Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA)

Mehra, Niven; Dolling, David; Sumanasuriya, Semini; Christova, Rossitza; Pope, Lorna; Carreira, Suzanne; Seed, George; Yuan, Wei; Goodall, Jane; Hall, Emma; Flohr, Penny; Boysen, Gunther; Bianchini, Diletta; Sartor, Oliver; Eisenberger, Mario A.; Fizazi, Karim; Oudard, Stéphane; Chadjaa, Mustapha; Macé, Sandrine; Bono, Johann S. de

doi:10.1016/j.eururo.2018.02.013

Cited by 87 publications

(54 citation statements)

References 31 publications

(40 reference statements)

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“…Consequently, tumor burden as ctDNA fraction or CTC counts is strongly correlated to conventional outcome measurements [ 49 , 56 ]. Recently, simple cfDNA concentration estimates were demonstrated to prognosticate patients in a retrospective analysis of two phase III clinical trials [ 57 ]. Here, cfDNA concentration was strongly correlated to ctDNA fraction (Additional file 6 : Figure S8) suggesting that cfDNA concentration estimation is a surrogate for ctDNA fraction.…”

Section: Discussionmentioning

confidence: 99%

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

et al. 2018

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BackgroundThere are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited.MethodsA combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients.ResultsctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays.ConclusionsctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.Electronic supplementary materialThe online version of this article (10.1186/s13073-018-0595-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

et al. 2018

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“…In two phase III clinical trials, a decline in cfDNA levels was positively correlated with both radiographic PFS and OS for mCRPC patients treated with taxane-based chemotherapy [85]. Furthermore, a decline in total cfDNA was associated with treatment response [85]. In a separate study, high cfDNA levels prior to chemotherapy was associated with poor sPSA response and could act as an independent predictor of shorter OS [86].…”

Section: Cell-free Dnamentioning

confidence: 97%

“…High cfDNA concentrations prior to therapy may indicate aggressive disease. In two phase III clinical trials, a decline in cfDNA levels was positively correlated with both radiographic PFS and OS for mCRPC patients treated with taxane-based chemotherapy [85]. Furthermore, a decline in total cfDNA was associated with treatment response [85].…”

Section: Cell-free Dnamentioning

confidence: 99%

Clinical utility of emerging biomarkers in prostate cancer liquid biopsies

Boerrigter¹,

Groen

Erp³

et al. 2019

Expert Review of Molecular Diagnostics

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Introduction: Prostate cancer (PCa) is one of the most common malignancies in men and a major cause of cancer deaths among men worldwide. Prostate specific antigen (PSA) monitoring and histopathological examination of tumor biopsies remain gold standards in PCa diagnostics. These clinical parameters are not well suited for patient stratification, predicting and monitoring treatment response. On the other hand, liquid biopsies offer a unique opportunity to easily isolate tumor-derived material for longitudinal clinical assessment. Areas covered: In this review we focus on the clinical application of novel liquid biomarkers that have the potential to monitor and stratify patients in order to achieve better therapeutic effects and improve clinical outcomes. Enumeration and characterization of circulating tumor cells (CTCs), tumor-educated platelets, exosomes, and cell-free nucleic acids have been studied for their clinical utility in PCa diagnostics, prognostics, monitoring treatment response and guiding treatment choice. Expert opinion: Liquid biomarkers have high potential to be used for prognosis, monitoring treatment response and guiding treatment selection. Although there is a remarkable progress in PCa biomarker discovery, their clinical validation is very limited. Research should be focused on biomarker validation and the incorporation of these biomarkers in clinical practice.

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“…12 cfDNA has been highlighted as a new potential biomarker for overall survival (OS) in various cancer subtypes. [13][14][15] To investigate the clinical utility of cfDNA in patients referred to phase 1 trials, we conducted a pre-planned examination of baseline plasma cfDNA levels in patients participating in the Copenhagen Prospective Personalized Oncology (CoPPO) trial. 16 The aim of the study was to investigate whether additional measurements of plasma cfDNA concentration improved the prognostic value of the RMH score and thus selection of patients for phase I trials.…”

Section: Introductionmentioning

confidence: 99%

Plasma total cell-free DNA is a prognostic biomarker of overall survival in metastatic solid tumour patients

et al. 2019

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BACKGROUND: Selecting patients for early clinical trials is a challenging process and clinicians lack sufficient tools to predict overall survival (OS). Circulating cell-free DNA (cfDNA) has recently been shown to be a promising prognostic biomarker. The aim of this study was to investigate whether baseline cfDNA measurement could improve the prognostic information of the Royal Marsden Hospital (RMH) score. METHODS: Solid tumour patients referred for phase I trials were included in the Copenhagen Personalized Oncology (CoPPO) programme. Baseline characteristics were collected prospectively, including the RMH prognostic score, Eastern Cooperative Oncology Group (ECOG) performance status and concentration of cfDNA per millilitre plasma. Cox proportional hazards model was used to assess the prognostic value of baseline variables. RESULTS: Plasma cfDNA concentration was quantifiable in 302 patients out of a total of 419 included in the study period of 2 years and 5 months. The RMH score was confirmed to be associated with OS. Cell-free DNA was shown to be an independent prognostic marker of OS and improved the risk model, including RMH, performance status and age. Furthermore, both plasma cfDNA concentration and RMH score were associated with treatment allocation (p < 0.00001). CONCLUSION: Our model based on RMH score, age, ECOG performance status and cfDNA improved prediction of OS and constitutes a clinically valuable tool when selecting patients for early clinical trials. An interactive version of the prognostic model is published on http://bit.ly/phase1survival.

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Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA)

Cited by 87 publications

References 31 publications

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

Clinical utility of emerging biomarkers in prostate cancer liquid biopsies

Plasma total cell-free DNA is a prognostic biomarker of overall survival in metastatic solid tumour patients

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