Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors.
David A. Quigley,Joshi J. Alumkal,Alexander W. Wyatt,Vishal Kothari,Adam Foye,Paul Lloyd,Rahul Aggarwal,Won Kim,Eric Lu,Jacob Schwartzman,Kevin Beja,Matti Annala,Rajdeep Das,Morgan E. Diolaiti,Colin C. Pritchard,George Thomas,Scott A. Tomlins,Karen E. Knudsen,Christopher J. Lord,Charles J. Ryan,Jack F. Youngren,Tomasz M. Beer,Alan Ashworth,Eric J. Small,Felix Y. Feng +24 more
TLDR
BRCA2 reversion mutations in patients with prostate cancer with metastatic disease who developed resistance to talazoparib and olaparib are identified and it is shown that PARPi resistance is highly multiclonal and that cfDNA allows monitoring for PAR Pi resistance.Abstract:
Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination repair (HRR) such as BRCA2 HRR defects confer synthetic lethality to PARP inhibitors (PARPi) such as olaparib and talazoparib. In ovarian or breast cancers, olaparib resistance has been associated with HRR restoration, including by BRCA2 mutation reversion. Whether similar mechanisms operate in prostate cancer, and could be detected in liquid biopsies, is unclear. Here, we identify BRCA2 reversion mutations associated with olaparib and talazoparib resistance in patients with prostate cancer. Analysis of circulating cell-free DNA (cfDNA) reveals reversion mutation heterogeneity not discernable from a single solid-tumor biopsy and potentially allows monitoring for the emergence of PARPi resistance.Significance: The mechanisms of clinical resistance to PARPi in DNA repair-deficient prostate cancer have not been described. Here, we show BRCA2 reversion mutations in patients with prostate cancer with metastatic disease who developed resistance to talazoparib and olaparib. Furthermore, we show that PARPi resistance is highly multiclonal and that cfDNA allows monitoring for PARPi resistance. Cancer Discov; 7(9); 999-1005. ©2017 AACR.See related commentary by Domchek, p. 937See related article by Kondrashova et al., p. 984See related article by Goodall et al., p. 1006This article is highlighted in the In This Issue feature, p. 920.read more
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Quantitative Mass Spectrometry-Based Proteomics for Biomarker Development in Ovarian Cancer
Joohyun Ryu,Stefani N. Thomas +1 more
TL;DR: In this article, the authors provide background information on the fundamental principles of biomarkers and the need for improved treatment strategies in ovarian cancer, and they also provide insight into the ways in which mass spectrometry-based targeted proteomics approaches can provide greatly needed solutions to many of the challenges related to ovarian cancer biomarker development.
Journal ArticleDOI
An Analysis of Patients with DNA Repair Pathway Mutations Treated with a PARP Inhibitor
Erkut Borazanci,Ronald L. Korn,Winnie S. Liang,Carol Guarnieri,Susan Haag,Courtney Snyder,Kristin Hendrickson,Lana Caldwell,Dan D. Von Hoff,Gayle S. Jameson +9 more
TL;DR: In individuals with metastatic PDAC who have mutations involved in DNA repair, Olaparib may provide clinical benefit and BRCA mutations affecting RAD51 binding domains translated to improved median OS.
Journal ArticleDOI
DNA Repair Gene Alterations and PARP Inhibitor Response in Patients With Metastatic Castration-Resistant Prostate Cancer.
Eric Lu,George Thomas,Yiyi Chen,Alexander W. Wyatt,Paul Lloyd,Jack F. Youngren,David A. Quigley,Raymond C. Bergan,Shawna Bailey,Tomasz M. Beer,Felix Y. Feng,Eric J. Small,Joshi J. Alumkal +12 more
TL;DR: The results demonstrate that not all DNA repair alterations are equally predictive of PARP inhibitor response, and the need to carefully examine the functional relevance of the DNA repair alteration identified, especially in genes other than BRCA2, when considering patients for PARP inhibitors treatment.
Journal ArticleDOI
Response to olaparib in metastatic castration-resistant prostate cancer with germline BRCA2 mutation: a case report
TL;DR: Evidence is provided that mCRPC with BRCA2 germline mutations could response to PARP inhibitor, which improves patient’s outcome and it is demonstrated that NGS-based genetic testing on liquid biopsy can be used to dynamically monitor the efficacy of treatment.
Journal ArticleDOI
The Role of PARP Inhibitors in the Treatment of Prostate Cancer: Recent Advances in Clinical Trials.
TL;DR: In this article, the authors reviewed the mechanism of PARP inhibition in the treatment of prostate cancer, the progress of clinical research, the mechanisms of drug resistance, and the strategies of combination treatments.
References
More filters
Journal Article
R: A language and environment for statistical computing.
TL;DR: Copyright (©) 1999–2012 R Foundation for Statistical Computing; permission is granted to make and distribute verbatim copies of this manual provided the copyright notice and permission notice are preserved on all copies.
Journal ArticleDOI
The Sequence Alignment/Map format and SAMtools
Heng Li,Bob Handsaker,Alec Wysoker,T. J. Fennell,Jue Ruan,Nils Homer,Gabor T. Marth,Gonçalo R. Abecasis,Richard Durbin +8 more
TL;DR: SAMtools as discussed by the authors implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments.
Journal ArticleDOI
Fast and accurate short read alignment with Burrows–Wheeler transform
Heng Li,Richard Durbin +1 more
TL;DR: Burrows-Wheeler Alignment tool (BWA) is implemented, a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps.
Journal ArticleDOI
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
Aaron McKenna,Matthew Hanna,Eric Banks,Andrey Sivachenko,Kristian Cibulskis,Andrew Kernytsky,Kiran V. Garimella,David Altshuler,Stacey Gabriel,Mark J. Daly,Mark A. DePristo +10 more
TL;DR: The GATK programming framework enables developers and analysts to quickly and easily write efficient and robust NGS tools, many of which have already been incorporated into large-scale sequencing projects like the 1000 Genomes Project and The Cancer Genome Atlas.
Journal ArticleDOI
BEDTools: a flexible suite of utilities for comparing genomic features
Aaron R. Quinlan,Ira M. Hall +1 more
TL;DR: A new software suite for the comparison, manipulation and annotation of genomic features in Browser Extensible Data (BED) and General Feature Format (GFF) format, which allows the user to compare large datasets (e.g. next-generation sequencing data) with both public and custom genome annotation tracks.
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