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
Acquired Resistance to Poly (ADP-ribose) Polymerase Inhibitor Olaparib in BRCA2-Associated Prostate Cancer Resulting From Biallelic BRCA2 Reversion Mutations Restores Both Germline and Somatic Loss-of-Function Mutations
Benedito A. Carneiro,Katharine Collier,Rebecca J. Nagy,Sahithi Pamarthy,Vinay Sagar,Stephen R. Fairclough,Justin I. Odegaard,Richard B. Lanman,Ricardo Costa,Timothy Taxter,Timothy M. Kuzel,Alice C. Fan,Young Kwang Chae,Massimo Cristofanilli,Maha Hussain,Sarki A. Abdulkadir,Francis J. Giles +16 more
TL;DR: The frequency of reversion mutations in a large cohort of prostate cancer patients carrying of BRCA mutations is documents and the potential utility of ctDNA analyses for early detection of reverted mutation driving tumor resistance is shown.
Journal ArticleDOI
Accelerating precision medicine in metastatic prostate cancer.
Joaquin Mateo,Rana R. McKay,Wassim Abida,Rahul Aggarwal,Joshi J. Alumkal,Ajjai Alva,Felix Y. Feng,Xin Gao,Julie N. Graff,Maha Hussain,Fatima Karzai,Bruce Montgomery,William Oh,Vaibhav G. Patel,Dana E. Rathkopf,Matthew Rettig,Nikolaus Schultz,Matthew R. Smith,David B. Solit,Cora N. Sternberg,Eliezer M. Van Allen,David J. VanderWeele,Jake Vinson,Howard R. Soule,Arul M. Chinnaiyan,Eric J. Small,Jonathan W. Simons,William L. Dahut,Andrea K. Miyahira,Himisha Beltran +29 more
TL;DR: How to accelerate precision oncology to inform broader genomically-driven clinical decisions for men with advanced prostate cancer, drug development and ultimately contribute to new treatment paradigms is discussed.
Journal ArticleDOI
Assessment of circulating tumor DNA in pediatric solid tumors: The promise of liquid biopsies.
Samuel Abbou,Samuel Abbou,David S. Shulman,Steven G. DuBois,Brian D. Crompton,Brian D. Crompton +5 more
TL;DR: The literature demonstrating the feasibility of applying liquid biopsy to pediatric solid malignancies is reviewed and new directions for future studies are suggested.
Journal ArticleDOI
Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy
Daniel H. Hovelson,Chia Jen Liu,Yugang Wang,Qing Kang,James Henderson,Amy Gursky,Scott Brockman,Nithya Ramnath,John C. Krauss,Moshe Talpaz,Malathi Kandarpa,Rashmi Chugh,Missy Tuck,Kirk Herman,Catherine S. Grasso,Michael J. Quist,Felix Y. Feng,Christine Haakenson,John P. Langmore,Emmanuel Kamberov,Tim Tesmer,Hatim Husain,Robert J. Lonigro,Dan R. Robinson,David Smith,Ajjai Alva,Maha Hussain,Maha Hussain,Arul M. Chinnaiyan,Muneesh Tewari,Ryan E. Mills,Todd M. Morgan,Scott A. Tomlins +32 more
TL;DR: This screening approach enables robust, broadly applicablecfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based Precision oncological workflow optimization.
Journal ArticleDOI
Prostate cancer and PARP inhibitors: progress and challenges.
Diego Teyssonneau,Henri Margot,Mathilde Cabart,Mylène Anonnay,Paul Sargos,Nam-Son Vuong,Isabelle Soubeyran,Nicolas Sevenet,Guilhem Roubaud +8 more
TL;DR: In this article, the authors synthesize and discuss the rationale and development of PARP inhibitors, biomarker-based approaches associated and the future challenges related to their prescription as well as patient pathways, and the first demonstration of an improvement in overall survival was provided by olaparib in patients with mCRPC harboring homologous recombination repair deficiencies.
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