Genomic correlates of clinical outcome in advanced prostate cancer

Abstract

Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.

Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Plasticity

“…A significant increase in the fraction of LOH in CRPC-NE as compared to CRPC-Adeno (proportion test, 6 alpha=0.05) was only noted for three genes: BRD7 (51% vs 30% respectively, p=0.005), SMARCD1 (11% vs 3%, p=0.04), and PBRM1 (18% vs 8%, p=0.049) ( Fig.1b). Given the modest differential abundance of genomic lesions, we next queried the expression levels of SWI/SNF subunits by examining RNA-seq data of 572 unique PCa patients, including 20 CRPC-NE cases 4,5 ( Supplementary Table ST1.4). The SMARCA4 ATPase subunit was significantly upregulated, with accompanying downregulation of its mutually exclusive paralogue SMARCA2 (BRM) 17,29 in CRPC-NE (n=20) compared to CRPC-Adeno (n=120): mean difference of averaged log2(FPKM+1) = 0.55 (p=0.015) for SMARCA4 and mean difference = -0.60 (p=0.02) for SMARCA2, respectively ( Fig.…”

“…Although most men are effectively treated by local therapies (surgery and/or radiotherapy) or can be followed by active surveillance, some develop metastatic recurrence or present with metastases at initial diagnosis. The mainstay of treatment for metastatic PCa is androgen deprivation therapy (ADT), but resistance ultimately develops with progression to castration-resistant prostate cancer (CRPC), which typically harbors a "luminal" (adenocarcinoma) differentiation (CRPC-Adeno) with continued dependence on androgen receptor (AR) signaling [3][4][5] . Improved, more potent androgen receptor signaling inhibitors (ARSi) have been developed for metastatic hormone naive prostate cancer in combination with ADT as well as for CRPC patients, yet patients also suffer acquired resistance.…”

“…Garraway et al 6 proposed a broader framework to appreciate the complexity of cancer cell drug resistance, describing three foundational resistance routes: pathway reactivation, pathway bypass and pathway indifference. In CRPC, indifference to AR signaling may manifest with a distinct histomorphology and expression of neural-like markers, leading to neuroendocrine or small cell prostate cancer (CRPC-NE) 5,7,8 . Approximately 10-20% of CRPC cases treated with ARSi display a neuroendocrine phenotype 5,9,10 .…”

“…In CRPC, indifference to AR signaling may manifest with a distinct histomorphology and expression of neural-like markers, leading to neuroendocrine or small cell prostate cancer (CRPC-NE) 5,7,8 . Approximately 10-20% of CRPC cases treated with ARSi display a neuroendocrine phenotype 5,9,10 . CRPC-NE no longer responds to ARSi and carries a dismal prognosis, with a mean overall survival of 7 months and no specific standard of care treatment options available to date 4,11 .…”

Genetic signature of prostate cancer resistant to optimized hK2 targeted alpha-particle therapy

“…Similarly, NTS-based radioligands have been developed for theranostic use 44,45 . NTS/ NTS receptor signaling has, amongst others, been associated with prostate cancer exhibiting neuroendocrine features such as down-regulation or loss of AR and PSA 46,47 . Thus, NTS-based imaging and therapy may be an option to monitor transition to to this very aggressive phenotype and to complement [ 225 Ac]hu11B6 RIT.…”