Prostate Adenocarcinoma (PRAD)

Overview

OncoTree code for prostate adenocarcinoma.

Cohorts in the corpus

  • msk_chord_2024 — 3,211 prostate cancer patients at MSK in the MSK-CHORD clinicogenomic harmonized real-world dataset PMID:39506116.
  • Commentary cohort: oligometastatic hormone-sensitive PRAD; synchronous de novo cases estimated at “several thousands” per year in the US; metachronous/oligorecurrent cases potentially the majority of men who progress to metastatic disease. No primary data collected. PMID:28045614
  • prad_msk_mdanderson_2023 — 44 PDX models from 38 prostate cancer patients at MD Anderson Cancer Center, spanning adenocarcinoma and NEPC, profiled by WGS, T200.1 targeted sequencing, and RNA-seq. PMID:38488813
  • prostate_msk_2024 — 2,257 PRAD patients at MSK sequenced by MSK-IMPACT (3,244 tumors); subgroups: 63 MSI-H/dMMR (2.8%), 33 TMB-H/MSS (1.5%). PMID:38949888
  • msk_ctdna_vte_2024 — PRAD comprised 5% of the 4,141-patient liquid biopsy VTE discovery cohort. PMID:39147831
  • ATLAS classifier validation — PRAD included in the 22-class site-of-origin model; de-differentiation score distinguishes PRAD from PRNE (AUC=0.834). PMID:27634761

