee M, et al. Smoothened variants explain the majority of drug resistance in basal cell carcinoma. Cancer Cell 2015; 27: 342-353.
https://doi.org/10.1016/j.ccell.2015.02.002 DOI: https://doi.org/10.1016/j.ccell.2015.02.002
Sharpe HJ, Pau G, Dijkgraaf GJ, Basset-Seguin N, Modrusan Z, Januario T, et al. Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma. Cancer Cell 2015; 27: 327-341.
https://doi.org/10.1016/j.ccell.2015.02.001 DOI: https://doi.org/10.1016/j.ccell.2015.02.001
Basset-Seguin N, Hauschild A, Grob JJ, Kunstfeld R, Dreno B, Mortier L, et al. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial. Lancet Oncol 2015; 16: 729-736.
https://doi.org/10.1016/S1470-2045(15)70198-1 DOI: https://doi.org/10.1016/S1470-2045(15)70198-1
Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, Lindgren J, Chang K, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012; 366: 2180-2188.
https://doi.org/10.1056/NEJMoa1113538 DOI: https://doi.org/10.1056/NEJMoa1113538
Tang JY, Ally MS, Chanana AM, Mackay-Wiggan JM, Aszterbaum M, Lindgren JA, et al. Inhibition of the hedgehog pathway in patients with basal-cell nevus syndrome: final results from the multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2016; 17: 1720-1731.
https://doi.org/10.1016/S1470-2045(16)30566-6 DOI: https://doi.org/10.1016/S1470-2045(16)30566-6
Verkouteren BJA, Wakkee M, Reyners AKL, Nelemans P, Aarts MJB, Racz E, et al. Eight years of experience with vismodegib for advanced and multiple basal cell carcinoma patients in the Netherlands: a retrospective cohort study. Br J Cancer 2021; 124: 1199-1206.
https://doi.org/10.1038/s41416-020-01220-w DOI: https://doi.org/10.1038/s41416-020-01220-w
Lear JT, Hauschild A, Stockfleth E, Squittieri N, Basset-Seguin N, Dummer R. Efficacy and safety of sonidegib in adult patients with nevoid basal cell carcinoma syndrome (Gorlin Syndrome): results from a Phase 2, double-blind, randomized trial. Clin Cosmet Investig Dermatol 2020; 13: 117-121.
https://doi.org/10.2147/CCID.S233097 DOI: https://doi.org/10.2147/CCID.S233097
Dreno B, Kunstfeld R, Hauschild A, Fosko S, Zloty D, Labeille B, et al. Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial. Lancet Oncol 2017; 18: 404-412.
https://doi.org/10.1016/S1470-2045(17)30072-4 DOI: https://doi.org/10.1016/S1470-2045(17)30072-4
Yang X, Dinehart SM. Intermittent vismodegib therapy in basal cell nevus syndrome. JAMA Dermatol 2016; 152: 223-224.
https://doi.org/10.1001/jamadermatol.2015.3210 DOI: https://doi.org/10.1001/jamadermatol.2015.3210
Valenzuela-Onate CA, Magdaleno-Tapial J, Garcia-Legaz Martinez M, Perez-Pastor G, Sanchez Carazo JL. Drug holiday approach for Vismodegib treatment in patients with nevoid basal cell carcinoma syndrome: three cases from real clinical practice. Dermatol Ther 2020: 33: e13540.
https://doi.org/10.1111/dth.13540 DOI: https://doi.org/10.1111/dth.13540
Mendes SR, Brinca A, Vieira R. Vismodegib hedgehog-signaling inhibition and treatment of basal cell carcinomas in gorlin-goltz syndrome. Available from https://www.wcd2019milan-dl.org/abstract-book/documents/abstracts/39-skin-cancer/vismodegib-hedgehog-signaling-inhibition-and-5398.pdf.
Hoffmann V, Husak R, Maiwirth F, Sasama B, Zahn A, Guski S, et al. Sonidegib in a patient with multiple basal cell carcinomas and HIV infection. J Dtsch Dermatol Ges 2021; 19: 592-594.
https://doi.org/10.1111/ddg.14355 DOI: https://doi.org/10.1111/ddg.14355
Tronconi MC, Solferino A, Giordano L, Borroni R, Mancini L, Santoro A. Tailored toxicity-driven administration of vismodegib in patients with multiple or locally advanced basal cell carcinoma: a pilot analysis. Front Oncol 2020; 10: 563404.
https://doi.org/10.3389/fonc.2020.563404 DOI: https://doi.org/10.3389/fonc.2020.563404
Villani A, Costa C, Fabbrocini G, Scalvenzi M. Drug holiday regimen for vismodegib treatment in patients with multiple primary basal cell carcinomas. Dermatol Ther 2020; 33: e13707.
https://doi.org/10.1111/dth.13707 DOI: https://doi.org/10.1111/dth.13707
Sohn GK, Kwon GP, Bailey-Healy I, Mirza A, Sarin K, Oro A, et al. Topical itraconazole for the treatment of basal cell carcinoma in patients with basal cell nevus syndrome or high-frequency basal cell carcinomas: a Phase 2, open-label, placebo-controlled trial. JAMA Dermatol 2019; 155: 1078-1080.
https://doi.org/10.1001/jamadermatol.2019.1541
Epstein EH, Lear JT, Saldanha G, Tang JY, Harwoord C. Hedgehog pathway inhibition by topical patidegib to reduce BCC burden in patients with basal cell nevus (Gorlin) syndrome. J Clin Oncol 2018; 36: 15_suppl.
