Non-Invasive Profiling of Advanced Prostate Cancer via Multi-Parametric Liquid Biopsy and Radiomic Analysis.

Gareth Morrison,Jeffrey Werbin,Alexander Cunha,Jonathan Buckley,Amir Goldkorn,Bino Varghese,Thaddeus George,Timothy Triche,David Quinn,Dejerianne Ostrow,Jeffrey Smith,Nolan Ericson,Vinay Duddalwar,Yi-Tsung Lu,Steven Y Cen

doi:10.3390/ijms23052571

Abstract

Integrating liquid biopsies of circulating tumor cells (CTCs) and cell-free DNA (cfDNA) with other minimally invasive measures may yield more comprehensive disease profiles. We evaluated the feasibility of concurrent cellular and molecular analysis of CTCs and cfDNA combined with radiomic analysis of CT scans from patients with metastatic castration-resistant PC (mCRPC). CTCs from 22 patients were enumerated, stained for PC-relevant markers, and clustered based on morphometric and immunofluorescent features using machine learning. DNA from single CTCs, matched cfDNA, and buffy coats was sequenced using a targeted amplicon cancer hotspot panel. Radiomic analysis was performed on bone metastases identified on CT scans from the same patients. CTCs were detected in 77% of patients and clustered reproducibly. cfDNA sequencing had high sensitivity (98.8%) for germline variants compared to WBC. Shared and unique somatic variants in PC-related genes were detected in cfDNA in 45% of patients (MAF > 0.1%) and in CTCs in 92% of patients (MAF > 10%). Radiomic analysis identified a signature that strongly correlated with CTC count and plasma cfDNA level. Integration of cellular, molecular, and radiomic data in a multi-parametric approach is feasible, yielding complementary profiles that may enable more comprehensive non-invasive disease modeling and prediction.

Highlights

Introduction distributed under the terms andApproval of novel therapies for treatment of advanced prostate cancer has accelerated at an unprecedented rate, improving clinical outcomes and quality of life [1–5]
In this cohort of advanced prostate cancer patients, we evaluated the feasibility of a multi-parametric, non-invasive profiling approach that integrates liquid biopsy readouts for circulating tumor cells (CTCs) enumeration, CTC Arv7 and synaptophysin (SYP) staining, genomic analysis of individual CTCs and matched plasma cell-free DNA (cfDNA), and CTC clustering analysis together with comprehensive radiomic analysis of companion bone metastasis computed tomography (CT) scans
At time of blood draw, the 22 men with advanced metastatic prostate cancer recruited to our study for liquid biopsy and radiomic analysis had a median age of 72 years and a median PSA of

Summary

Introduction

Introduction distributed under the terms andApproval of novel therapies for treatment of advanced prostate cancer has accelerated at an unprecedented rate, improving clinical outcomes and quality of life [1–5]. Biopsies have limited utility in advanced metastatic disease [6], which has driven the field to consider alternative diagnostic tools such as radiomics [7] and liquid biopsies [8]. These technologies are repeatable, non-invasive or minimally invasive and hold the promise for discovering prognostic biomarkers, with a single blood draw enabling characterization of circulating tumor cells (CTCs), cell-free DNA and RNA, germline DNA and extracellular vesicles. Treated with androgen receptor signaling inhibitors (ARSIs) has been validated prospectively in multiple clinical trials [9–11], and dynamic monitoring of CTC counts early during treatment demonstrated an association with clinical response [12–15]. Clinically validated CTC biomarkers are currently limited to androgen receptor splice variant 7 (ARv7)-positive CTC assays that identified patients who respond better to taxane chemotherapy versus ARSIs [18–21]

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