Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity. We subsequently identify and validate a novel mutational signature in post-treatment tumors consistent with known characteristics of cisplatin damage and repair. We find that post-treatment tumor heterogeneity predicts worse overall survival, and further observe alterations in cell-cycle and immune checkpoint regulation genes in post-treatment tumors. These results provide insight into the clinical and genomic dynamics of tumor evolution with cisplatin-based chemotherapy, suggest mechanisms of clinical resistance, and inform development of clinically relevant biomarkers and trials of combination therapies.
Our data support a direct role for ERCC2 mutations in driving cisplatin response, define the functional landscape of ERCC2 mutations in bladder cancer, and provide an opportunity to apply combined genomic and functional approaches to prospectively guide therapy decisions in bladder cancer.
Purpose
Lymphopenia as a likely index of poor systemic immunity is an independent predictor of inferior outcome in clear renal cell carcinoma (ccRCC). We sought to evaluate the prognostic relevance of preoperative absolute lymphocyte count (ALC) in a cohort of papillary renal cell carcinoma (PRCC) patients.
Materials & Methods
A prospectively maintained, renal cancer database was analyzed. Patients with preoperative ALC, within 3 months prior to surgery, were eligible for the study. Those with multifocal or bilateral renal tumors were excluded. Correlations between ALC and age, gender, smoking, Charlson comorbidity index (CCI), pathologic (pT) stage, PRCC subtype, and TNM stage were evaluated. Differences in overall survival (OS) & cancer-specific survival (CSS) by ALC status were assessed using the log–rank test and cumulative incident estimators, respectively. Cox proportional hazards modeling was used for multivariable analyses (MVA).
Results
192 patients met the inclusion criteria As a continuous variable, preoperative ALC was associated with higher TNM stage (p=0.001) and older age (p=0.01). As a dichotomous variable, lymphopenia (<1,300 cells/μl) was associated with higher TNM stage (p=0.003). On MVA, controlling for covariates, after a median follow up of 37.3 months, lymphopenia was associated with inferior OS (HR=2.3 [95%CI 1.2–4.3], p=0.011) and trended to significance for CSS (p=0.071). Among non-metastatic, lymphopenic patients, OS at 37.5 months was shorter compared to those with normal ALC (83% vs. 93%, p=0.0006).
Conclusions
In patients with PRCC, lymphopenia is associated with lower survival independent of TNM stage, age, and histology. ALC may provide an additional pre-operative prognostic factor.
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