Prognostic association of plasma cell-free DNA-based androgen receptor amplification and circulating tumor cells in pre-chemotherapy metastatic castration-resistant prostate cancer patients

Manish Kohli, Jian Li, Meijun Du, David W. Hillman, Scott M. Dehm, Winston Tan, Rachel Carlson, Michael B. Campion, Liguo Wang, Liewei M Wang, Huijuan Zhang, Peng Zhang, Deepak Kilari, Chiang Ching Huang, Liang Wang

Research output: Contribution to journalArticle

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Abstract

Background: The prognostic significance of plasma cell-free DNA (cfDNA) androgen receptor amplification (ARamp) in metastatic castration-resistant prostate cancer (mCRPC) compared with circulating tumor cell (CTC) counts is not known. Methods: As part of correlative aims of a prospective study in mCRPC, concurrent and serial collections of plasma and CTCs were performed. Specimen collections were performed at baseline after progression on androgen deprivation therapy and then 12 weeks later. QuantStudio3D digital PCR system was used to determine plasma cfDNA AR copy number variations and Cell search assay for enumerating CTC counts. Association of baseline cfDNA ARamp status/CTC counts with overall survival (OS) (primary goal) was evaluated using Kaplan–Meier method and log-rank test (p ≤ 0.05 for significance) and receiver operator curves (ROCs) for ARamp status and CTC counts ≥5. A multivariate analysis was performed using Cox regression models that included ARamp, CTC counts, and other clinical factors. Results: ARamp was detected in 19/70 patients at baseline. At the time of analysis, 28/70 patients had died (median follow-up 806 days; interquartile range: 535–966). ARamp was associated with poor OS (2-year OS of 35% in ARamp vs. 71% in non-ARamp; log-rank p value ≤0.0001). Baseline CTC counts ≥5 (vs. <5) was also associated with poor survival (2-year OS of 44 vs. 74%; log-rank p = 0.001). ROC analysis demonstrated area under the curve of 0.66 for ARamp-based prognosis and 0.68 for CTC count-based prognosis (p = 0.84 for difference). The best two variables included for multivariable analysis were ARamp and CTC counts ≥5; however, the two-factor model was not significantly better than using ARamp alone for predicting survival (hazard ratio = 5.25; p = 0.0002). Conclusions: CTCs and plasma cfDNA ARamp were observed to have equal prognostic value in mCRPC. Larger cohorts that incorporate molecular and clinical factors are needed to further refine prognosis in CRPC.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalProstate Cancer and Prostatic Diseases
DOIs
StateAccepted/In press - Jun 1 2018

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Circulating Neoplastic Cells
Castration
Androgen Receptors
Plasma Cells
Prostatic Neoplasms
Drug Therapy
DNA
Cell Count
Survival
DNA Copy Number Variations
Specimen Handling
Proportional Hazards Models
Androgens
Area Under Curve
Multivariate Analysis

ASJC Scopus subject areas

  • Oncology
  • Urology
  • Cancer Research

Cite this

Prognostic association of plasma cell-free DNA-based androgen receptor amplification and circulating tumor cells in pre-chemotherapy metastatic castration-resistant prostate cancer patients. / Kohli, Manish; Li, Jian; Du, Meijun; Hillman, David W.; Dehm, Scott M.; Tan, Winston; Carlson, Rachel; Campion, Michael B.; Wang, Liguo; Wang, Liewei M; Zhang, Huijuan; Zhang, Peng; Kilari, Deepak; Huang, Chiang Ching; Wang, Liang.

In: Prostate Cancer and Prostatic Diseases, 01.06.2018, p. 1-8.

Research output: Contribution to journalArticle

Kohli, Manish ; Li, Jian ; Du, Meijun ; Hillman, David W. ; Dehm, Scott M. ; Tan, Winston ; Carlson, Rachel ; Campion, Michael B. ; Wang, Liguo ; Wang, Liewei M ; Zhang, Huijuan ; Zhang, Peng ; Kilari, Deepak ; Huang, Chiang Ching ; Wang, Liang. / Prognostic association of plasma cell-free DNA-based androgen receptor amplification and circulating tumor cells in pre-chemotherapy metastatic castration-resistant prostate cancer patients. In: Prostate Cancer and Prostatic Diseases. 2018 ; pp. 1-8.
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title = "Prognostic association of plasma cell-free DNA-based androgen receptor amplification and circulating tumor cells in pre-chemotherapy metastatic castration-resistant prostate cancer patients",
abstract = "Background: The prognostic significance of plasma cell-free DNA (cfDNA) androgen receptor amplification (ARamp) in metastatic castration-resistant prostate cancer (mCRPC) compared with circulating tumor cell (CTC) counts is not known. Methods: As part of correlative aims of a prospective study in mCRPC, concurrent and serial collections of plasma and CTCs were performed. Specimen collections were performed at baseline after progression on androgen deprivation therapy and then 12 weeks later. QuantStudio3D digital PCR system was used to determine plasma cfDNA AR copy number variations and Cell search assay for enumerating CTC counts. Association of baseline cfDNA ARamp status/CTC counts with overall survival (OS) (primary goal) was evaluated using Kaplan–Meier method and log-rank test (p ≤ 0.05 for significance) and receiver operator curves (ROCs) for ARamp status and CTC counts ≥5. A multivariate analysis was performed using Cox regression models that included ARamp, CTC counts, and other clinical factors. Results: ARamp was detected in 19/70 patients at baseline. At the time of analysis, 28/70 patients had died (median follow-up 806 days; interquartile range: 535–966). ARamp was associated with poor OS (2-year OS of 35{\%} in ARamp vs. 71{\%} in non-ARamp; log-rank p value ≤0.0001). Baseline CTC counts ≥5 (vs. <5) was also associated with poor survival (2-year OS of 44 vs. 74{\%}; log-rank p = 0.001). ROC analysis demonstrated area under the curve of 0.66 for ARamp-based prognosis and 0.68 for CTC count-based prognosis (p = 0.84 for difference). The best two variables included for multivariable analysis were ARamp and CTC counts ≥5; however, the two-factor model was not significantly better than using ARamp alone for predicting survival (hazard ratio = 5.25; p = 0.0002). Conclusions: CTCs and plasma cfDNA ARamp were observed to have equal prognostic value in mCRPC. Larger cohorts that incorporate molecular and clinical factors are needed to further refine prognosis in CRPC.",
author = "Manish Kohli and Jian Li and Meijun Du and Hillman, {David W.} and Dehm, {Scott M.} and Winston Tan and Rachel Carlson and Campion, {Michael B.} and Liguo Wang and Wang, {Liewei M} and Huijuan Zhang and Peng Zhang and Deepak Kilari and Huang, {Chiang Ching} and Liang Wang",
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T1 - Prognostic association of plasma cell-free DNA-based androgen receptor amplification and circulating tumor cells in pre-chemotherapy metastatic castration-resistant prostate cancer patients

