Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition.
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Date
2017-09-01ICR Author
Author
Goodall, J
Mateo, J
Yuan, W
Mossop, H
Porta, N
Miranda, S
Perez-Lopez, R
Dolling, D
Robinson, DR
Sandhu, S
Fowler, G
Ebbs, B
Flohr, P
Seed, G
Rodrigues, DN
Boysen, G
Bertan, C
Atkin, M
Clarke, M
Crespo, M
Figueiredo, I
Riisnaes, R
Sumanasuriya, S
Rescigno, P
Zafeiriou, Z
Sharp, A
Tunariu, N
Bianchini, D
Gillman, A
Lord, CJ
Hall, E
Chinnaiyan, AM
Carreira, S
de Bono, JS
TOPARP-A investigators,
Type
Journal Article
Metadata
Show full item recordAbstract
Biomarkers for more precise patient care are needed in metastatic prostate cancer. We have reported a phase II trial (TOPARP-A) of the PARP inhibitor olaparib in metastatic prostate cancer, demonstrating antitumor activity associating with homologous recombination DNA repair defects. We now report targeted and whole-exome sequencing of serial circulating cell-free DNA (cfDNA) samples collected during this trial. Decreases in cfDNA concentration independently associated with outcome in multivariable analyses (HR for overall survival at week 8: 0.19; 95% CI, 0.06-0.56; P = 0.003). All tumor tissue somatic DNA repair mutations were detectable in cfDNA; allele frequency of somatic mutations decreased selectively in responding patients (χ2P < 0.001). At disease progression, following response to olaparib, multiple subclonal aberrations reverting germline and somatic DNA repair mutations (BRCA2, PALB2) back in frame emerged as mechanisms of resistance. These data support the role of liquid biopsies as a predictive, prognostic, response, and resistance biomarker in metastatic prostate cancer.Significance: We report prospectively planned, serial, cfDNA analyses from patients with metastatic prostate cancer treated on an investigator-initiated phase II trial of olaparib. These analyses provide predictive, prognostic, response, and resistance data with "second hit" mutations first detectable at disease progression, suggesting clonal evolution from treatment-selective pressure and platinum resistance. Cancer Discov; 7(9); 1006-17. ©2017 AACR.See related commentary by Domchek, p. 937See related article by Kondrashova et al., p. 984See related article by Quigley et al., p. 999This article is highlighted in the In This Issue feature, p. 920.
Subject
TOPARP-A investigators
Humans
Prostatic Neoplasms
Piperazines
Phthalazines
Antineoplastic Agents
Prognosis
Gene Frequency
Mutation
Male
Poly(ADP-ribose) Polymerase Inhibitors
Whole Exome Sequencing
Cell-Free Nucleic Acids
Research team
Cancer Biomarkers
Clinical Trials & Statistics Unit
ICR-CTSU Urology and Head and Neck Trials Team
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Gene Function
Language
eng
Date accepted
2017-04-26
License start date
2017-09
Citation
Cancer discovery, 2017, 7 (9), pp. 1006 - 1017
Publisher
AMER ASSOC CANCER RESEARCH