Abstract
Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (~0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castration-resistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable AR amplifications predicted reduced time on therapy, independent of therapy type (Kaplan-Meier log-rank test, chi-square = 24.9, p < 0.0001). Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based precision oncology workflow optimization.
Highlights
Clinical and commercial next-generation sequencing (NGS) based precision oncology strategies have expanded rapidly [1, 2]
As copy number alteration (CNA) can be robustly detected at substantially lower sequencing coverage than typically required for somatic mutation calling in genome-wide or targeted pan-cancer workflows, we sought to exploit genome-wide CNAs as a biomarker through a pan-cancer, rapid, inexpensive, ultra-low pass next generation sequencing (NGS) cell-free DNA (cfDNA) (PRINCe) precision oncology screening approach, which has the potential to directly inform precision oncology workflows through genomewide CNA detection and tumor content approximation (Figure 1C)
Given current precision oncology NGS testing is typically performed in patients with multiple-therapy refractory advanced cancers usually exhibiting significant disease burden [67], here we describe a pan-cancer, rapid, inexpensive, ultra-low pass NGS cfDNA (PRINCe) based precision oncology first stage “screening” approach
Summary
Clinical and commercial next-generation sequencing (NGS) based precision oncology strategies have expanded rapidly [1, 2]. Multiple experiments have leveraged similar principles using low-pass cfDNA WGS to infer somatic whole-genome copy-number profiles in patients with advanced cancer, occasionally deploying higher depth disease-specific strategies for approximating cfDNA tumor content [22, 37,38,39,40,41]. These approaches often rely on disease specificity trade-offs that limit widespread prospective implementation [39]. Initiatives comparing comprehensive tissue-based molecular profiles to those obtained from cfDNA have far been limited in size, in metastatic castration resistant prostate cancer (mCRPC) [30, 31, 40]
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