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.

The baseline neutrophil-to-lymphocyte ratio is a validated marker for a poor prognosis. Multiple assessments of the pre-treatment neutrophil-to-lymphocyte ratio might be required. Reduction in the neutrophil-to-lymphocyte ratio during chemotherapy may be associated with improved survival.

2062 Background: GBM is the most common and aggressive primary brain tumor. The neutrophil to lymphocyte ratio (NLR) gives a measure of systemic inflammatory response and lymphopenia, both of which are poor prognostic factors in many malignancies. No published study has assessed the prognostic impact of NLR in GBM. Methods: Patients treated for GBM at our regional referral centre with assessable complete blood count at first presentation (prior to corticosteroid therapy or surgery) were identified. Medical notes were reviewed to extract demographic and treatment data. Survival curves were estimated via Kaplan-Meier method and compared via log-rank method. Multivariate analysis was performed via Cox proportional hazards regression modelling. Results: A total of 86 patients were identified, of which 65(76%) were male. Median age at diagnosis was 58 years (range: 18–76). At the time of analysis all patients still alive had ≥ 2 years follow-up. Median overall survival (OS) was 9.3 months (range: 1-82). 57% completed the standard adjuvant Stupp protocol and 43% discontinued early due to disease progression or treatment toxicity. Median OS was 11.2 months in patients with NLR<4 and 7.5 months in patients with NLR>4 (HR 0.59, p=.04). Other significant prognostic factors based on univariate analysis were consistent with published data (Table). After correcting for known prognostic factors NLR remained a significant predictor of survival (Table). Conclusions: Recent advances in immunotherapy have highlighted the importance of the immune system in the treatment and prognosis of cancer patients. Many GBM patients are on corticosteroids for a significant proportion of their disease course which may abrogate the effects of host immunity on outcome. Nevertheless, we have shown that NLR at diagnosis is an independent predictor of survival in GBM patients. Investigation of therapies which harness the immune response are warranted in this disease. [Table: see text]

4509 Background: Somatic DDR alts are associated with increased mutation load (ML) and improved clinical outcomes for platinum-treated mUC (Teo et al, CCR 2017). We examined the relationship between DDR alts and response to PD1/PDL1 blockade. Methods: mUC pts enrolled to phase 2 trials of atezolizumab or nivolumab who had targeted exon sequencing of 410 genes (MSK-IMPACT) were identified. Pts were dichotomized based on presence of alts in a panel of 34 DDR genes. Analyses were performed based on: (1) any DDR alts and (2) deleterious DDR alts (frameshift, splice site, nonsense or Hotspot point mutations). Study endpoint was overall response (OR) per RECIST. ML was defined as total number of nonsynonymous mutations by MSK-IMPACT. Fisher exact, Wilcoxon rank sum, and stratified logistic regression were used. Results: Fifty two pts were identified (atezo: n=18, nivo: n=34). Median age was 67 years (range: 32 – 84) and majority (44) was male. Median platinum-free interval was 10.2 months (range: 0.3 – 150.4). DDR and deleterious DDR were seen in 25 (48.1%) and 14 (26.9%) pts (including 2 MSI and 1 POLE). OR rate was 46.2%. Responses were associated with DDR alts but not with age, gender, treatment, platinum-free interval or ML (table). In univariate logistic regression model, DDR status was associated with OR (p<.001) while a trend was observed with ML as a continuous variable (p=.051). While DDR alts were associated with higher ML (all: p=.001, deleterious: p=.004), the effect of DDR alts on OR remained significant regardless of ML (>median: p=.027; ≤median: p=.023), indicating that the effect of DDR was independent of ML. Conclusions: DDR alts appeared to be associated with OR to PD1/PDL1 blockade and should be integrated into future validation efforts along with other potential predictors of response. [Table: see text]

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