Genomic alterations in penile squamous cell carcinoma (PSCC) appear similar to squamous cell carcinomas of the head and neck and esophagus but not lung, skin, bladder, and cervix. PSCCs display genomic heterogeneity, low mutation burden, and potentially actionable alterations in the Notch, DNA repair, kinase, and cell-cycle pathways.

See related article by Chahoud et al., p. 2560

In this issue of Clinical Cancer Research, Chahoud and colleagues report whole-exome sequencing (WES) of tumors from 34 patients with penile squamous cell carcinoma (PSCC), which represents the largest such dataset ever analyzed (1). Subsequently, tumor mutation signatures were estimated on the basis of their association with the COSMIC mutation signatures. They then underwent a genomic comparison between their cohort and other squamous cell carcinomas in The Cancer Genome Atlas.

PSCC is a rare malignancy with approximately 2,200 cases estimated to be diagnosed in the United States in 2021 and nearly 500 deaths. However, the incidence is higher in developing countries. While platinum-based combination chemotherapy for locally advanced and metastatic disease induces tumor responses in approximately 50% of patients, it is not curative and subsequent salvage therapeutic options are marginally active and the availability of trials is unfortunately limited by the rarity of the disease. While the association of approximately 50% of PSCC with human papilloma virus (HPV) is well established, better understanding of the pathogenesis of PSCC is critical to develop new strategies to advance care for patients with PSCC.

In a proportion of patients, HPV DNA integrates into the host genome, leading to overexpression of E6 and E7, which may also lead to inactivation of p53 and RB1 and upregulation of telomerase. Multiple analyses of modest sized datasets have revealed the heterogeneous molecular landscape of PSCC with multiple pathways identified by different studies as potentially critical to PSCC pathogenesis (Fig. 1; refs. 2–5). Collectively, these studies demonstrate that PSCC appears to share genomic traits with squamous cell carcinomas of the head and neck and esophagus but not squamous cell carcinomas of the lung, skin, bladder, and cervix.

Figure 1.

Molecular alterations in penile squamous cell carcinoma. Chahoud and colleagues (1) report that the Notch pathway was the most frequently affected with mutations (70.6%) followed by the Hippo (58.8%), RTK-RAS (47.1%), p53 (44.1%), PI3K, cell cycle, and Wnt pathways (32.3%). Others have also shown amplification of the Her family using different molecular platforms and IGF-1R protein. Epigenetic alterations of DNMT3B, and upregulated androgen receptor, NFκB, and PPARG have also been identified suggesting the relevance of epigenetic modulation and transcription factors in penile carcinogenesis. Targets in the angiogenesis pathways such as VEGF and IL8 have been identified. Moreover, inflammatory pathways (COX2, prostaglandin E2) and immune regulation have also been demonstrated to promote PSCC with frequent overexpression of the PD-L1 protein.

Figure 1.

Molecular alterations in penile squamous cell carcinoma. Chahoud and colleagues (1) report that the Notch pathway was the most frequently affected with mutations (70.6%) followed by the Hippo (58.8%), RTK-RAS (47.1%), p53 (44.1%), PI3K, cell cycle, and Wnt pathways (32.3%). Others have also shown amplification of the Her family using different molecular platforms and IGF-1R protein. Epigenetic alterations of DNMT3B, and upregulated androgen receptor, NFκB, and PPARG have also been identified suggesting the relevance of epigenetic modulation and transcription factors in penile carcinogenesis. Targets in the angiogenesis pathways such as VEGF and IL8 have been identified. Moreover, inflammatory pathways (COX2, prostaglandin E2) and immune regulation have also been demonstrated to promote PSCC with frequent overexpression of the PD-L1 protein.

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This work by Chahoud and colleagues partly validates the prior WES of PSCC tumors from 27 patients by Feber and colleagues (2), which identified an HPV-associated APOBEC mutational signature and an NpCpG signature in HPV-negative disease, which are akin to the MP1 APOBEC mutational signature and MP2 DNA mismatch repair and microsatellite instability signatures identified by Chahoud and colleagues MP1 tumors were associated with high tumor mutation burden (TMB) and worse survival. Mutations in the Notch pathway exhibited the highest prevalence (70.6%) followed by the Hippo, receptor tyrosine kinase (RTK)-RAS, p53, and cell-cycle pathways. PIK3CA and CDKN2A were significantly enriched in specific protein loci suggesting they may be driver mutations in PSCC. Expanding the analysis of DNA damage repair (DDR) alterations, nearly a quarter of patients had a pathogenic or likely pathogenic variant in DDR genes. In contrast to the study by Feber and colleagues, the study by Chahoud and colleagues did not identify alterations of CSN1, a tumor suppressor gene, which disrupts miRNA-mediated gene silencing when mutated (2). These differences are possibly due to differences in sequencing depth and modest number of patients studied.

