Purpose Alterations in DNA damage response and repair (DDR) genes are associated with increased mutation load and improved clinical outcomes in platinum-treated metastatic urothelial carcinoma. We examined the relationship between DDR alterations and response to PD-1/PD-L1 blockade. Methods Detailed demographic, treatment response, and long-term outcome data were collected on patients with metastatic urothelial carcinoma treated with atezolizumab or nivolumab who had targeted exon sequencing performed on pre-immunotherapy tumor specimens. Presence of DDR alterations was correlated with best objective response per Response Evaluation Criteria in Solid Tumors (RECIST) and progression-free and overall survival. Results Sixty patients with urothelial cancer enrolled in prospective trials of anti-PD-1/PD-L1 antibodies met inclusion criteria. Any DDR and known or likely deleterious DDR mutations were identified in 28 (47%) and 15 (25%) patients, respectively. The presence of any DDR alteration was associated with a higher response rate (67.9% v 18.8%; P < .001). A higher response rate was observed in patients whose tumors harbored known or likely deleterious DDR alterations (80%) compared with DDR alterations of unknown significance (54%) and in those whose tumors were wild-type for DDR genes (19%; P < .001). The correlation remained significant in multivariable analysis that included presence of visceral metastases. DDR alterations also were associated with longer progression-free and overall survival. Conclusion DDR alterations are independently associated with response to PD-1/PD-L1 blockade in patients with metastatic urothelial carcinoma. These observations warrant additional study, including prospective validation and exploration of the interaction between tumor DDR alteration and other tumor/host biomarkers of immunotherapy response.

Purpose To investigate associations between computed tomography (CT) features of clear-cell renal cell carcinoma (ccRCC) and mutations in VHL, PBRM1, SETD2, KDM5C or BAP1 genes. Materials and Methods The institutional review board approved this retrospective, hypotheses-generating study of 233 patients with ccRCC and waived the informed consent requirement. The study was HIPAA compliant. Three radiologists independently reviewed pre-treatment CT images of all ccRCC without knowledge of their genomic profile. One radiologist measured largest diameter and enhancement parameters of each ccRCC. Associations between CT features and mutations in VHL, PBRM1, SETD2, KDM5C and BAP1 genes were tested using Fisher’s exact tests. Associations between mutations and size/enhancement were assessed using independent t-tests. Interreader agreements were calculated using Fleiss’ Kappa. Results Mutation frequencies among ccRCC were: VHL, 53.2% (124/233); PBRM1, 28.8% (67/233); SETD2, 7.3% (17/233); KDM5C, 6.9% (16/233); BAP1, 6% (14/233). Mutations of VHL were significantly associated with well-defined tumor margins (p=0.013), nodular tumor enhancement (p=0.021) and gross appearance of intratumoral vascularity (p=0.018). Mutations of KDM5C and BAP1 were significantly associated with evidence of renal vein invasion (p=0.022 and 0.046, respectively). The genotype of solid ccRCC differed significantly from the one of multicystic ccRCC. While mutations of SETD2, KDM5C and BAP1 were absent in multicystic ccRCC, mutations of VHL (p=0.016) and PBRM1 (p=0.017) were significantly more common among solid ccRCC. Interreader agreements for CT feature assessments ranged from substantial to excellent (κ=0.791–0.912). Conclusion This preliminary Radiogenomics analysis of ccRCC revealed associations between CT features and underlying mutations which warrant further investigation and validation.

Purpose To investigate whether qualitative magnetic resonance (MR) features can distinguish leiomyosarcoma (LMS) from atypical leiomyoma (ALM) and assess the feasibility of texture analysis (TA). Methods This retrospective study included 41 women (ALM=22, LMS=19) imaged with MRI prior to surgery. Two readers (R1, R2) evaluated each lesion for qualitative MR features. Associations between MR features and LMS were evaluated with Fisher's exact test. Accuracy measures were calculated for the four most significant features. TA was performed for 24 patients (ALM=14, LMS=10) with uniform imaging following lesion segmentation on axial T2-weighted images. Texture features were pre-selected using Wilcoxon signed-rank test with Bonferroni correction and analyzed with unsupervised clustering to separate LMS from ALM. Results Four qualitative MR features most strongly associated with LMS were nodular borders, haemorrhage, “T2 dark” area(s), and central unenhanced area(s) (p≤0.0001 each feature/reader). The highest sensitivity [1.00 (95%CI:0.82-1.00)/0.95 (95%CI: 0.74-1.00)] and specificity [0.95 (95%CI:0.77-1.00)/1.00 (95%CI:0.85-1.00)] were achieved for R1/R2, respectively, when a lesion had ≥3 of these four features. Sixteen texture features differed significantly between LMS and ALM (p-values: <0.001-0.036). Unsupervised clustering achieved accuracy of 0.75 (sensitivity: 0.70; specificity: 0.79). Conclusions Combination of ≥3 qualitative MR features accurately distinguished LMS from ALM. TA was feasible.

PURPOSE Urothelial cancers (UCs) have a substantial hereditary component, but, other than their association with Lynch syndrome, the contribution of genetic risk factors to UC pathogenesis has not been systematically defined. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in patients with UC and identify associated clinical factors. PATIENTS AND METHODS Overall, 586 patients with UC underwent prospective, matched tumor-normal DNA sequencing. Seventy-seven genes associated with cancer predisposition were analyzed; allele frequencies were compared with publicly available database. RESULTS P/LP germline variants were identified in 80 (14%) of 586 individuals with UC. The most common P/LP variants in high- or moderate-penetrance genes were BRCA2 (n = 9; 1.5%), MSH2 (n = 8; 1.4%), BRCA1 (n = 8; 1.4%), CHEK2 (n = 6; 1.0%), ERCC3 (n = 4; 0.7%), and NBN and RAD50 (n = 3; 0.5% each). Sixty-six patients (83%) had germline P/LP variants in DNA-damage repair (DDR) genes, of which 28 (42%) had biallelic inactivation. Patients with P/LP variants were more commonly diagnosed at an early age (22% v 6% in those without variants; P = .01). BRCA2 and MSH2 were significantly associated with an increased risk for UC (odds ratio, 3.7 [ P = .004] and 4.6 [ P = .001], respectively). Current clinical guidelines for referral for genetic testing failed to identify 6 (26%) patients with high-penetrance variants. CONCLUSION Clinically significant P/LP germline variants in DDR genes frequently are present in patients with advanced UC. The presence of DDR germline variants could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. Family history–based criteria to identify patients with hereditary UC susceptibility are insensitive. Broader germline testing in UC, particularly in those of young ages, should be considered.