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

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

Research output: Contribution to journalArticle

Abstract

Background: Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment. Objective: To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy. Design, setting, and participants: Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Patients received docetaxel (75mg/m2) or cabazitaxel (20 or 25mg/m2) as first-line chemotherapy (FIRSTANA), and cabazitaxel (20 or 25mg/m2) as second-line chemotherapy (PROSELICA). Outcome measurements and statistical analysis: Associations between cfDNA concentration and prostate-specific antigen (PSA) response were tested using logistic regression models. Survival was estimated using Kaplan-Meier methods for cfDNA concentration grouped by quartile. Cox proportional hazard models, within each study, tested for associations with radiological progression-free survival (rPFS) and overall survival (OS), with multivariable analyses adjusting for baseline prognostic variables. Two-stage individual patient meta-analysis combined results for cfDNA concentrations for both studies. Results and limitations: In 2502 samples, baseline log10 cfDNA concentration correlated with known prognostic factors, shorter rPFS (hazard ratio [HR]=1.54; 95% confidence interval [CI]: 1.15-2.08; p =0.004), and shorter OS on taxane therapy (HR=1.53; 95% CI: 1.18-1.97; p =0.001). In multivariable analyses, baseline cfDNA concentration was an independent prognostic variable for rPFS and OS in both first- and second-line chemotherapy settings. Patients with a PSA response experienced a decline in log10 cfDNA concentrations during the first four cycles of treatment (per cycle -0.03; 95% CI: -0.044 to -0.009; p =0.003). Study limitations included the fact that blood sample collection was not mandated for all patients and the inability to specifically quantitate tumour-derived cfDNA fraction in cfDNA. Conclusions: We report that changes in cfDNA concentrations correlate with both rPFS and OS in patients receiving first- and second-line taxane therapy, and may serve as independent prognostic biomarkers of response to taxanes. Patient summary: In the past decade, several new therapies have been introduced for men diagnosed with metastatic prostate cancer. Although metastatic prostate cancer remains incurable, these novel agents have extended patient survival and improved their quality of life in comparison with the last decade. To further optimise treatment allocation and individualise patient care, better tests (biomarkers) are needed to guide the delivery of improved and more precise care. In this report, we assessed cell-free DNA in over 2500 blood samples from men with prostate cancer who were recruited to two separate international studies and received taxane chemotherapy. We quantified the concentration of cell-free DNA fragments in blood plasma, which partly originates from tumour. We identified that higher concentrations of circulating cell-free DNA fragments, prior to starting taxane chemotherapy, can be used to identify patients with aggressive prostate cancer. A decline in cell-free DNA concentration during the first 3-9 wk after initiation of taxane therapy was seen in patients deriving benefit from taxane chemotherapy. These results identified circulating cell-free DNA as a new biomarker of aggressive disease in metastatic prostate cancer and imply that the study of cell-free DNA has clinical utility, supporting further efforts to develop blood-based tests on this circulating tumour-derived DNA. Plasma cell-free DNA comprises fragmented nucleic acids from normal and tumour cells, and has utility as a biomarker of radiological progression-free and overall survival from first- and second-line treatment with taxane in advanced prostate cancer.

Original languageEnglish (US)
JournalEuropean Urology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Castration
Plasma Cells
Prostatic Neoplasms
DNA
Therapeutics
Biomarkers
Disease-Free Survival
Drug Therapy
Survival
taxane
docetaxel
Confidence Intervals
Prostate-Specific Antigen
Neoplasms
Logistic Models
Taxoids
Phase III Clinical Trials
Hematologic Tests

Keywords

  • Cabazitaxel
  • Cell-free DNA
  • Circulating cell-free DNA
  • Docetaxel
  • FIRSTANA
  • PROSELICA
  • Taxane chemotherapy

ASJC Scopus subject areas

  • Urology

Cite this

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; Fizazi, Karim; Oudard, Stephane; Chadjaa, Mustapha; Macé, Sandrine; de Bono, Johann S.

In: European Urology, 01.01.2018.