In a previous study of 43 PSCC tumors, targeted next-generation sequencing identified that MYC and CCND1 amplifications were significantly associated with poor outcomes and also reported the presence of actionable alterations including EGFR and CDK4 amplifications (3). Furthermore, targeted gene sequencing of tumors from 20 patients with PSCC in a separate study reported that the most common clinically relevant genomic alterations were CDKN2A point mutations/homozygous deletions, NOTCH1 point mutations and rearrangements, PIK3CA point mutations and amplification, EGFR amplification, CCND1 amplification, BRCA2 insertions/deletions, RICTOR amplifications and FBXW7 point mutations (4). Similarly, another targeted genomic profiling study reported alterations in the mTOR, DNA repair, and tyrosine kinase (EGFR, ERBB2, FGFR3) genes (5).

To that end, while it is challenging to design trials based on genomic signatures, redesigning trials grouping those cancers which share common genomic drivers has merits. Notably, NOTCH deregulation, frequent alteration in head and neck carcinoma, was noted in over 70% of samples of PSCC in the Chahoud study. These patients displayed a trend toward worse overall survival in this as well as other studies. Given the shared pathway with genomic similarity to head and neck squamous cell carcinoma, expanding trials evaluating PI3K or Notch pathway inhibitors in head and neck carcinoma to those with PSCC offers an intriguing option to improve oncologic outcomes for those with this rare disease. The presence of DDR alterations could offer a potential clinical benefit from the synthetic lethality of PARP inhibition. The NCI Match trial does offer targeted therapeutic interventions to target CDK4/6, PI3KCA, and mTOR genomic alterations, although the rarity of the disease may limit the number of patients with PSCC.

Given the recent advances with immune checkpoint inhibitors in multiple malignancies, it is logical to inquire the role of these agents in PSCC. To that end, while both MP1 and MP2 signatures offer the potential for response to immune checkpoint blockade, preclinical work suggests rational combinations may be required to overcome resistance to immune checkpoint blockade. While there were variations in TMB among the different signatures, the overall TMB for PSCC remains low. Recent small studies have reported disappointing overall response rates with PD1/L1 inhibitor monotherapy as well as combined PD1/L1 and CTLA-4 immune checkpoint inhibitor therapy. Nevertheless, it is important to consider pembrolizumab for patients with PSCC with a high TMB ≥10 mutations/Mb, given its approval across malignancies when meeting this threshold. Further work is needed to not only understand the genomics of PSCC but also the complete tumor microenvironment. It is intriguing that the addition of cabozantinib (VEGF and MET receptor inhibitor) to nivolumab and ipilimumab was associated with preliminarily promising response rates. This difference in response is supported by data from other malignancies demonstrating synergistic efficacy of immune checkpoint and angiogenesis blockade. Given that NOTCH signaling upregulates the PI3K pathway, a resistance mechanism, a rationale may be made to evaluate the combination of PI3K with immune checkpoint blockade to restore response. Other immunotherapeutic approaches for those with HPV-associated PSCC include the combination of immune checkpoint inhibitors with HPV-specific T cells harvested and grown from the blood and engineered to kill HPV-infected cancer cells (NCT02379520).

While the work conducted to date has been critical in advancing the understanding of the genomic landscape of PSCC, further advances will need studies of larger datasets. In addition, translating this information into the design of clinical trials will be critical to advance care for this unmet need. In moving toward this goal, the comprehensive evaluation of tumor material on multiple orthogonal platforms for epigenomic, transcriptomic, and proteomic alterations will shed deeper insights. Moreover, preliminary advances have occurred in the construction of PSCC cell lines, organoids, and animal model systems.

B.A. McGregor reports consulting from Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, Dendreon, Bristol-Myers Squibb, and EMD Serono and research support for the Dana‐Farber Cancer Institute from Bristol‐Myers Squibb, Calithera, Exelixis, and Seattle Genetics. G.P. Sonpavde is an advisory board member with BMS, Genentech, EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, and Immunomedics; reports research support from Sanofi, AstraZeneca, and Immunomedics; travel costs from BMS and AstraZeneca; speaking fees from Physicians Education Resource (PER), Onclive, Research to Practice, and Medscape; writing fees from Uptodate; Editor of Elsevier Practice Update Bladder Cancer Center of Excellence; and Steering committee of trials/studies membership with BMS, Bavarian Nordic, Seattle Genetics, QED (all unpaid), and Astrazeneca, EMD Serono, and Debiopharm (paid).

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