AbstractBackgroundAdvanced 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 MethodsA 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).ResultsPIK3CAwas the most frequently identified potentially “actionable” GA (22%-43%), followed bymTORpathway [PTEN(0%-18%),FBXW7(7%-29%)], and cell-cycle GAs. DNA-damage response (DDR) GAs and receptor-tyrosine kinase (RTK) targeted options were uncommon.NOTCH1GAs 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.ConclusionDespite similar histology, pSCCs can differ in GAs and HPV status. Overall,PIK3CAis the most frequent potentially “targetable” GA followed bymTORand 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.