Research output: Contribution to journalArticle

Mehra, N, Dolling, D, Sumanasuriya, S, Christova, R, Pope, L, Carreira, S, Seed, G, Yuan, W, Goodall, J, Hall, E, Flohr, P, Boysen, G, Bianchini, D, Sartor, O, Eisenberger, M, Fizazi, K, Oudard, S, Chadjaa, M, Macé, S & de Bono, JS 2018, 'Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA)', European Urology. https://doi.org/10.1016/j.eururo.2018.02.013
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 ; Fizazi, Karim ; Oudard, Stephane ; Chadjaa, Mustapha ; Macé, Sandrine ; de Bono, Johann S. / Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA). In: European Urology. 2018.
@article{7e7391a67d2644908c127d08a0606c46,
title = "Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA)",
abstract = "Background: Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment. Objective: To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy. Design, setting, and participants: Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Patients received docetaxel (75mg/m2) or cabazitaxel (20 or 25mg/m2) as first-line chemotherapy (FIRSTANA), and cabazitaxel (20 or 25mg/m2) as second-line chemotherapy (PROSELICA). Outcome measurements and statistical analysis: Associations between cfDNA concentration and prostate-specific antigen (PSA) response were tested using logistic regression models. Survival was estimated using Kaplan-Meier methods for cfDNA concentration grouped by quartile. Cox proportional hazard models, within each study, tested for associations with radiological progression-free survival (rPFS) and overall survival (OS), with multivariable analyses adjusting for baseline prognostic variables. Two-stage individual patient meta-analysis combined results for cfDNA concentrations for both studies. Results and limitations: In 2502 samples, baseline log10 cfDNA concentration correlated with known prognostic factors, shorter rPFS (hazard ratio [HR]=1.54; 95{\%} confidence interval [CI]: 1.15-2.08; p =0.004), and shorter OS on taxane therapy (HR=1.53; 95{\%} CI: 1.18-1.97; p =0.001). In multivariable analyses, baseline cfDNA concentration was an independent prognostic variable for rPFS and OS in both first- and second-line chemotherapy settings. Patients with a PSA response experienced a decline in log10 cfDNA concentrations during the first four cycles of treatment (per cycle -0.03; 95{\%} CI: -0.044 to -0.009; p =0.003). Study limitations included the fact that blood sample collection was not mandated for all patients and the inability to specifically quantitate tumour-derived cfDNA fraction in cfDNA. Conclusions: We report that changes in cfDNA concentrations correlate with both rPFS and OS in patients receiving first- and second-line taxane therapy, and may serve as independent prognostic biomarkers of response to taxanes. Patient summary: In the past decade, several new therapies have been introduced for men diagnosed with metastatic prostate cancer. Although metastatic prostate cancer remains incurable, these novel agents have extended patient survival and improved their quality of life in comparison with the last decade. To further optimise treatment allocation and individualise patient care, better tests (biomarkers) are needed to guide the delivery of improved and more precise care. In this report, we assessed cell-free DNA in over 2500 blood samples from men with prostate cancer who were recruited to two separate international studies and received taxane chemotherapy. We quantified the concentration of cell-free DNA fragments in blood plasma, which partly originates from tumour. We identified that higher concentrations of circulating cell-free DNA fragments, prior to starting taxane chemotherapy, can be used to identify patients with aggressive prostate cancer. A decline in cell-free DNA concentration during the first 3-9 wk after initiation of taxane therapy was seen in patients deriving benefit from taxane chemotherapy. These results identified circulating cell-free DNA as a new biomarker of aggressive disease in metastatic prostate cancer and imply that the study of cell-free DNA has clinical utility, supporting further efforts to develop blood-based tests on this circulating tumour-derived DNA. Plasma cell-free DNA comprises fragmented nucleic acids from normal and tumour cells, and has utility as a biomarker of radiological progression-free and overall survival from first- and second-line treatment with taxane in advanced prostate cancer.",
keywords = "Cabazitaxel, Cell-free DNA, Circulating cell-free DNA, Docetaxel, FIRSTANA, PROSELICA, Taxane chemotherapy",
author = "Niven Mehra and David Dolling and Semini Sumanasuriya and Rossitza Christova and Lorna Pope and Suzanne Carreira and George Seed and Wei Yuan and Jane Goodall and Emma Hall and Penny Flohr and Gunther Boysen and Diletta Bianchini and Oliver Sartor and Mario Eisenberger and Karim Fizazi and Stephane Oudard and Mustapha Chadjaa and Sandrine Mac{\'e} and {de Bono}, {Johann S.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.eururo.2018.02.013",
language = "English (US)",
journal = "European Urology",
issn = "0302-2838",
publisher = "Elsevier",