Recurrent alterations

  • Included in pan-cancer MSK-IMPACT pathway and metastasis analyses PMID:39506116.
  • 91% of PDX models harbored oncogenic alterations in at least one of AR, RB1, TP53, or PTEN. PMID:38488813
  • TMPRSS2-ERG fusion detected in 13/44 PDX models; correlated with ERG overexpression in AR-expressing models. PMID:38488813
  • CDK12 biallelic loss via dual mutations or structural variation in 4 PDX models; CDK12-loss-associated focal copy-number gains observed. PMID:38488813
  • 63 (2.8%) patients had MSI-H/dMMR tumors, 33 (1.5%) had TMB-H/MSS tumors among 2,257 PRAD patients. MSI-H/dMMR had significantly higher TMB than TMB-H/MSS (median 41 vs. 15 mut/Mb, P<0.01). PMID:38949888
  • BRAF fusions in PRAD: SND1 was the dominant 5’ fusion partner in prostate adenocarcinoma BRAF fusions (21% of PRAD BRAF fusions). PMID:38922339
  • No specific gene-level alterations identified for the oligometastatic hormone-sensitive state; genetic and transcriptomic profiling of hormone-sensitive localized and metastatic castration-resistant PRAD has been described but a hormone-sensitive oligometastatic data set was noted as “still unavailable.” PMID:28045614
  • MSH2, MSH6, MLH1, PMS2 — deleterious MMR gene alterations in 75% of MSI-H/dMMR PRAD patients. PMID:38949888
  • Integrative genomic profiling of 218 PRAD tumors (MSKCC cohort) identified recurrent copy-number alterations and somatic mutations via SNP arrays and whole-exome sequencing PMID:20579941
  • WES of 112 prostate adenocarcinoma tumors identified SPOP, FOXA1, and MED12 as recurrent driver genes PMID:22610119
  • WES of 112 prostate tumors (Michigan cohort, prad_mich) identified recurrent ETS family fusions and SPOP mutations as key drivers of prostate adenocarcinoma PMID:22722839
  • WGS of 55 treatment-naïve primary PRAD identified chromoplexy (chains of ≥5 interdependent rearrangements) in 88% of tumors; TMPRSS2-ERG fusion arose within chromoplexy chains in 58% of ERG+ cases; recurrent SCNA burden tracks with Gleason grade (p=0.0059) PMID:23622249
  • CNA burden (fraction of autosomal genome with copy-number alterations) predicts biochemical recurrence (HR 1.09 per 1%, P<0.001) and metastasis in two independent prostatectomy cohorts (n=168 and n=104); prognostic independent of PSA, Gleason score, and the Stephenson nomogram, and measurable from FFPE needle biopsies by low-pass WGS PMID:25024180
  • Seven patient-derived 3D organoid lines from metastatic CRPC recapitulated the molecular landscape of advanced prostate cancer, including PTEN biallelic loss (6/7 lines), TP53 inactivation (4/7), CHD1 deletion (3/7), SPOP F133L hotspot (1/7, first in vitro model), and diverse AR status; AR-amplified MSK-PCa2 was sensitive to enzalutamide and everolimus in vitro and in xenografts. PMID:25201530
  • Prospective WES + transcriptome sequencing of 150 mCRPC bone/soft-tissue biopsies (SU2C-PCF Dream Team; dataset: prad_su2c_2015): AR altered in 62.7%, ETS fusions 56.7%, TP53 53.3%, PTEN 40.7%; DNA-repair pathway (BRCA2/BRCA1/ATM) aberrations in 19.3% — substantially higher than primary PRAD; 89% of patients harbored a clinically actionable alteration; 8% had pathogenic germline variants; novel recurrent focal homozygous deletion of ZBTB16 at chr11q23 in 5% of cases PMID:26000489
  • Prostate adenocarcinoma (PRAD) multi-omic profiling identified subtypes defined by ETS fusions, SPOP/FOXA1/IDH1 mutations, and distinct epigenetic signatures PMID:26544944
  • Beltran et al. profiled 114 metastatic biopsies from 81 castration-resistant prostate cancer patients (51 CRPC-Adeno, 30 CRPC-NE); concurrent RB1+TP53 loss hallmarks neuroendocrine transdifferentiation (53.3% CRPC-NE vs 13.7% CRPC-Adeno); CYLD deleted in 51% CRPC-NE; 70-gene NEPC classifier (precision/recall >0.99) detects CRPC-NE in up to 8% of metastatic cases across external cohorts PMID:26855148
  • WES + array-CGH + expression microarray on 176 tumors from 63 men with mCRPC (rapid autopsy cohort) showed high intra-individual metastatic concordance for key drivers (AR amplification/mutation 63%, TMPRSS2-ERG 100% concordant); somatic FA-pathway or ATM defects predicted longer carboplatin response (log-rank P=0.02) PMID:26928463
  • TRMT10A overexpressed in prostate cancer/mCRPC vs normal tissue (TCGA prad_tcga; n=500 tumor, n=52 normal); high TRMT10A IHC associated with shorter OS (P=0.014, log-rank) in 54 mCRPC patients; TRMT10A loss sensitizes BRCA1/2-WT mCRPC cells to PARPi (olaparib) by impairing ATM-dependent BRCA1 recruitment; USP10 inhibitor spautin-1 degrades TRMT10A and synergizes with olaparib in 22Rv1 CDX and two mCRPC PDX models PMID:28068672
  • In the MSK-IMPACT pan-cancer cohort (n=10,945 tumors), AR was mutated in 18% of metastatic PRAD vs 1% in TCGA primary tumors; recurrent acquired-resistance hotspots L702H and H875Y were observed in 10 patients each; TP53 was significantly enriched vs TCGA in metastatic prostate cancer; TMPRSS2-ERG was the most common rearrangement (n=151) with 23 cryptic TMPRSS2 rearrangements consistent with chromoplexy; MSI-detected prostate cancer (n=1) responded to anti-PD-L1 therapy. PMID:28481359
  • MET500 metastatic cohort: prostate adenocarcinoma was the largest lineage represented (93/500, 18.6%); AR alterations (12.6%) were lineage-restricted (predominantly PRAD); mutation burden was significantly elevated vs TCGA primaries with the largest increase in prostate cancer; germline pathogenic variants in HOXB13 (3 carriers, prostate-susceptibility allele) observed. PMID:28783718
  • MSK-IMPACT targeted profiling of 504 tumors from 451 PRAD patients spanning locoregional to mCRPC: actionable alterations in 36%, 22% somatic HR-gene alterations, 19% germline pathogenic variants in 221 tested (BRCA2 9%, CHEK2 4%, ATM 2%); AR, TP53, PTEN, RB1, ATM frequencies escalate with castration resistance; TP53 and BRCA2 alterations are early clonal events. PMID:28825054
  • SNPs-seq screen of 374 PRAD GWAS loci nominated rs4519489 (NOL10 intron, 2p25) as functional: A allele drives higher NOL10 expression via USF1 binding; elevated NOL10 tracks with advanced stage, lymph-node metastasis, Gleason score, BCR, and shorter OS across CPGEA, TCGA PRAD, and multiple validation cohorts (meta-analysis BCR HR=2.49, P=1.81e-9). PMID:28927585
  • WES meta-analysis of 1,013 prostate tumor/normal pairs (680 primary, 333 metastatic castration-resistant) identified 97 SMGs; novel drivers include CUL3 (1.3%, SPOP-like), SPEN (2.4%, metastasis-enriched AR-pathway), SF3B1/U2AF1 spliceosome pathway (4%), PIK3R2 p.Asp557Tyr, CDK12 biallelic inactivation, MRE11, and PALB2; TMPRSS2–ERG fusions define the dominant fusion subtype PMID:29610475
  • Pan-cancer fusion study (9,624 TCGA samples) identified TMPRSS2–ERG as the most recurrent single-cancer fusion (38.2% of PRAD, 205 samples); 205 PRAD samples were annotated as druggable via TMPRSS2, making it the largest druggable-fusion group in the pan-cancer cohort PMID:29617662

