@article{86e086770dbb4c04a3f0f4f99cdc76b1,
title = "Evolution of castration-resistant prostate cancer in ctDNA during sequential androgen receptor pathway inhibition",
abstract = "Purpose: Cross-resistance renders multiple lines of androgen receptor (AR) signaling inhibitors increasingly futile in metastatic castration-resistant prostate cancer (mCRPC). We sought to determine acquired genomic contributors to cross-resistance. Experimental Design: We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 patients with mCRPC receiving sequential AR signaling inhibitors (abiraterone and enzalutamide) in a randomized phase II clinical trial (NCT02125357). We utilized deep targeted and whole-exome sequencing to compare baseline and posttreatment somatic genomic profiles in circulating tumor DNA (ctDNA). Results: Patient ctDNA abundance was correlated across plasma collections and independently prognostic for sequential therapy response and overall survival. Most driver alterations in established prostate cancer genes were consistently detected in ctDNA over time. However, shifts in somatic populations after treatment were identified in 53% of patients, particularly after strong treatment responses. Treatment-associated changes converged upon the AR gene, with an average 50% increase in AR copy number, changes in AR mutation frequencies, and a 2.5-fold increase in the proportion of patients carrying AR ligand binding domain truncating rearrangements. Conclusions: Our data show that the dominant AR genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance in patients with mCRPC.",
author = "Matti Annala and Sinja Taavitsainen and Khalaf, {Daniel J.} and Gillian Vandekerkhove and Kevin Beja and Joonatan Sipola and Warner, {Evan W.} and Cameron Herberts and Amanda Wong and Simon Fu and Finch, {Daygen L.} and Oja, {Conrad D.} and Joanna Vergidis and Muhammad Zulfiqar and Eigl, {Bernhard J.} and Kollmansberger, {Christian K.} and Matti Nykter and Gleave, {Martin E.} and Chi, {Kim N.} and Wyatt, {Alexander W.}",
note = "Funding Information: This work was supported by the Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, Prostate Cancer Canada, Movember Foundation, Prostate Cancer Foundation, Jane and Aatos Erkko Foundation, Academy of Finland, Terry Fox New Frontiers Program, BC Cancer Foundation, Janssen, and Astellas. No funding sources were involved in the design or execution of the study. The authors are thankful to all contributing patients and their families. Funding Information: M. Annala reports grants from Jane and Aatos Erkko Foundation and Academy of Finland during the conduct of the study. S. Taavitsainen reports grants from Jane and Aatos Erkko Foundation during the conduct of the study. D.J. Khalaf reports personal fees from Janssen outside the submitted work. D.L. Finch reports other support from Janssen, Astellas, and Bayer outside the submitted work. J. Vergidis reports personal fees from BMS and non-financial support from Bayer outside the submitted work. B.J. Eigl reports personal fees from AstraZeneca, Pfizer, Seagen, Johnson and Johnson, EMD Serono, and Merck outside the submitted work. C.K. Kollmansberger reports personal fees from Astellas, Janssen, Pfizer, BMS, Eisai, Merck, Ipsen, and Bayer outside the submitted work. M. Nykter reports grants from Jane and Aatos Erkko Foundation and Academy of Finland during the conduct of the study. K.N. Chi reports grants from Astellas and Janssen during the conduct of the study. K.N. Chi also reports grants and personal fees from AstraZeneca, Bayer, Novartis, Pfizer, Point Bio-pharma, Roche, and Sanofi, as well as personal fees from Daiichi Sankyo, Merck, and Bristol Myers Squibb outside the submitted work. A.W. Wyatt reports personal fees from AstraZeneca, Merck, and Astellas; grants and personal fees Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research",
year = "2021",
month = aug,
doi = "10.1158/1078-0432.CCR-21-1625",
language = "English",
volume = "27",
pages = "4610--4623",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research",
number = "16",
}
