Abstract
Background: Plasma tumor DNA fraction is prognostic in metastatic cancers. This could improve risk stratification before commencing a new treatment. We hypothesized that a second sample collected after one cycle of treatment could refine outcome prediction of patients identified as poor prognosis based on plasma DNA collected pre-treatment. Patients and methods: Plasma DNA [128 pre-treatment, 134 cycle 2 day 1 (C2D1), and 49 progression] from 151 chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) patients in a phase II study of abiraterone acetate (NCT01867710) were subjected to custom targeted next-generation sequencing covering exons of these genes: TP53, AR, RB1, PTEN, PIK3CA, BRCA1, BRCA2, ATM, CDK12, CHEK2, FANCA HDAC2 and PALB2. We also captured 1500 pan-genome regions enriched for single nucleotide polymorphisms to allow detection of tumor DNA using the rolling B-allele method. We tested associations with overall survival (OS) and progression-free survival (PFS). Results: Plasma tumor DNA detection was associated with shorter OS [hazard ratio (HR): 2.89, 95% confidence intervals (CI): 1.77-4.73, P ≤ 0.0001] and PFS (HR: 2.05; 95% CI: 1.36-3.11, P < 0.001). Using a multivariable model including plasma tumor DNA, patients who had a TP53, RB1 or PTEN gene alteration pre-treatment and at C2D1 had a significantly shorter OS than patients with no alteration at either time point (TP53: HR 7.13, 95% CI 2.37-21.47, P < 0.001; RB1: HR 6.24, 95% CI 1.97-19.73, P = 0.002; PTEN: HR 11.9, 95% CI 3.6-39.34, P < 0.001). Patients who were positive pre-treatment and converted to undetectable had no evidence of a difference in survival compared with those who were undetectable pre-treatment (P = 0.48, P = 0.43, P = 0.5, respectively). Progression samples harbored AR gain in all patients who had gain pre-treatment (9/49) and de novo AR somatic point mutations were detected in 8/49 patients. Conclusions: Plasma gene testing after one cycle treatment refines prognostication and could provide an early indication of treatment benefit.
| Original language | English |
|---|---|
| Journal | Annals of Oncology |
| Volume | 32 |
| Issue number | 6 |
| Pages (from-to) | 726-735 |
| Number of pages | 10 |
| ISSN | 0923-7534 |
| DOIs | |
| Publication status | Published - 06.2021 |
Funding
GW has received honoraria from AstraZeneca. CNS has consulted for Janssen, Pfizer, MSD, Merck, AstraZeneca, Astellas, Sanofi-Genzyme, Roche-Genentech, Incyte, Clovis, Immunomedics, Medscape and UroToday. RJ has received honoraria from Janssen, Astellas, Bayer, Clovis and AAA, and research funding from Astellas and Bayer. AB has consulted for and received honoraria from Janssen, Astellas and Ipsen. FL , ML , ST , MG and DR are employees of Janssen and are shareholders in Johnson & Johnson. FM , KG , and LPL are employees and shareholders of Resolution Bioscience, Inc. ASM reports personal fees, research support and travel support from Janssen during the conduct of the study; personal fees and/or travel support from Astellas, Bayer, Ferring, Pfizer, Ipsen, Novartis, Takeda and Sanofi-Aventis; and research funding from AstraZeneca. BT has received research funding from Astellas and Ferring, and honoraria from Janssen, Amgen, Astellas, Ferring, Bayer, and Sanofi. GA reports personal fees, research support and travel support from Janssen during the conduct of the study; personal fees and/or travel support from Astellas, Pfizer, Millennium Pharmaceuticals, Ipsen, Ventana, Veridex, Novartis, Abbott Laboratories, ESSA Pharmaceuticals, Bayer Healthcare Pharmaceuticals, Takeda and Sanofi-Aventis and research funding from AstraZeneca, Innocrin Pharma and Arno Therapeutics outside the submitted work; in addition, GA 's former employer, The Institute of Cancer Research (ICR), receives royalty income from abiraterone acetate and GA receives a share of this income through ICR's Rewards to Discoverers Scheme. All other authors have declared no conflicts of interest. The authors thank the study participants and study centers (Supplementary Table S8, available at https://doi.org/10.1016/j.annonc.2021.03.196) for their contributions. The study participants did not receive compensation. The study centers received compensation for the costs of conducting the study. Shweta Pitre, CMPP (SIRO Clinpharm Pvt. Ltd.) provided assistance with finalizing the manuscript and coordinating submission. The study was supported by Janssen Research & Development, LLC, NJ, USA (no grant number). GA is funded by a Cancer Research UK Advanced Clinician Scientist Fellowship (garnt no: A22744). AKJ is funded by a Medical Research Council Clinical Research Training Fellowship (grant no: MR/P002072/1). GW has received honoraria from AstraZeneca. CNS has consulted for Janssen, Pfizer, MSD, Merck, AstraZeneca, Astellas, Sanofi-Genzyme, Roche-Genentech, Incyte, Clovis, Immunomedics, Medscape and UroToday. RJ has received honoraria from Janssen, Astellas, Bayer, Clovis and AAA, and research funding from Astellas and Bayer. AB has consulted for and received honoraria from Janssen, Astellas and Ipsen. FL, ML, ST, MG and DR are employees of Janssen and are shareholders in Johnson & Johnson. FM, KG, and LPL are employees and shareholders of Resolution Bioscience, Inc. ASM reports personal fees, research support and travel support from Janssen during the conduct of the study; personal fees and/or travel support from Astellas, Bayer, Ferring, Pfizer, Ipsen, Novartis, Takeda and Sanofi-Aventis; and research funding from AstraZeneca. BT has received research funding from Astellas and Ferring, and honoraria from Janssen, Amgen, Astellas, Ferring, Bayer, and Sanofi. GA reports personal fees, research support and travel support from Janssen during the conduct of the study; personal fees and/or travel support from Astellas, Pfizer, Millennium Pharmaceuticals, Ipsen, Ventana, Veridex, Novartis, Abbott Laboratories, ESSA Pharmaceuticals, Bayer Healthcare Pharmaceuticals, Takeda and Sanofi-Aventis and research funding from AstraZeneca, Innocrin Pharma and Arno Therapeutics outside the submitted work; in addition, GA's former employer, The Institute of Cancer Research (ICR), receives royalty income from abiraterone acetate and GA receives a share of this income through ICR's Rewards to Discoverers Scheme. All other authors have declared no conflicts of interest. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu. The study was supported by Janssen Research & Development , LLC, NJ, USA (no grant number). GA is funded by a Cancer Research UK Advanced Clinician Scientist Fellowship (garnt no: A22744). AKJ is funded by a Medical Research Council Clinical Research Training Fellowship (grant no: MR/P002072/1).
DFG Research Classification Scheme
- 2.22-14 Hematology, Oncology
- 2.22-23 Reproductive Medicine, Urology