Subtypes

  • MSI-H/dMMR (2.8%) vs. TMB-H/MSS (1.5%) vs. TMB-L/MSS (95.7%) distinct subgroups by immunogenicity; both MSI-H and TMB-H/MSS are more commonly Gleason grade group 5 (62% and 59% vs. 40%, P<0.001). PMID:38949888
  • Oligometastatic PRAD (≤5 radiographically visible metastatic lesions) operationalized as a clinically defined intermediate state on the metastatic spectrum; working definition endorsed pending a biologic/genomic definition. PMID:28045614
  • NEPC/PRNE: defined by AR expression loss, RB1 enrichment; DDR pathway transcriptomically upregulated. ATLAS RNA classifier distinguishes PRAD from PRNE with AUC=0.834. PMID:38488813 PMID:27634761

Therapeutic landscape

  • NLP-augmented integrated models outperformed stage- or genomics-only models for overall-survival prediction PMID:39506116.
  • MSI-H/dMMR PRAD: 45% RECIST ORR and 65% PSA50 response with immune checkpoint blockade (n=27 treated); MSI-H/dMMR patients should receive somatic tumor testing per NCCN recommendations. PMID:38949888
  • TMB-H/MSS PRAD: 0% RECIST response with ICB despite FDA approval of pembrolizumab for TMB-H tumors; TMB alone is an insufficient biomarker in PRAD. PMID:38949888
  • FGFR1 downstream signature (NRP2, LRP4, TGFBI) stratifies patients for FGFR-targeted therapy in bone-metastatic CRPC; PARP inhibition investigated in NEPC. PMID:38488813
  • ctDNA detection associated with higher VTE rates in PRAD patients (5% of pan-cancer cohort); anticoagulation associated with lower VTE in ctDNA-positive patients (adjusted HR=0.50). PMID:39147831
  • ATLAS lineage de-differentiation score prognostic for prostate cancer survival and neuroendocrine transformation detection. PMID:27634761
  • ROBIN OligoMET center (U54 CA273956; UMB, Weill Cornell Medicine, Thomas Jefferson University) conducts parallel co-clinical studies in oligometastatic PRAD: the TERPS Phase II RCT (NCT05223803) of metastasis-directed SABR had enrolled 47 patients (80+ screened) as of writing; digital-pathology multimodal AI, plasma proteomics, and T-cell receptor repertoire analyses yielded preliminary SABR-benefit signatures. Preclinical dietary interventions showed low-fat/calorie-restricted diets enhanced radiosensitivity while ketogenic diets promoted radio-resistance. These findings catalyzed the biomarker-designed KNIGHTS integral-biomarker RCT (NCT06212583). OligoMET also explicitly investigates molecular drivers of poorer outcomes in African-American patients. PMID:41941260
  • Local metastasis-directed therapies (e.g., SABR) in oligometastatic hormone-sensitive PRAD may alter natural history by ablating macroscopic metastases acting as “communal sanctuaries” seeded by circulating tumor cells from multiple sites (self-seeding model); current standard of care remains systemic ADT and any local therapies should be implemented in a clinical trial. PMID:28045614
  • 14q32-encoded microRNA signatures and blood-based biomarkers proposed as candidate oligometastatic biomarkers in PRAD, analogous to NSCLC, but none are clinically validated. PMID:28045614

Sources

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