Although squamous cell carcinoma of the penis (pSCC) and male urethral epithelium (uSCC) appear in nearby localizations and may have similar histology, its clinical manifestations, disease course and treatment options are distinct
During the 2021 Genitourinary Cancers Symposium, a comparative genomic profiling trial was presented that examined differences between penile and male urethral SCC.
Tissues obtained from men with pSCC (n = 230) and clinically advanced uSCC (n = 17) were subjected to a comparative genomic profiling trial based on hybrid capture to assess all classes of genomic alterations. Tumor mutational burden (TMB) was determined at up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined in up to 114 loci. The expression of PD-L1 was determined by immunohistochemistry.
Results:
Mean ages were similar in both groups. pSCC exhibited a slightly higher frequency of infection by HPV-16 and 18 (29% versus 12%; P = 0.16), although the TP53 mutation frequencies were almost identical (55% versus 59%, not significant). CDKN2A inactivation (P = 0.08), CCND1 amplification trending upward, and TERT promoter mutations (P = 0.01) were more frequent in pSCC, potentially indicating previous HPV infection.
Genomic changes in NOTCH1 were identified exclusively in pSCC. The potentially actionable changes identified in both groups included activating mutations of PIK3CA (tyrosine kinase inhibitors), as well as pathogenic changes in FBXW7 and PTEN (MTOR inhibitors). Rare inactivation of BRCA1 and BRCA2 (PARP inhibitors) was observed only in pSCC.
The expression of highly positive PD-L1 was higher in pSCC (34 versus 14%, P = 0.06). Although the mean TMB was similar in both groups, the pSCC exhibited a high frequency of cases with CD274 amplification (gene encoding the PD-L1 protein), as well as TMB > 10 mut/Mb that are on the label for treatment with immune coreceptor inhibitors.
The authors conclude that the comparative genomic profiling trial for penile and male urethral SCC identified opportunities for targeted therapies and immunotherapy treatment. Compared to uSCC, the pSCC presented genomic characteristics more similar to head and neck SCC, including a slight increase in cell cycle impairment, HPV infection, and signaling alterations of the NOTCH pathway.
References:
Spiess PE, et al. Clinically advanced penile (pSCC) and male urethral (uSCC) squamous cell carcinoma: A comparative genomic profiling (CGP) study. Abstract 2. 2021 Genitourinary Cancers Symposium. DOI:10.1200/JCO.2021.39.6_suppl.2
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