Jayaram, A;
Wingate, A;
Wetterskog, D;
Wheeler, G;
Sternberg, CN;
Jones, R;
Berruti, A;
... Attard, G; + view all
(2021)
Plasma tumor gene conversions after one cycle abiraterone acetate for metastatic castration-resistant prostate cancer: a biomarker analysis of a multi-center international trial.
Annals of Oncology
, 32
(6)
pp. 726-735.
10.1016/j.annonc.2021.03.196.
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Abstract
BACKGROUND: Plasma tumor DNA fraction is prognostic in metastatic cancers. This could improve risk stratification prior to commencing a new treatment. We hypothesized that a second sample collected after one cycle 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-naïve metastatic castration resistant prostate cancer (mCRPC) patients in a phase 2 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 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 or 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 to those who were undetectable pre-treatment (respectively p=0.48, p=0.43, p=0.5). 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.
| Type: | Article |
|---|---|
| Title: | Plasma tumor gene conversions after one cycle abiraterone acetate for metastatic castration-resistant prostate cancer: a biomarker analysis of a multi-center international trial |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.annonc.2021.03.196 |
| Publisher version: | https://doi.org/10.1016/j.annonc.2021.03.196 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Prostate Cancer, biomarkers, genomic alterations, liquid biopsies, next-generation sequencing, plasma DNA |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10126203 |
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