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

Abstract

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.

Tissue- and Blood-derived Genomic Biomarkers for Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review

“…AR aberrations were exclusively identified in tumour samples that were collected following ADT exposure, consistent with the known role of the transition towards castration-resistant disease [19]. Alterations in the PI3K pathway were most frequently observed in the STAMPEDE [16] cohort (43%) in comparison with the Abida et al [3] cohort (24%). In contrast, alterations in the Wnt pathway including loss/inactivating mutations in APC or RNF43 and activating mutations in CTNNB1 appeared to be more common in the Abida et al [3] population (20%) in comparison with the JHU (16%) and Mayo Clinic cfDNA (10%) cohorts.…”

“…Two studies [4,16] stratified high-volume patients by the CHAARTED trial's criteria [8], requiring four or more bone metastases with at least one outside the axial skeleton or visceral metastases, whereas one study [15] used a modified definition without requirements for extra-axial metastases. Four studies [15][16][17][18] based their assessment of disease volume on conventional imaging, including bone scans, computed tomography, or magnetic resonance imaging, whereas one study [4] did not report which imaging modalities were used. None of the studies reported on which imaging modality was used on a per-patient basis, and details on the metastases, such as the exact location and their number, were incomplete or not specified.…”

Population-Based Study of Docetaxel or Abiraterone Effectiveness and Predictive Markers of Progression Free Survival in Metastatic Castration-Sensitive Prostate Cancer

“…The presence of germline DNA damage repair alterations predicts early progression from de novo mCSPC to mCRPC, yet such patients might be amenable to treatment with poly (ADP-ribose) polymerase inhibitors (39). Finally, deep tumor sequencing is expected to aid further in the precise molecular classification of mCSPC for therapeutic decision making (40)(41)(42).…”

Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial

“…The clinical impact of molecular alterations in mHSPC remains largely undefined despite significant advances in therapy. Limited data of the mutational profile of mHSPC reveal recurrent aberrations in AR, PTEN, TP53, RB1, BRCA2 and SPOP, with frequencies that lie intermediately between localized PC and metastatic CRPC 9,10,22 . Our study has shed first light on the mHSPC transcriptome, with specific focus on subtyping tied to clinical outcomes.…”