CtDNA as a predictor of outcome in patients treated with neoadjuvant atezolizumab in muscle invasive urothelial cancer

Abstract

To explore the clinical utility of circulating tumor DNA (ctDNA) with neoadjuvant atezolizumab and radical cystectomy (RC) in muscle invasive urothelial bladder cancer (MIUC). Forty patients from a phase II of neoadjuvant atezolizumab (2 cycles) and RC study in MIUC were included (NCT02662309). Whole-exome sequencing was performed on tumor and matched normal DNA to identify tumor-specific mutations and design a personalized multiplexed PCR Next Generation Sequencing (NGS) assay (bespoke, Signatera TM ) for ctDNA detection in plasma. Samples were taken at baseline, post-atezolizumab but pre-surgery, and 1-6 months post-surgery. Response (pathological complete response (pCR) and major pathological response (mPR)) and recurrence free survival (RFS) were correlated with ctDNA status (Pos/Neg) and level. Responders are pCR and mPR patients, whereas non-responders are SD and relapse patients. The pCR rate and 2 years RFS was 21.4% and 73.5%, respectively. ctDNA positivity at baseline, post-neoadjuvant pre-surgery (PreCx), and post-surgery (PostCx) were 25/40 (63%), 14/30 (47%), and 5/36 (14%), respectively. ctDNA status was highly prognostic at all timepoints, where PostCx had an HR of 78.11 (p<0.001), and zero events were observed for ctDNA negative patients at baseline and PreCx. An association between the change in ctDNA during neoadjuvant atezolizumab treatment and patient outcome was observed (mean of -90% ctDNA change in responders versus +27% in non-responders (p=0.04)). Patients who were PDL1 positive at baseline were more likely to be ctDNA positive at baseline (p=0.01), which was not the case for post-treatment time points. For patients who were ctDNA positive at baseline, PDL1-positive patients had better response rates than PDL1-negative (35% vs. 0%), as well as superior RFS (HR=0.11, p=0.0085). Pre-treatment ctDNA positivity was enriched in SCCL (Lund) and basal squamous (TCGA) patients. Tumors from ctDNA positive patients at baseline were enriched for immune signatures and the epithelial to mesenchymal transition (EMT) signature. ctDNA dynamics across timepoints correlates with clinical outcomes, including response rates and RFS in patients treated with neoadjuvant atezolizumab in MIUC. Immune biomarkers may be relevant in these responses. ctDNA may help the development of personalized therapy in this setting in the future.