Background: Penile squamous cell carcinoma (SCC) is now categorized based on human papillomavirus (HPV) status as HPV associated (SCCa) or HPV-independent. While most HPV-independent cases are of the usual type (Usual-SCCi), the prognostic significance of this subclassification—particularly between Usual-SCCi and other SCC HPV-independent variants (Variant-SCCi)—remains unclear. Materials and Methods: Using SEER data (2000–2021), patients with penile SCC were categorized into Usual-SCCi, Variant-SCCi (verrucous, papillary, and sarcomatoid), and SCCa groups. Cancer-specific survival (CSS) was evaluated using Kaplan–Meier estimates and Cox proportional hazard regression adjusted for demographic and clinical factors, with Firth’s penalized likelihood correction applied when appropriate. Temporal trends and subtype-specific outcomes were also analyzed. Results: Among 6332 patients, 5706 (90.1%) were Usual-SCCi, 416 (6.6%) were Variant-SCCi, and 210 (3.3%) were SCCa. Overall, 5-year CSS (proportion of patients (%) [95% CI]) was the highest in Variant-SCCi (90.9% [87.8–94.0]), compared to Usual-SCCi (73.7% [72.4–75.0]) and SCCa (71.5% [63.3–80.8). Within Variant-SCCi, verrucous SCC had the most favorable outcome (94.1% [91.3–97.0]), followed by papillary (81.9% [68.2–98.4]) and sarcomatoid (63.4% [47.4–84.7]). Multivariable analysis confirmed verrucous SCC as being independently associated with significantly lower cancer-specific mortality (HR: 0.31 [95% CI, 0.20–0.45]; p < 0.001). Time-stratified analysis revealed that in the latter half of the study period, SCCa outcomes improved markedly, and no statistically significant differences in CSS were observed among the SCCa, papillary, and Usual-SCCi groups, leaving verrucous SCC as the only subtype with consistently superior survival (p < 0.001). Conclusions: The CSS of SCCa improved over time to become equivalent to those of the SCCi subtypes except for the verrucous SCCi variant, which had a significantly better CSS. Our study clearly demonstrates a temporal shift toward improved CSS in the SCCa subtype, which may be related to increased awareness following recognition as a separate entity in the WHO 2022 classification and other factors.

Purpose: To evaluate the efficacy and safety of poly (ADP-ribose) polymerase inhibitors (PARP inhibitors [PARPi]) in managing advanced prostate cancer (PCa) in patients with and without homologous recombination repair (HRR) genomic alterations (GAs). Methods: Following PRISMA 2020 guidelines, we systematically searched PubMed, Google Scholar, and ScienceDirect for studies published through January 2025. Randomized controlled trials and observational studies assessing PARPi in advanced PCa with documented HRR GA status were included. Primary outcomes included radiographic progression-free survival (rPFS) and overall survival (OS); secondary outcomes were prostate specific antigen 50 response and safety. Data were pooled using a random-effects meta-analysis model, with hazard ratios (HRs) and 95% confidence intervals (CIs) calculated for time-to-event outcomes. Results: Of 363 articles identified, 6 studies met the inclusion criteria. In patients harboring HRR GAs, PARPi significantly improved rPFS (HR 0.61; 95% CI 0.55-0.68; P < .00001) and OS (HR 0.82; 95% CI 0.69-0.96; P = .01) compared with the control. Subgroup analysis revealed that this improvement in survival was predominantly driven by BRCA1/2 alterations. Patients carrying non-BRCA HRR GAs (eg, ATM, CHECK2, CDK12, PALB2, FANCA, BRIP1, HDAC2) receiving PARPi did not have a significant improvement in their rPFS compared with the controls. Similarly, HRR-negative patients had no significant improvement in rPFS (HR 1.21; 95% CI 0.97-1.51; P = .10) or OS (HR 0.93; 95% CI 0.78-1.10; P = .40). Conclusions: PARPi confer superior efficacy over standard therapy in advanced PCa harboring BRCA1/2 GAs, underscoring the need for routine genomic profiling. In patients with other HRR alterations or HRR-negative PCa, the effect size has wide CIs, indicating the possibility of efficacy of PARPi in these patients. However, this survival does not reach statistical significance.

Purpose: Tumor location influences survival in bladder cancer, potentially due to genetic heterogeneity driven by distinct embryological origins and structural compositions. We investigate location-specific somatic gene alterations (GAs) and their potential clinical implications in muscle-invasive bladder cancer (MIBC). Methods: We explored the role of the intra-bladder tumor location in determining survival and underlying genetic alterations in MIBC patients using multiple large independent databases. We analyzed the tumor location’s impact on survival using the Surveillance, Epidemiology, and End Results (SEER) database and validated these findings using cBioPortal (CBP), which also contains gene sequencing data, enabling a comparison of GA frequency by tumor location. We investigated GA combinations to identify potential synthetic lethal (SL) combinations and co-occurrence signatures for survival prediction. Using the ROC Plotter database, we explored how significantly altered genes affect the response to immune checkpoint inhibitors (ICI). Results: An analysis of 6712 SEER and 570 CBP patients revealed significant (p < 0.001) differences in overall survival stratified by tumor location, with trigone tumors showing the worst survival. Genomic analysis identified 35 genes with location-specific alteration frequencies. Three of these genes, CDKN2A, SPTAN1, and BIRC6, were significantly predictive of ICI response, and three genes were uniquely associated with a specific location: BPTF (anterior wall), RYR1, and OBSCN (dome). Furthermore, we identified 349 SL pairs from the 35 significantly altered genes, and a co-occurrence analysis revealed two novel gene pairs associated with improved survival. Conclusions: Intra-bladder tumor location determines survival and distinct genetic profiles in MIBC. These location-specific alterations predict ICI response and identify novel synthetic lethal targets, guiding precision oncology.