Circulating Tumor DNA and Response to Cisplatin-based Chemotherapy in Patients with Metastatic Urothelial Carcinoma Enrolled in CALGB 90601 (Alliance).

BACKGROUND AND OBJECTIVE: Cisplatin-based chemotherapy has been a cornerstone of therapy for advanced/metastatic urothelial cancer (mUC). However, no genomic characteristics have been validated as prognostic biomarkers for this therapy. We sought to identify prognostic biomarkers using plasma cell-free (cf)DNA collected in a phase 3 cooperative group trial. METHODS: We analyzed pretreatment cfDNA from a cohort nested in CALGB 90601 (Alliance), a first-line trial of gemcitabine/cisplatin with bevacizumab or placebo in mUC. We examined associations between cfDNA features and overall survival (OS), progression-free survival (PFS), and treatment response. KEY FINDINGS AND LIMITATIONS: Baseline cfDNA was sequenced from 201 patients with mUC. There was no statistically significant association between alterations in DNA damage response (DDR) genes and response to cisplatin-based chemotherapy (12/24; 50% response rate in DDR+ vs 60/145; 41% response rate in DDR-; p = 0.4), OS (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.50-1.22; p = 0.3) or PFS (HR 0.77, 95% CI 0.48-1.22; p = 0.3), although the DDR analysis was underpowered owing to the low frequency of DDR gene alterations. Higher variant allele frequency (VAF) in circulating tumor (ct)DNA was associated with shorter OS (HR 2.51, 95% CI 1.26-5.00; p = 0.009) and PFS (HR 2.18, 95% CI 1.02-4.67; p = 0.045). Shorter OS was associated with cfDNA alterations in TERT (HR 1.59, 95% CI 1.15-2.19; p = 0.005), PIK3CA (HR 1.91, 95% CI 1.20-3.04; p = 0.006), and ERBB2 (HR 1.64, 95% CI 1.08-2.49; p = 0.019). CONCLUSIONS AND CLINICAL IMPLICATIONS: Among patients with mUC treated with cisplatin-based chemotherapy, high pretreatment VAF in ctDNA and alterations in the TERT promoter, PIK3CA, and ERBB2 were associated with poor prognosis. PATIENT SUMMARY: We looked at the link between tumor DNA present in blood and outcomes after chemotherapy for patients with advanced bladder cancer. Higher amounts of tumor DNA in blood and mutations in specific cancer genes were linked to worse survival. The results may help in the design of new studies to improve survival for patients with advanced bladder cancer.This trial is registered on ClinicalTrials.gov as NCT00942331.

Duke Scholars

Author Susan Halabi Biostatistics & Bioinformatics, Division of Biostatistics