Advanced Squamous Cell Carcinomas of the Pelvic and Perineal Region: A Comprehensive Genomic Profiling Study

Background Advanced pelvic squamous cell carcinoma (pSCC) is a broad category of cancers affecting different pelvic organs and usually featuring unfavorable clinical outcomes. Thus, we aimed to assess genomic differences among pSCC cases and learn whether pSCC could potentially benefit from targeted therapies and/or immunotherapy. Materials and Methods A total of 1917 advanced pSCCs, including penile (penSCC), male urethral (murthSCC), male anal (manSCC), female urethral (furthSCC), vulvar (vulSCC), cervical (crvSCC), female anal (fanSCC), and vaginal (vagSCC), underwent comprehensive genomic profiling (CGP). We used hybrid capture-based CGP to evaluate recurrent genomic alterations (GAs). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 95 loci. Programmed cell-death-ligand-1 (PD-L1) expression was determined by immunohistochemistry (IHC; Dako 22C3). Results PIK3CA was the most frequently identified potentially "actionable" GA (22%-43%), followed by mTOR pathway [PTEN (0%-18%), FBXW7 (7%-29%)], and cell-cycle GAs. DNA-damage response (DDR) GAs and receptor-tyrosine kinase (RTK) targeted options were uncommon. NOTCH1 GAs were present in >15% of penSCC and vulvSCC. TMB >= 10 mut/Mb was >15% in manSCC, fanSCC, crvSCC, and vagSCC. PD-L1 high expression was >18% in all pSCC except urthSCC, manSCC, and vagSCC. HPV-16/18 detection was highest in manSCC, fanSCC, and crvSCC. Conclusion Despite similar histology, pSCCs can differ in GAs and HPV status. Overall, PIK3CA is the most frequent potentially "targetable" GA followed by mTOR and cell cycle pathway. RTK and DDR GAs are rare in pSCC. Immunotherapy could be considered for pSCC management based on TMB and PD-L1 expression. This study assesses genomic differences among a large series of pelvic squamous cell carcinoma (pSCC) cases to determine whether pSCC could potentially benefit from targeted therapies and/or immunotherapy.