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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Journal ArticleDOI
Androgen receptor genomic alterations and treatment resistance in metastatic prostate cancer
TL;DR: There is hope that AR genomic alterations can act as prognostic and/or predictive biomarkers to guide patient management with an increasingly crowded treatment landscape.
Journal ArticleDOI
Relevance of Platinum-free Interval and BRCA Reversion Mutations for Veliparib Monotherapy after Progression on Carboplatin/Paclitaxel for gBRCA Advanced Breast Cancer (BROCADE3 Crossover).
Shannon Puhalla,Véronique Diéras,Banu Arun,Bella Kaufman,Hans Wildiers,Hyo S. Han,Jean-Pierre M. Ayoub,Vered Stearns,Yuan Yuan,Teresa Helsten,Bridget Riley-Gillis,Erin Murphy,Madan Gopal Kundu,Meijing Wu,David Maag,Christine K. Ratajczak,Cyril Ramathal,Michael Friedlander +17 more
TL;DR: The crossover veliparib monotherapy as mentioned in this paper demonstrated limited antitumor activity in patients who experienced disease progression on placebo plus carboplatin/paclitaxel, while patients had variable platinum-free intervals (PFI) at progression.
Journal ArticleDOI
Beyond the androgen receptor II: New approaches to understanding and treating metastatic prostate cancer; Report from the 2017 Coffey-Holden Prostate Cancer Academy Meeting.
Andrea K. Miyahira,Heather H. Cheng,Heather H. Cheng,Wassim Abida,Leigh Ellis,Leigh Ellis,Lauren C. Harshman,Daniel E. Spratt,Jonathan W. Simons,Kenneth J. Pienta,Howard R. Soule +10 more
TL;DR: The 2017 Coffey‐Holden Prostate Cancer Academy (CHPCA) Meeting, “Beyond the Androgen Receptor II: New Approaches to Understanding and Treating Metastatic Prostate cancer,” was held in Carlsbad, California from June 14‐17, 2017.
Journal ArticleDOI
Longitudinal analysis of a secondary BRCA2 mutation using digital droplet PCR.
Saira Khalique,Saira Khalique,Stephen J. Pettitt,Ger Kelly,Nina Tunariu,Rachael Natrajan,Susana Banerjee,Christopher J. Lord +7 more
TL;DR: A case of somatic BRCA2 mutation in a patient with high grade serous ovarian carcinoma with no evidence for the secondary mutation being present prior to the final progression biopsy, suggesting that this mutation was acquired late in the course of treatment.
Journal ArticleDOI
Circulating cell-free DNA: Translating prostate cancer genomics into clinical care.
TL;DR: This review focuses on the clinical implications of prostate cancer genomics and the potential of cfDNA in facilitating treatment management and the importance of reliable methods that enable sequential monitoring of evolving genotypes in individual patients.
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