Genomic profiles of de novo high- and low-volume metastatic prostate cancer: results from a 2-stage feasibility and prevalence study in the STAMPEDE Trial
Authors
Gilson, C.Ingleby, F.
Gilbert, D. C.
Parry, M. A.
Atako, N. B.
Ali, Adnan
Hoyle, Alex P
Clarke, Noel W
Gannon, M.
Wanstall, C.
Brawley, C.
Mason, M. D.
Malik, Z.
Simmons, A.
Loehr, A.
Parry-Jones, A.
Eeles, R.
Kote-Jarai, Z.
James, N. D.
Amos, C.
Parmar, M. K. B.
Langley, R. E.
Sydes, M. R.
Attard, G.
Chowdhury, S.
Affiliation
MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London,Issue Date
2020
Metadata
Show full item recordAbstract
PURPOSE The STAMPEDE trial recruits men with newly diagnosed, high-risk, hormone-sensitive prostate cancer. To ascertain the feasibility of targeted next-generation sequencing (tNGS) and the prevalence of baseline genomic aberrations, we sequenced tumor and germline DNA from patients with metastatic prostate cancer (mPCa) starting long-term androgen-deprivation therapy (ADT). METHODS In a 2-stage approach, archival, formalin-fixed, paraffin-embedded (FFPE) prostate tumor core biopsy samples were retrospectively subjected to 2 tNGS assays. Prospective enrollment enabled validation using tNGS in tumor and germline DNA. RESULTS In stage 1, tNGS data were obtained from 185 tumors from 287 patients (65%); 98% had de novo mPCa. We observed PI3K pathway aberrations in 43%, due to PTEN copy-number loss (34%) and/or activating mutations in PIK3 genes or AKT (18%) and TP53 mutation or loss in 33%. No androgen receptor (AR) aberrations were detected; RB1 loss was observed in < 1%. In stage 2, 93 (92%) of 101 FFPE tumors (biopsy obtained within 8 months) were successfully sequenced prospectively. The prevalence of DNA damage repair (DDR) deficiency was 14% (somatic) and 5% (germline). BRCA2 mutations and mismatch repair gene mutations were exclusive to high-volume disease. Aberrant DDR (22% v 15%), Wnt pathway (16% v 4%), and chromatin remodeling (16% v 8%) were all more common in high-volume compared with low-volume disease, but the small numbers limited statistical comparisons. CONCLUSION Prospective genomic characterization is feasible using residual diagnostic tumor samples and reveals that the genomic landscapes of de novo high-volume mPCa and advanced metastatic prostate cancer have notable similarities (PI3K pathway, DDR, Wnt, chromatin remodeling) and differences (AR, RB1). These results will inform the design and conduct of biomarker-directed trials in men with metastatic hormone-sensitive prostate cancer.Citation
Gilson C, Ingleby F, Gilbert DC, Parry MA, Atako NB, Ali A, et al. Genomic Profiles of De Novo High- and Low-Volume Metastatic Prostate Cancer: Results From a 2-Stage Feasibility and Prevalence Study in the STAMPEDE Trial. JCO Precision Oncology. 2020;4(4):882-97.Journal
JCO Precision OncologyDOI
10.1200/po.19.00388Additional Links
https://dx.doi.org/10.1200/po.19.00388Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1200/po.19.00388