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J Goodall, J Mateo, W Yuan, H Mossop, N Porta, S Miranda, R Perez-Lopez, D Dolling, DR Robinson, S Sandhu, G Fowler, B Ebbs, P Flohr, G Seed, D Nava Rodrigues, G Boysen, C Bertan, M Atkin, M Clarke, M Crespo, I Figueiredo, R Riisnaes, S Sumanasuriya, P Rescigno, Z Zafeiriou, A Sharp, N Tunariu, D Bianchini, A Gillman, CJ Lord, E Hall, AM Chinnaiyan, S Carreira and JS de Bono
Abstract
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.
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Concepts
Homologous recombination, Mutation, Genetics, Evolution, Prostate cancer, DNA repair, DNA, Cancer
MeSH headings
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