Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition

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.

Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer

“…those with high ctDNA fraction). Nevertheless, as liquid biopsies are also showing great promise in monitoring patients for reversion mutations linked to PARPi resistance (27,28), they are likely to have broad clinical utility in patients with HRR defective tumors. Future studies must assess the degree to which defects in other HRR genes (e.g.…”

Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer

“…In both high-grade serous ovarian cancer and metastatic prostate cancer, multiple secondary mutations in both germ-line and somatically mutated BRCA2 and PALB2 were identified in cfDNA from patients with recurrent disease (Christie et al 2017, Goodall et al 2017, Quigley et al 2017). Interestingly, in the case of prostate cancers treated with PARPi (either olaparib or talazoparib), analysis of mutations in cfDNA revealed evidence of multiclonal heterogeneity of BRCA2 reversion mutations, information that would be difficult to glean from a single tumor biopsy sample (Quigley et al 2017).…”

“…As every one of these mutations restores the reading frame, the confidence that these mutations confer therapy resistance is extremely high. cfDNA analysis was also suggested to have prognostic value, as responders were more likely to have reductions in cfDNA with the primary mutation compared with nonresponders (Goodall et al 2017). …”

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer

“…[3][4][5][6] Tumor-derived cell-free DNA (cfDNA) in serum or plasma likely originates from apoptotic, dead or dying tumor cells, and may constitute genetic information associated with tumor cell evolution and heterogeneity during treatment and metastatic progression. 10,11 While some studies have found concordance between selected cfDNA genomic alterations and paired tumor biopsies, 12,13 few studies have examined the consistency of whole-genome alterations across paired CTC and cfDNA samples. 10,11 While some studies have found concordance between selected cfDNA genomic alterations and paired tumor biopsies, 12,13 few studies have examined the consistency of whole-genome alterations across paired CTC and cfDNA samples.…”