The incidence of penile squamous cell carcinoma (PSCC) has increased in developed countries over the past decades owing to increased human papilloma virus (HPV) exposure. Despite successful surgical treatment of locoregional PSCC, effective treatment options for advanced disease are limited. The prognosis of patients with bulky nodal and metastatic PSCC is dismal and new management approaches are urgently needed. Genomic analyses have provided transformative knowledge on the genomic and molecular landscape and tumour microenvironment of PSCC. Around one-quarter of patients with metastatic PSCC have clinically actionable genomic alterations in mechanistic target of rapamycin, DNA repair and receptor tyrosine kinase pathways. These patients might benefit from combined and sequential targeted therapies. HPV vaccination might be another therapeutic option as PSCC is genetically similar to other HPV-driven cancers. In addition, 40–60% of PSCC tumours show strong PDL1 expression, and the frequency of mutational signatures suggestive of immunotherapy resistance is low, pointing to potential utility of immunotherapy for PSCC. Finally, identification of the composition of the penile microbiota and its biological role might lead to new cancer prevention and treatment strategies.
Penile squamous cell carcinoma (PSCC) displays a wide range of therapeutically targetable somatic alterations, and patients with treatment-resistant advanced PSCC might benefit from combined and sequential targeted therapies.
PSCC seems to be genetically similar to other human papilloma virus (HPV)-driven cancers and HPV vaccination might be a useful therapeutic option in nearly half of patients with PSCC infected with high-risk HPV.
Particular subsets of patients with PSCC might benefit from immunotherapy as some PSCC tumours display strong PDL1 expression and a low frequency of mutational signatures suggestive of immunotherapy resistance.
The evaluation of the spatial relationship between cellular and molecular components by multiplex immunofluorescence immunohistochemistry might provide valuable insights into the molecular profile of PSCC.
Further research to identify the composition of the penile microbiota and its association with HPV infection and penile cancer oncogenesis might lead to new cancer prevention and treatment strategies for PSCC.
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A comprehensive analysis of penile cancer in the region with the highest worldwide incidence reveals new insights into the disease
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J.S.R.: employment: Foundation Medicine; leadership: Foundation Medicine; stock and other ownership interests: Foundation Medicine; research funding: Foundation Medicine. A.N.: employment: Bayer A.G.; stock and other ownership interests: Bayer A.G.; honoraria: Roche Merck, AstraZeneca, Janssen Pharmaceuticals, and Foundation Medicine; consulting or advisory role: Merck Sharp & Dohme, Roche, Bayer A.G., AstraZeneca, Clovis Oncology, Janssen Pharmaceuticals, Incyte, Seattle Genetics, Astellas Pharma, Bristol-Myers Squibb and Rainier Therapeutics; research funding: Merck Sharp & Dohme (to the institute) and AstraZeneca (to the institute); travel, accommodations, expenses: Roche, Merck Sharp & Dohme, AstraZeneca and Janssen Pharmaceuticals. P.E.S.: consulting or advisory role: Genentech and Pfizer. A.M.A., J.C., J.J.A., M.A. and A.M. declare no competing interests.
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Aydin, A.M., Chahoud, J., Adashek, J.J. et al. Understanding genomics and the immune environment of penile cancer to improve therapy. Nat Rev Urol 17, 555–570 (2020). https://doi.org/10.1038/s41585-020-0359-z
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