br Discussion br In this study we demonstrate
In this study, we demonstrate that genomic alterations of TP53, PTEN, or RB1 are common events across the entire clinical spectrum of significant prostate cancer. Leveraging the application of a clinical-grade targeted sequencing assay (OncoPanel) and using clinical FFPE tumor specimens, we show that men who harbor tumor alterations in these TSGs are at a significantly increased risk of poorer clinical outcomes. Cumulative TSG loss leads to incrementally poorer outcomes and furthermore identifies a subset of adverse-risk patients who may be prospectively identified for investigational therapies.
Our findings demonstrate frequent TP53, PTEN, and RB1 aberrations in advanced prostate cancer , in keeping with an evolutionary model of selective pressure for molecularly and phenotypically resistant clones that are present early and become increasingly frequent with advanced disease.
The prognostic[2T$DIF] impact[23T$DIF] of compound TSG loss (present before testosterone suppression in a minority of patients)[7T$DIF]is consistent with preclinical modeling, suggesting that compound loss leads to more aggressive disease biology through cooperative cellular mechanisms. Loss of TP53, PTEN, and RB1 drives transdifferentiation to a non-AR– driven anaplastic tumor phenotype akin to neuroendocrine prostate cancer [19,20]. Pten/TP53 null prostate progenitor/ stem EPZ-6438 results in the development of neuroendocrine cells and a tumor-initiating phenotype . In mouse models, either Rb1[24T$DIF]or Trp53[2T$DIF] inactivation develops prostatic intraepithelial neoplasia; however, dual inactivation leads to neuroendocrine differentiation with rapid development of metastasis , antiandrogen resistance, and lineage switch through upregulation of Sox2 [13,14], a reprogram-ming factor notably[26T$DIF] upregulated in enzalutamide-resistant prostate cancer cell lines .
Eleven percent of patients with localized disease had evidence of two or more TSG hits, suggesting that initiation of resistant disease can occur early in a subset of patients. We hypothesize that early compound loss of these TSGs results in aggressive disease marked by altered proliferative signaling and early genomic instability well before overt castration resistance.TMB and PGA, markers of global genomic instability, were significantly prognostic for relapse consistent with previous reports [23,24]. Multivari-able analysis adjusting for genomic instability did not demonstrate a significant independent association of increasing gene hits and risk of relapse or castration resistance. The interpretation of this finding requires some consideration. Cumulative TSG loss may well be a repre-sentation of increased genome-wide mutational and copy number burden, the upstream mechanisms that remain unclearly defined. In turn, cumulative TSG loss may be a fundamental driver of genomic instability through aberrant genome maintenance and replication fidelity. Either asso-ciation does not preclude a significant biological role of co-operative TSG loss in disease progression, and the sequence
and complex interplay of these drivers remain an area of active investigation.
The[27$DIF] implications of early TSG aberrations may well be significant, as men with tumor TSG alterations who underwent definitive treatment were at an increased risk of recurrence, independent of clinical stage and ISUP grade. Genomic profiling for TSGs at the time of prostate biopsy may identify tumors harboring compound altera-tions and therefore identify men suitable for study of intensified systemic therapy (such as PI3K/Akt inhibitors for tumor PTEN loss,[28T$DIF]or chemotherapy). In contrast, we observed four (8%) TSG wild-type patients in the CRPC cohort who appeared to be prognostic outliers, with one death at 5.2 yr after CRPC diagnosis despite median OS of about 3 yr in modern trials of treatment-naive M1-CRPC patients [25,26]. It is notable that in the M1-CSPC cohort, there is no evidence of earlier TTCRPC with presence of TSG alterations. This may reflect imprecision in a hospital registry or indicate that response to primary ADT is not affected, as dominant clones are sensitive to castration, but resistant clones emerge with time (either present de novo or secondary) and impact the efficacy of CRPC therapies.