https://doi.org/10.1200/JCO.2018.36.15_suppl.e21626 DOI: https://doi.org/10.1200/JCO.2018.36.15_suppl.e21626
Skvara H, Kalthoff F, Meingassner JG, Wolff-Winiski B, Aschauer H, Kelleher JF, et al. Topical treatment of basal cell carcinomas in nevoid basal cell carcinoma syndrome with a smoothened inhibitor. J Invest Dermatol 2011; 131: 1735-1744.
https://doi.org/10.1038/jid.2011.48 DOI: https://doi.org/10.1038/jid.2011.48
Chang AL, Oro AE. Initial assessment of tumor regrowth after vismodegib in advanced basal cell carcinoma. Arch Dermatol 2012; 148: 1324-1325.
https://doi.org/10.1001/archdermatol.2012.2354 DOI: https://doi.org/10.1001/archdermatol.2012.2354
Sinx KAE, Roemen G, van Zutven V, Janssen R, Speel EM, Steijlen PM, et al. Vismodegib-resistant basal cell carcinomas in basal cell nevus syndrome: clinical approach and genetic analysis. JAAD Case Rep 2018; 4: 408-411.
https://doi.org/10.1016/j.jdcr.2017.11.011 DOI: https://doi.org/10.1016/j.jdcr.2017.11.011
Banvolgyi A, Anker P, Lorincz K, Kiss N, Marton D, Fesus L, et al. Smoothened receptor inhibitor vismodegib for the treatment of basal cell carcinoma: a retrospective analysis of efficacy and side effects. J Dermatolog Treat 2020; 31: 387-398.
https://doi.org/10.1080/09546634.2019.1601155 DOI: https://doi.org/10.1080/09546634.2019.1601155
Wolfe CM, Green WH, Cognetta AB, Jr., Hatfield HK. Basal cell carcinoma rebound after cessation of vismodegib in a nevoid basal cell carcinoma syndrome patient. Dermatol Surg 2012; 38: 1863-1866.
https://doi.org/10.1111/j.1524-4725.2012.02513.x DOI: https://doi.org/10.1111/j.1524-4725.2012.02513.x
Tauber G, Pavlovsky L, Fenig E, Hodak E. Vismodegib for radiation-induced multiple basal cell carcinomas (BCCs) of the scalp. J Am Acad Dermatol 2015; 73: 799-801.
https://doi.org/10.1016/j.jaad.2015.07.016 DOI: https://doi.org/10.1016/j.jaad.2015.07.016
Kirkpatrick E, Dobriansky D, Scurry J. Gorlin syndrome, vulvar basal cell carcinomas, vismodegib, and lichen sclerosus: from the ISSVD Case Consultation Committee. J Low Genit Tract Dis 2016; 20: e40-e41.
https://doi.org/10.1097/LGT.0000000000000209 DOI: https://doi.org/10.1097/LGT.0000000000000209
Soura E, Plaka M, Dessinioti C, Syrigos K, Stratigos AJ. 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. J Eur Acad Dermatol Venereol 2016; 30: 1726-1729.
https://doi.org/10.1111/jdv.13754 DOI: https://doi.org/10.1111/jdv.13754
Piccerillo A, Di Stefani A, Costantini A, Peris K. Sonidegib after vismodegib discontinuation in a patient with Gorlin-Goltz syndrome and multiple basal cell carcinomas. Dermatol Ther 2021; 34: e15095.
https://doi.org/10.1111/dth.15095 DOI: https://doi.org/10.1111/dth.15095
Van Eecke L, Wolter P, Bechter O, Rogiers A, De Smedt J, Garmyn M. P129: Long-term follow-up of two patients with nevoid basal cell carcinoma syndrome (NBCCS) treated with vismodegib. Melanoma Res 2016; 26: e75-e76.
Kesireddy M, Mendiola VL, Jana B, Patel S. Long-term response to vismodegib in a patient with Gorlin-Goltz syndrome: a case report and review of pathological mechanisms involved. Cureus 2019; 11: e5383.
https://doi.org/10.7759/cureus.5383 DOI: https://doi.org/10.7759/cureus.5383
Schadendorf D, Hauschild A, Fosko S, Zloty D, Labeille B, Grob JJ, et al. Quality-of-life analysis with intermittent vismodegib regimens in patients with multiple basal cell carcinomas: patient-reported outcomes from the MIKIE study. J Eur Acad Dermatol Venereol 2020; 34: e526-e529.
https://doi.org/10.1111/jdv.16446 DOI: https://doi.org/10.1111/jdv.16446
Chren MM, Sahay AP, Bertenthal DS, Sen S, Landefeld CS. Quality-of-life outcomes of treatments for cutaneous basal cell carcinoma and squamous cell carcinoma. J Invest Dermatol 2007; 127: 1351-1357.
https://doi.org/10.1038/sj.jid.5700740 DOI: https://doi.org/10.1038/sj.jid.5700740
Sohn GK, Kwon GP, Bailey-Healy I, Mirza A, Sarin K, Oro A, et al. Topical itraconazole for the treatment of basal cell carcinoma in patients with basal cell nevus syndrome or high-frequency basal cell carcinomas: a Phase 2, open-label, placebo-controlled trial. JAMA Dermatol 2019; 155: 1078-1080.
https://doi.org/10.1001/jamadermatol.2019.1541 DOI: https://doi.org/10.1001/jamadermatol.2019.1541
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