}

TY - JOUR

T1 - Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA)

AU - Mehra, Niven

AU - Dolling, David

AU - Sumanasuriya, Semini

AU - Christova, Rossitza

AU - Pope, Lorna

AU - Carreira, Suzanne

AU - Seed, George

AU - Yuan, Wei

AU - Goodall, Jane

AU - Hall, Emma

AU - Flohr, Penny

AU - Boysen, Gunther

AU - Bianchini, Diletta

AU - Sartor, Oliver

AU - Eisenberger, Mario

AU - Fizazi, Karim

AU - Oudard, Stephane

AU - Chadjaa, Mustapha

AU - Macé, Sandrine

AU - de Bono, Johann S.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment. Objective: To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy. Design, setting, and participants: Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Patients received docetaxel (75mg/m2) or cabazitaxel (20 or 25mg/m2) as first-line chemotherapy (FIRSTANA), and cabazitaxel (20 or 25mg/m2) as second-line chemotherapy (PROSELICA). Outcome measurements and statistical analysis: Associations between cfDNA concentration and prostate-specific antigen (PSA) response were tested using logistic regression models. Survival was estimated using Kaplan-Meier methods for cfDNA concentration grouped by quartile. Cox proportional hazard models, within each study, tested for associations with radiological progression-free survival (rPFS) and overall survival (OS), with multivariable analyses adjusting for baseline prognostic variables. Two-stage individual patient meta-analysis combined results for cfDNA concentrations for both studies. Results and limitations: In 2502 samples, baseline log10 cfDNA concentration correlated with known prognostic factors, shorter rPFS (hazard ratio [HR]=1.54; 95% confidence interval [CI]: 1.15-2.08; p =0.004), and shorter OS on taxane therapy (HR=1.53; 95% CI: 1.18-1.97; p =0.001). In multivariable analyses, baseline cfDNA concentration was an independent prognostic variable for rPFS and OS in both first- and second-line chemotherapy settings. Patients with a PSA response experienced a decline in log10 cfDNA concentrations during the first four cycles of treatment (per cycle -0.03; 95% CI: -0.044 to -0.009; p =0.003). Study limitations included the fact that blood sample collection was not mandated for all patients and the inability to specifically quantitate tumour-derived cfDNA fraction in cfDNA. Conclusions: We report that changes in cfDNA concentrations correlate with both rPFS and OS in patients receiving first- and second-line taxane therapy, and may serve as independent prognostic biomarkers of response to taxanes. Patient summary: In the past decade, several new therapies have been introduced for men diagnosed with metastatic prostate cancer. Although metastatic prostate cancer remains incurable, these novel agents have extended patient survival and improved their quality of life in comparison with the last decade. To further optimise treatment allocation and individualise patient care, better tests (biomarkers) are needed to guide the delivery of improved and more precise care. In this report, we assessed cell-free DNA in over 2500 blood samples from men with prostate cancer who were recruited to two separate international studies and received taxane chemotherapy. We quantified the concentration of cell-free DNA fragments in blood plasma, which partly originates from tumour. We identified that higher concentrations of circulating cell-free DNA fragments, prior to starting taxane chemotherapy, can be used to identify patients with aggressive prostate cancer. A decline in cell-free DNA concentration during the first 3-9 wk after initiation of taxane therapy was seen in patients deriving benefit from taxane chemotherapy. These results identified circulating cell-free DNA as a new biomarker of aggressive disease in metastatic prostate cancer and imply that the study of cell-free DNA has clinical utility, supporting further efforts to develop blood-based tests on this circulating tumour-derived DNA. Plasma cell-free DNA comprises fragmented nucleic acids from normal and tumour cells, and has utility as a biomarker of radiological progression-free and overall survival from first- and second-line treatment with taxane in advanced prostate cancer.

