Elucidating Prostate Cancer Behaviour During Treatment via Low-pass Whole-genome Sequencing of Circulating Tumour DNA

Abstract

Cabazitaxel; Cell-free DNA; Tumour fraction

Cabazitaxel; ADN lliure de cèl·lules; Fracció tumoral

Cabazitaxel; ADN libre de células; Fracción tumoral

Background Better blood tests to elucidate the behaviour of metastatic castration-resistant prostate cancer (mCRPC) are urgently needed to drive therapeutic decisions. Plasma cell-free DNA (cfDNA) comprises normal and circulating tumour DNA (ctDNA). Low-pass whole-genome sequencing (lpWGS) of ctDNA can provide information on mCRPC behaviour. Objective To validate and clinically qualify plasma lpWGS for mCRPC. Design, setting, and participants Plasma lpWGS data were obtained for mCRPC patients consenting to optional substudies of two prospective phase 3 trials (FIRSTANA and PROSELICA). In FIRSTANA, chemotherapy-naïve patients were randomised to treatment with docetaxel (75 mg/m2) or cabazitaxel (20 or 25 mg/m2). In PROSELICA, patients previously treated with docetaxel were randomised to 20 or 25 mg/m2 cabazitaxel. lpWGS data were generated from 540 samples from 188 mCRPC patients acquired at four different time points (screening, cycle 1, cycle 4, and end of study). Outcome measurements and statistical analysis lpWGS data for ctDNA were evaluated for prognostic, response, and tumour genomic measures. Associations with response and survival data were determined for tumour fraction. Genomic biomarkers including large-scale transition (LST) scores were explored in the context of prior treatments. Results and limitations Plasma tumour fraction was prognostic for overall survival in univariable and stratified multivariable analyses (hazard ratio 1.75, 95% confidence interval 1.08–2.85; p = 0.024) and offered added value compared to existing biomarkers (C index 0.722 vs 0.709; p = 0.021). Longitudinal changes were associated with drug response. PROSELICA samples were enriched for LSTs (p = 0.029) indicating genomic instability, and this enrichment was associated with prior abiraterone and enzalutamide treatment but not taxane or radiation therapy. Higher LSTs were correlated with losses of RB1/RNASEH2B, independent of BRCA2 loss. Conclusions Plasma lpWGS of ctDNA describes CRPC behaviour, providing prognostic and response data of clinical relevance. The added prognostic value of the ctDNA fraction over established biomarkers should be studied further.

This work was supported by Prostate Cancer UK and the Movember Foundation through the London Movember Centre of Excellence (CEO13-2-002), Cancer Research UK (Centre Programme grant), Experimental Cancer Medicine Centre grant funding from Cancer Research UK and the Department of Health, and Biomedical Research Centre funding to the Royal Marsden ECMC (CRM064X). George Seed was funded by a Prostate Cancer UK PhD Studentship (grant ref. TLD-S15-006, 2016–2020) and a Prostate Cancer UK research fellowship (grant ref. TLD-PF19-005, from 2021). Semini Sumanasuriya was funded by a Prostate Cancer UK grant (ref. RIA1 5-ST2-O18). The authors are grateful for support and funding from Sanofi Aventis. The sponsor played a role in collection of the data and review and approval of the manuscript.