# Analysis of circulating cell-free DNA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors

Source: https://onco.cc/key-papers/paper-quigley-brca2-reversion-cfdna-parp-resistance-cancer-discov-2017/  
OnCo record `paper-quigley-brca2-reversion-cfdna-parp-resistance-cancer-discov-2017` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

When PARP inhibitors stop working in prostate cancer, the tumour has repaired the broken gene, and a blood test shows it has done so in several different ways at once.

## Summary

About 20% of metastatic prostate cancers carry mutations in genes required for DNA repair by homologous recombination, such as BRCA2, and those defects confer synthetic lethality to PARP inhibitors. In ovarian and breast cancer, olaparib resistance has been associated with restoration of homologous recombination, including by BRCA2 mutation reversion. This study identified BRCA2 reversion mutations associated with olaparib and talazoparib resistance in patients with prostate cancer. Analysis of circulating cell-free DNA revealed reversion mutation heterogeneity that was not discernible from a single solid-tumour biopsy, and suggested that cell-free DNA can be used to monitor for the emergence of PARP inhibitor resistance.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Cancer Discovery
- Year: 2017
- DOI: 10.1158/2159-8290.CD-17-0146
- Authors: Quigley D, Alumkal JJ, Wyatt AW, et al.
- Findings: BRCA2 reversion mutations identified in men with prostate cancer resistant to olaparib and to talazoparib.; Resistance was highly multiclonal, with several independent restoring events.; Cell-free DNA revealed heterogeneity a single solid-tumour biopsy could not show.
- What it means: It establishes that PARP inhibitor resistance in prostate cancer is a restored repair pathway rather than a bypass, which is why platinum and PARP inhibitors lose activity together, and it is the argument for sampling plasma rather than one lesion at progression.
- Caveats: A small series of patients, published as a brief report.; No licensed assay reports reversion mutations.; Reversion is one mechanism among several and its frequency in prostate cancer has not been counted prospectively.

## Sources

- Quigley et al., Cancer Discov 2017: multiclonal BRCA2 reversion mutations in cell-free DNA and resistance to PARP inhibitors in prostate cancer: https://doi.org/10.1158/2159-8290.CD-17-0146
- PubMed: https://pubmed.ncbi.nlm.nih.gov/28450426/

## Connected records

- cancers: [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/)
- targets: [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [PARP](https://onco.cc/targets/parp/)
- pathways: [Base excision repair, PARP & alkylation damage](https://onco.cc/pathways/base-excision-repair-parp/), [Double-strand break repair: HR versus end joining](https://onco.cc/pathways/homologous-recombination-repair/), [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/), [Synthetic lethality: paired dependencies](https://onco.cc/pathways/synthetic-lethality-map/)
- terms: [BRCA reversion mutations](https://onco.cc/terms/brca-reversion-mutations/), [Cell-free DNA (cfDNA)](https://onco.cc/terms/cfdna/), [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Homologous recombination deficiency (HRD)](https://onco.cc/terms/hrd/)
- journals: [Cancer Discovery](https://onco.cc/journals/cancer-discovery/)
- biomarkers: [Homologous recombination repair gene mutation in prostate cancer](https://onco.cc/biomarkers/hrr-gene-mutation/), [Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations](https://onco.cc/biomarkers/brca-somatic/)

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