AU - Kohli, Manish

AU - Li, Jian

AU - Du, Meijun

AU - Hillman, David W.

AU - Dehm, Scott M.

AU - Tan, Winston

AU - Carlson, Rachel

AU - Campion, Michael B.

AU - Wang, Liguo

AU - Wang, Liewei M

AU - Zhang, Huijuan

AU - Zhang, Peng

AU - Kilari, Deepak

AU - Huang, Chiang Ching

AU - Wang, Liang

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Background: The prognostic significance of plasma cell-free DNA (cfDNA) androgen receptor amplification (ARamp) in metastatic castration-resistant prostate cancer (mCRPC) compared with circulating tumor cell (CTC) counts is not known. Methods: As part of correlative aims of a prospective study in mCRPC, concurrent and serial collections of plasma and CTCs were performed. Specimen collections were performed at baseline after progression on androgen deprivation therapy and then 12 weeks later. QuantStudio3D digital PCR system was used to determine plasma cfDNA AR copy number variations and Cell search assay for enumerating CTC counts. Association of baseline cfDNA ARamp status/CTC counts with overall survival (OS) (primary goal) was evaluated using Kaplan–Meier method and log-rank test (p ≤ 0.05 for significance) and receiver operator curves (ROCs) for ARamp status and CTC counts ≥5. A multivariate analysis was performed using Cox regression models that included ARamp, CTC counts, and other clinical factors. Results: ARamp was detected in 19/70 patients at baseline. At the time of analysis, 28/70 patients had died (median follow-up 806 days; interquartile range: 535–966). ARamp was associated with poor OS (2-year OS of 35% in ARamp vs. 71% in non-ARamp; log-rank p value ≤0.0001). Baseline CTC counts ≥5 (vs. <5) was also associated with poor survival (2-year OS of 44 vs. 74%; log-rank p = 0.001). ROC analysis demonstrated area under the curve of 0.66 for ARamp-based prognosis and 0.68 for CTC count-based prognosis (p = 0.84 for difference). The best two variables included for multivariable analysis were ARamp and CTC counts ≥5; however, the two-factor model was not significantly better than using ARamp alone for predicting survival (hazard ratio = 5.25; p = 0.0002). Conclusions: CTCs and plasma cfDNA ARamp were observed to have equal prognostic value in mCRPC. Larger cohorts that incorporate molecular and clinical factors are needed to further refine prognosis in CRPC.

AB - Background: The prognostic significance of plasma cell-free DNA (cfDNA) androgen receptor amplification (ARamp) in metastatic castration-resistant prostate cancer (mCRPC) compared with circulating tumor cell (CTC) counts is not known. Methods: As part of correlative aims of a prospective study in mCRPC, concurrent and serial collections of plasma and CTCs were performed. Specimen collections were performed at baseline after progression on androgen deprivation therapy and then 12 weeks later. QuantStudio3D digital PCR system was used to determine plasma cfDNA AR copy number variations and Cell search assay for enumerating CTC counts. Association of baseline cfDNA ARamp status/CTC counts with overall survival (OS) (primary goal) was evaluated using Kaplan–Meier method and log-rank test (p ≤ 0.05 for significance) and receiver operator curves (ROCs) for ARamp status and CTC counts ≥5. A multivariate analysis was performed using Cox regression models that included ARamp, CTC counts, and other clinical factors. Results: ARamp was detected in 19/70 patients at baseline. At the time of analysis, 28/70 patients had died (median follow-up 806 days; interquartile range: 535–966). ARamp was associated with poor OS (2-year OS of 35% in ARamp vs. 71% in non-ARamp; log-rank p value ≤0.0001). Baseline CTC counts ≥5 (vs. <5) was also associated with poor survival (2-year OS of 44 vs. 74%; log-rank p = 0.001). ROC analysis demonstrated area under the curve of 0.66 for ARamp-based prognosis and 0.68 for CTC count-based prognosis (p = 0.84 for difference). The best two variables included for multivariable analysis were ARamp and CTC counts ≥5; however, the two-factor model was not significantly better than using ARamp alone for predicting survival (hazard ratio = 5.25; p = 0.0002). Conclusions: CTCs and plasma cfDNA ARamp were observed to have equal prognostic value in mCRPC. Larger cohorts that incorporate molecular and clinical factors are needed to further refine prognosis in CRPC.

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