AB - Background: Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment. Objective: To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy. Design, setting, and participants: Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Patients received docetaxel (75mg/m2) or cabazitaxel (20 or 25mg/m2) as first-line chemotherapy (FIRSTANA), and cabazitaxel (20 or 25mg/m2) as second-line chemotherapy (PROSELICA). Outcome measurements and statistical analysis: Associations between cfDNA concentration and prostate-specific antigen (PSA) response were tested using logistic regression models. Survival was estimated using Kaplan-Meier methods for cfDNA concentration grouped by quartile. Cox proportional hazard models, within each study, tested for associations with radiological progression-free survival (rPFS) and overall survival (OS), with multivariable analyses adjusting for baseline prognostic variables. Two-stage individual patient meta-analysis combined results for cfDNA concentrations for both studies. Results and limitations: In 2502 samples, baseline log10 cfDNA concentration correlated with known prognostic factors, shorter rPFS (hazard ratio [HR]=1.54; 95% confidence interval [CI]: 1.15-2.08; p =0.004), and shorter OS on taxane therapy (HR=1.53; 95% CI: 1.18-1.97; p =0.001). In multivariable analyses, baseline cfDNA concentration was an independent prognostic variable for rPFS and OS in both first- and second-line chemotherapy settings. Patients with a PSA response experienced a decline in log10 cfDNA concentrations during the first four cycles of treatment (per cycle -0.03; 95% CI: -0.044 to -0.009; p =0.003). Study limitations included the fact that blood sample collection was not mandated for all patients and the inability to specifically quantitate tumour-derived cfDNA fraction in cfDNA. Conclusions: We report that changes in cfDNA concentrations correlate with both rPFS and OS in patients receiving first- and second-line taxane therapy, and may serve as independent prognostic biomarkers of response to taxanes. Patient summary: In the past decade, several new therapies have been introduced for men diagnosed with metastatic prostate cancer. Although metastatic prostate cancer remains incurable, these novel agents have extended patient survival and improved their quality of life in comparison with the last decade. To further optimise treatment allocation and individualise patient care, better tests (biomarkers) are needed to guide the delivery of improved and more precise care. In this report, we assessed cell-free DNA in over 2500 blood samples from men with prostate cancer who were recruited to two separate international studies and received taxane chemotherapy. We quantified the concentration of cell-free DNA fragments in blood plasma, which partly originates from tumour. We identified that higher concentrations of circulating cell-free DNA fragments, prior to starting taxane chemotherapy, can be used to identify patients with aggressive prostate cancer. A decline in cell-free DNA concentration during the first 3-9 wk after initiation of taxane therapy was seen in patients deriving benefit from taxane chemotherapy. These results identified circulating cell-free DNA as a new biomarker of aggressive disease in metastatic prostate cancer and imply that the study of cell-free DNA has clinical utility, supporting further efforts to develop blood-based tests on this circulating tumour-derived DNA. Plasma cell-free DNA comprises fragmented nucleic acids from normal and tumour cells, and has utility as a biomarker of radiological progression-free and overall survival from first- and second-line treatment with taxane in advanced prostate cancer.

KW - Cabazitaxel

KW - Cell-free DNA

KW - Circulating cell-free DNA

KW - Docetaxel

KW - FIRSTANA

KW - PROSELICA

KW - Taxane chemotherapy

UR - http://www.scopus.com/inward/record.url?scp=85042491133&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042491133&partnerID=8YFLogxK

U2 - 10.1016/j.eururo.2018.02.013

DO - 10.1016/j.eururo.2018.02.013

M3 - Article

C2 - 29500065

AN - SCOPUS:85042491133

JO - European Urology

JF - European Urology

SN - 0302-2838

ER -