Circulating Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition

Biomarkers for a more precise patient care are needed in metastatic prostate cancer (mPC). We have reported a Phase II trial (TOPARP-A) of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib in mPC, demonstrating antitumor activity associating with homologous recombination DNA repair defects. We now report targeted and whole exome sequencing of serial circulating-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 (Chi-squared p<0.001). At disease progression, following response to olaparib, multiple sub-clonal 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 predictive, prognostic, response and resistance biomarker in mPC.

Cancer discovery. 2017 Apr 27 [Epub ahead of print]

Jane Goodall, Joaquin Mateo, Wei Yuan, Helen Mossop, Nuria Porta, Susana Miranda, Raquel Perez-Lopez, David Dolling, Dan R Robinson, Shahneen Sandhu, Gemma Fowler, Berni Ebbs, Penny Flohr, George Seed, Daniel Nava Rodrigues, Gunther Boysen, Claudia Bertan, Mark Atkin, Matthew Clarke, Mateus Crespo, Ines Figueiredo, Ruth Riisnaes, Semini Sumanasuriya, Pasquale Rescigno, Zafeiris Zafeiriou, Adam Sharp, Nina Tunariu, Diletta Bianchini, Alexa Gillman, Christopher J Lord, Emma Hall, Arul M Chinnaiyan, Suzanne Carreira, Johann S de Bono

Section of Medicine, The Institute of Cancer Research., Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research., Cancer Biomarkers, The Institute of Cancer Research., The Institute of Cancer Research., Division of Clinical Studies, The Institute of Cancer Research., Institute of Cancer Research., Department of Pathology, University of Michigan., Peter MacCallum Cancer Centre., Oncogenetics, The Institute of Cancer Research., Cancer Biomarkers Team, The Institute of Cancer Research., Breakthrough Breast Cancer Research Center, The Institute of Cancer Research., Drug Development Unit, The Institute for Cancer Research and the Royal Marsden NHS Foundation Trust., Prostate Cancer Targeted Therapy Group, The Institute of Cancer Research., Radiology Department, The Institute of Cancer Research., The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research., Clinical Trials and Statistics Unit, The Institute of Cancer Research., Pathology, University of Michigan., The Institute of Cancer Research .

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