Circulating Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition
Menée à partir d'échantillons sanguins prélevés au cours d'un essai de phase II évaluant l'olaparib, un inhibiteur de PARP, et incluant 50 patients atteints d'un cancer métastatique de la prostate, cette étude analyse l'intérêt de séquencer l'ADN tumoral circulant pour identifier des mutations de la tumeur durant le traitement et adapter la prise en charge thérapeutique
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 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 (
χ2 P < 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.
Cancer Discovery , résumé, 2016