HPV-positive and HPV-negative penile squamous cell carcinoma are molecularly distinct tumours

Penile squamous cell carcinoma is an aggressive malignancy with few effective treatment options. Genomic and molecular profiling of the tumours reveals targetable genetic alterations.

Penile squamous cell carcinoma is a rare and aggressive malignancy with few treatments in the advanced setting and little success of immune checkpoint inhibitors. Around half of penile squamous cell carcinoma cases are linked to HPV infection. More insight into the landscape of somatic alterations and immune checkpoint inhibitor-related biomarkers in penile squamous cell carcinoma could establish signatures for HPV-dependent and HPV-independent oncogenesis. Therefore, Dr Bassel Nazha (Emory University, GA, USA) and colleagues retrospectively analysed data of 108 patients with penile squamous cell carcinoma [1].

Penile squamous cell carcinoma tumours were genetically and molecularly characterised using next-generation sequencing, PD-L1 expression, microsatellite instability (MSI), tumour mutational burden (TMB), and HPV16/18 status. Among the entire cohort (n=108), 86% of tumours were primary and 22% of tumours were metastatic. In the overall cohort, the most frequently detected mutations were TP53 (46%), CDKN2A (26%), PIK3CA (25%), TERT promoter (22%), KMT2C (16%), and NOTCH1 (14%). Overall, 51% of tumours were PD-L1-positive, 10.7% had high TMB, and 1.1% had dMMR/MSI-H.

Of the 108 tumours, 29 had HPV status tested (16 HPV-negative, HPV-positive). KMT2C mutations (33.3% vs 0%), CREBBP mutations (23% vs 0%), and FGF3 amplifications (30.8% vs 0%) were specific to HPV-positive tumours, while CDKN2A mutations (37.5% vs 0%) were exclusive to HPV-negative tumours. HPV-negative tumours also had a trend towards increased TP53 (62.5% vs 7.7%) and TERT promoter (76.9% vs 25%) alterations.

TMB-high status was exclusively found in the HPV-positive tumours (30.8% vs 0%), while PD-L1 and dMMR/MSI-H status were not statistically different between the 2 groups.

Based on these results, Dr Nazha concluded that “HPV-positive and HPV-negative penile squamous cell carcinoma are molecularly distinct tumours. In addition, penile squamous cell carcinomas harbour potentially targetable alterations; e.g. one third of patients in the cohort had alterations in the PIK3 pathway. The finding that TMB-high status was exclusive to patients with HPV-positive tumours requires confirmation in larger datasets and could be used for better patient stratification in immune checkpoint inhibitor clinical trials.”

1. Nazha B, et al. Comprehensive genomic profiling of penile squamous cell carcinoma and impact of HPV status on immune-checkpoint inhibition-related biomarkers. Abstract 4, ASCO GU 2022, 17–19 February.

 

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Posted on 8 April 2022