Understanding Genomics and the Immune Environment of Penile Cancer to Improve Therapy – Beyond the Abstract

Over the last fifty years, the survival of patients with penile squamous cell carcinoma (PSCC) has stagnated, and meanwhile, the number of new PSCC cases also increased.1 The only first randomized clinical trial in PSCC, the InPACT trial, is currently enrolling patients to determine the therapeutic benefit of neoadjuvant chemotherapy, radiotherapy, and prophylactic pelvic lymph node dissection in PSCC.2 Nonetheless, the current accepted standard treatments have demonstrated limited therapeutic efficacy in several previous retrospective and small prospective studies.3 Understanding genomics and the immune environment of PSCC is vital to improve therapy. 

With the recent advances in biotechnologies, genetic, epigenetic, and transcriptomic data on PSCC has accumulated rapidly. Moreover, immunotherapy with immune checkpoint blockade has been proven successful for many other cancers. The potential therapeutic effect of microbiome manipulation is currently being tested in several cancer clinical trials. Thus in this review, we discussed the current knowledge of the biology of PSCC and explored future potential therapeutic approaches.4

It has been recently demonstrated that about one-quarter of patients with metastatic PSCC harbored clinically actionable genomic alterations.5 It appears that there are many targetable alterations in PSCC. Based on the recent data coming from next-generation sequencing studies, some of the currently available agents such as cetuximab, gefitinib and erlotinib (EGFR inhibitors), trastuzumab (ERBB2 inhibitor), dacomitinib (second-generation pan-EGFR inhibitor), erdafitinib, and infigratinib (FGFR3 inhibitors) can be used for this purpose.4 Poly(ADP-ribose) polymerase (PARP) enzyme inhibitors, such as olaparib, rucaparib, and niraparib, MEK inhibitors, such as selumetinib and trametinib, mTOR inhibitors, such as everolimus, temsirolimus, and sirolimus, and PI3Kinhibitor, alpelisib can also be other potential treatment options for PSCC.4

In addition, about half of PSCC demonstrates strong PDL1 expression, and PSCC is characterized by a paucity of mutations suggestive of immunotherapy resistance.4 Currently, many immunotherapy trials for patients with PSCC are ongoing, and their results are eagerly awaited. To date, knowledge of the composition of the penile microbiota and its effect on penile cancer oncogenesis is limited. However, with the increased use of metagenomic sequencing with next-generation sequencing (NGS) technology and a better understanding of the penile microbiome, microbiota modulation can be a part of the treatment or prevention strategy for PSCC in the future.

Written by: Ahmet Murat Aydin, MD, Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA


  1. Pham, M. N. et al. Contemporary survival trends in penile cancer: results from the National Cancer Database. Urol. Oncol. 35, 674.e1–674.e9 (2017).
  2. Canter, D. J. et al. The International Penile Advanced Cancer Trial (InPACT): rationale and current status. Eur. Urol. Focus. 5, 706–709 (2019).
  3. Clark PE, et al. Penile cancer: Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 11, 594-615 (2013). 
  4. Aydin AM, Chahoud J, Adashek JJ, Azizi M, Magliocco A, Ross JS, Necchi A, Spiess PE. Understanding genomics and immune microenvironment of penile cancer in improving therapies. Nat Rev Urol. 2020 Aug 18. doi: 10.1038/s41585-020-0359-z.
  5. Jacob, J. M. et al. Comparative genomic profiling of refractory and metastatic penile and nonpenile cutaneous squamous cell carcinoma: implications for selection of systemic therapy. J. Urol. 201, 541–548 (2019).
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