Comparative Genomic Profiling of Refractory/Metastatic Penile and non-Penile Cutaneous Squamous Cell Carcinoma: Implications for Selection of Systemic Therapy

Metastatic penile squamous cell carcinoma (mPSCC) is an aggressive malignancy with limited treatment options. We compared the potential therapy impacting genomic alterations (GA) between mPSCC and non-penile cutaneous metastatic squamous cell carcinoma (mCSCC).

DNA was extracted from 40 microns of FFPE samples from 78 cases of mPSCC and 338 mCSCC. Comprehensive genomic profiling (CGP), was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of >500X. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci.

Potential targeted therapy opportunities in mPSCC included alterations in MTOR pathway (NF1 GA in 7% and PTEN GA in 4%) and DNA repair pathway (BRCA2 and ATM GA, each in 7%) and tyrosine kinase (EGFR GA in 6%; FGFR3 and ERBB2 GA each in 4%). TMB was significantly higher in the predominantly UV light exposed mSCC than mPSCC, making mSCC potentially more responsive to immunotherapies than mPSCC. MSI-High status was extremely rare for both mPSCC and mCSCC. CD274 (PD-L1) amplification was also rare in both tumor types.

mPSCC is a unique subtype of SCC with distinctive genomic features that contrast with those identified in mCSCC of non-penile UV light exposed skin. Although not rich in predictors for response to immunotherapy (low TMB and MSI low), more than one quarter of mPSCC may potentially benefit from existing and available therapies targeting MTOR, DNA repair, and Tyrosine Kinase pathways.

The Journal of urology. 2018 Oct 03 [Epub ahead of print]

J M Jacob, E K Ferry, L M Gay, J A Elvin, J Vergilio, S Ramkissoon, E Severson, A Necchi, J K Killian, S M Ali, A B Schrock, Nick W Liu, J Chung, V A Miller, P J Stephens, A Welsh, R J Corona, J S Ross, G Bratslavsky