Purpose: Penile squamous cell carcinoma (PSCC) is rare with limited treatment options. We report the first whole-exome sequencing (WES) analysis and compare the molecular landscape of PSCC with other squamous cell carcinomas (SCC), with the goal to identify common novel targets. Experimental Design: PSCC and matched normal penile tissues from 34 prospectively followed patients, underwent genomic WES and human papilloma virus testing. We performed tumor mutation signature estimation by two methods, first to identify APOBEC-related mutation enrichments and second to classify PSCC-enriched mutational patterns based on their association with the Catalogue of Somatic Mutations in Cancer mutation signatures. We performed an extensive genomic comparison between our PSCC cohort and other SCCs in The Cancer Genome Atlas studies. Results: We identified that most PSCC samples showed enrichment for Notch pathway (n = 24, 70.6%) alterations, comparable with head and neck squamous cell carcinoma (HNSC). PSCC mutation signatures are most comparable with HNSC signatures. PSCC samples showed an enrichment of two distinct mutational signatures, the first, associated with oncogenic activity of AID/APOBEC, and the second, associated with defective DNA mismatch repair and microsatellite instability. MP1 enrichment was positively correlated with increased tumor mutation burden (TMB; CC, 0.71; P < 0.0001) and correlated with significantly worse survival in comparison with those with the MP2 subset [HR, 10.2 (1.13–92.9); P = 0.039]. We show that a subset of PSCC (38%), with enrichment of APOBEC-related mutation signature, had significantly higher TMB and worse overall survival in comparison with non-APOBEC–enriched subset [HR, 2.41 (1.11–6.77); P = 0.042]. Conclusions: This study identified novel druggable targets and similarities in mutational signatures between PSCC and HNSC with potential clinical implications. See related commentary by McGregor and Sonpavde, p. 2375

Introduction:The choice of approach for partial nephrectomy often depends on surgical complexity. We aimed to determine if surgeon intuition was equivalent to markers of operative complexity, such as RENAL nephrometry and Mayo adhesive probability (MAP) score, in determining the surgical approach for partial nephrectomy (PN).Materials and Methods:We retrospectively identified 119 masses removed for suspected renal cell carcinoma from January 2012 to September 2014 by a single surgeon who intuitively chose treatment with one of three surgical approaches: Open PN (OPN), robotic-assisted transperitoneal PN (RATPN), or robotic-assisted retroperitoneal PN (RARPN). Clinicodemographic characteristics, pathological features, and postoperative outcomes were compared for each approach. Logistic regression was performed to identify independent predictors of open surgical resection, our primary endpoint.Results:Fifty-four tumors (45%) were resected via OPN, 40 (34%) via RATPN, and 25 (21%) via RARPN. OPN was performed in patients with more comorbidities (P = 0.02), lower baseline renal function (P < 0.01), more solitary kidneys (P < 0.01), and more multifocal disease (P < 0.01). Patients undergoing OPN had higher median nephrometry scores compared to RATPN and RARPN patients (8 vs. 7 vs. 7, respectively; P = 0.03), but MAP scores were no different among all three groups (P = 0.36). On multivariate analysis, higher nephrometry scores (odds ratio: 1.41, 95% confidence interval: 1.10-1.81; P = 0.007) were independently associated with open surgical resection. Nephrometry score was predictive of OPN (area under curve = 0.64, P = 0.01) with a score of 6.5 having the highest sensitivity and specificity (76% and 42%, respectively).Conclusions:RENAL nephrometry score was associated with surgical approach intuitively chosen by an experienced surgeon, but the presence of adherent perinephric fat did not correlate with decision-making.

Locally advanced, non-metastatic renal cell carcinoma (RCC) is conventionally managed with surgery. However, patients are at a high risk of RCC recurrence and have poor survival outcomes. An effective adjuvant systemic treatment is needed to improve on these outcomes. Targeted molecular and immune-based therapies have been investigated, or are under investigation, but their role in this setting remains unclear. Areas covered: A comprehensive search of PubMed and ClinicalTrials.gov was performed for relevant literature. The following topics pertinent to adjuvant therapy in RCC were evaluated: strategies for patient selection, cytokine-based immunotherapy, vaccine therapy, VEGF and non-VEGF targeted molecular agents, and immune checkpoint inhibitors. Expert commentary: Strong evidence for the incorporation of adjuvant therapy in high-risk RCC is lacking. Multiple targeted molecular therapies have been examined with only one approved for use. Genetic and molecular-based prognostic models are needed to determine who may benefit from adjuvant therapy. Developing adjuvant therapy strategies in the future depends on the results of important ongoing trials with immunotherapy and targeted agents.

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505 Background: PSCC is rare with limited treatment options for advanced disease. There have been no published genome-wide studies on the genetic alterations of PSCCs or on the differences between HPV (+) and HPV (−) PSCCs. We report the largest WES analysis of PSCC. Methods: We identified 34 pts diagnosed with PSCC, at MD Anderson, with primary tumors or metastatic lesions sufficient for WES. Patients, tumor and surgical characteristics were available through the MD Anderson prospective registry. Genomic DNAs from both Fresh frozen macrodissected tumors and paired-normal penile tissues were analyzed by WES. Results: Patients clinical characteristics are summarized in table 1. Eight of the most frequently mutated PSCC genes (NOTCH1 (35%), TP53 (35%), CDKN2A (24%), PIK3CA (21%), CASP8 (21%), FAT1 (18%), FBXW7 (15%) and EP300 (12%)) were significantly mutated in other SCC tumor types. Importantly, 8/8 and 5/8 genes were significant in head and neck SCC and cervical SCC, respectively, including 3 (CASP8, FXBW7, and EP300) genes that are only significant in these tumor types. TP53 mutations were associated with HPV (-) PSCC and were absent in HPV (+) SCC (P= 0.03). EP300 mutations were associated with advanced primary tumor stage. Of note we did not identify unique mutations associated with lymph node status. Conclusions: This is the largest systematic analyses of PSCC genomics uncovering the involvement of multiple cancer genes that are likely to be contributing to tumor development including; TP53, squamous differentiation, cell cycle, and chromatin regulation. PSCC are genomically similar to other HPV related SCC, and provide a therapeutic rationale for considering strategies successful in HPV related cancers. [Table: see text]