Combined Cell-free DNA and RNA Profiling of the Androgen Receptor: Clinical Utility of a Novel Multianalyte Liquid Biopsy Assay for Metastatic Prostate Cancer
| Autor: | Lisa Jane K. Graham, Manish Kohli, Heidi Fettke, Pan Du, Arun Azad, Patricia Bukczynska, Zhixin Zhao, Shidong Jia, Jianjun Yu, Maria Docanto, Edmond M. Kwan, Kate L. Mahon, Tiantian Zheng, Christine Hauser, Winston Tan, Kemin Zhou, Lisa G. Horvath, Nicole Ng, Yong Huang, Xiaohong Wang |
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| Rok vydání: | 2019 |
| Předmět: |
Oncology
Male medicine.medical_specialty Urology 030232 urology & nephrology Article 03 medical and health sciences chemistry.chemical_compound Prostate cancer 0302 clinical medicine Internal medicine medicine Enzalutamide Humans Prospective Studies Liquid biopsy Neoplasm Metastasis Prospective cohort study Aged Aged 80 and over Taxane business.industry Gene Expression Profiling Liquid Biopsy Prostatic Neoplasms Middle Aged medicine.disease Androgen receptor chemistry Cell-free fetal DNA Receptors Androgen 030220 oncology & carcinogenesis RNA Biomarker (medicine) business Cell-Free Nucleic Acids Biomarkers |
| Zdroj: | Eur Urol |
| ISSN: | 1873-7560 |
| Popis: | Background The androgen receptor (AR) remains a critical driver in metastatic castration-resistant prostate cancer (mCRPC). Profiling AR aberrations in both circulating DNA and RNA may identify key predictive and/or prognostic biomarkers in the context of contemporary systemic therapy. Objective To profile AR aberrations in circulating nucleic acids and correlate with clinical outcomes. Design, setting, and participants We prospectively enrolled 67 mCRPC patients commencing AR pathway inhibitors (ARPIs; n = 41) or taxane chemotherapy (n = 26). Using a first-in-class next-generation sequencing-based assay, we performed integrated cell-free DNA (cfDNA) and cell-free RNA (cfRNA) profiling from a single 10 ml blood tube. Outcome measurements and statistical analysis Kaplan-Meier survival estimates and multivariable Cox regression analyses were used to assess associations between clinical outcomes and the following AR aberrations: copy number variation, splice variants (AR-V7 and AR-V9) and somatic mutations. Results and limitations Cell-free DNA and cfRNA were successfully sequenced in 67 (100%) and 59 (88%) patients, respectively. Thirty-six (54%) patients had one or more AR aberrations. AR gain and cumulative number of AR aberrations were independently associated with clinical/radiographic progression-free survival (PFS; hazard ratio [HR] 3.2, p = 0.01 and HR 3.0 for 0 vs ≥2, p = 0.04) and overall survival (HR 2.8, p = 0.04 and HR 2.9 for 0 vs ≥2, p = 0.03). Notably, concurrent AR gain and AR splice variant expression (AR gain/AR-V+) was associated with shorter prostate-specific antigen PFS on both ARPIs (HR 6.7, p = 0.009) and chemotherapy (HR 3.9, p = 0.04). Importantly, key findings were validated in an independent cohort of mCRPC patients (n = 40), including shorter OS in AR gain/AR-V+ disease (HR 3.3, p = 0.02). Limitations include sample size and follow-up period. Conclusions We demonstrate the utility of a novel, multianalyte liquid biopsy assay capable of simultaneously detecting AR alterations in cfDNA and cfRNA. Concurrent profiling of cfDNA and cfRNA may provide vital insights into disease biology and resistance mechanisms in mCRPC. Patient summary In this study of men with advanced prostate cancer, DNA and RNA abnormalities in the androgen receptor detected in blood were associated with poor outcomes on available drug treatments. This information could be used to better guide treatment of advanced prostate cancer. |
| Databáze: | OpenAIRE |
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