Associations of Luminal and Basal Subtyping of Prostate Cancer With Prognosis and Response to Androgen Deprivation Therapy

Zhao, Shuang G.; Chang, S. Laura; Erho, Nicholas; Yu, Menggang; Lehrer, Jonathan; Alshalalfa, Mohammed; Speers, Corey; Cooperberg, Matthew R.; Kim, Won; Ryan, Charles J.; Den, Robert B.; Freedland, Stephen J.; Posadas, Edwin M.; Sandler, Howard M.; Klein, Eric A.; Black, Peter C.; Seiler, Roland; Tomlins, Scott A.; Chinnaiyan, Arul M.; Jenkins, Robert B.; Davicioni, Elai; Ross, Ashley E.; Schaeffer, Edward M.; Nguyen, Paul L.; Carroll, Peter R.; Karnes, R. Jeffrey; Spratt, Daniel E.; Feng, Felix Y.

doi:10.1001/jamaoncol.2017.0751

Cited by 238 publications

(291 citation statements)

References 48 publications

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“…Importantly, we here demonstrate that morphological characteristics of bone metastasis subtypes can be traced back to their corresponding primary tumors (see below). In line with this, the MetA, MetB, and MetC subtypes show phenotypic characteristics resembling those previously described for molecular subtypes of primary prostate tumors: the PC subtypes 2, 1, and 3 (You et al ., ) and the luminal A, luminal B, and basal subtypes as determined by the PAM50 breast cancer panel (Zhao et al ., ), respectively. Taken together, this may suggest that the primary tumor subtype could be maintained in bone metastases.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor

et al. 2019

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Bone metastasis is the lethal end‐stage of prostate cancer (PC), but the biology of bone metastases is poorly understood. The overall aim of this study was therefore to explore molecular variability in PC bone metastases of potential importance for therapy. Specifically, genome‐wide expression profiles of bone metastases from untreated patients ( n = 12) and patients treated with androgen‐deprivation therapy (ADT, n = 60) were analyzed in relation to patient outcome and to morphological characteristics in metastases and paired primary tumors. Principal component analysis and unsupervised classification were used to identify sample clusters based on mRNA profiles. Clusters were characterized by gene set enrichment analysis and related to histological and clinical parameters using univariate and multivariate statistics. Selected proteins were analyzed by immunohistochemistry in metastases and matched primary tumors ( n = 52) and in transurethral resected prostate (TUR‐P) tissue of a separate cohort ( n = 59). Three molecular subtypes of bone metastases (MetA‐C) characterized by differences in gene expression pattern, morphology, and clinical behavior were identified. MetA (71% of the cases) showed increased expression of androgen receptor‐regulated genes, including prostate‐specific antigen (PSA), and glandular structures indicating a luminal cell phenotype. MetB (17%) showed expression profiles related to cell cycle activity and DNA damage, and a pronounced cellular atypia. MetC (12%) exhibited enriched stroma–epithelial cell interactions. MetB patients had the lowest serum PSA levels and the poorest prognosis after ADT. Combined analysis of PSA and Ki67 immunoreactivity (proliferation) in bone metastases, paired primary tumors, and TUR‐P samples was able to differentiate MetA‐like (high PSA, low Ki67) from MetB‐like (low PSA, high Ki67) tumors and demonstrate their different prognosis. In conclusion, bone metastases from PC patients are separated based on gene expression profiles into molecular subtypes with different morphology, biology, and clinical outcome. These findings deserve further exploration with the purpose of improving treatment of metastatic PC.

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Section: Discussionmentioning

confidence: 99%

Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor

et al. 2019

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“…Based on the gene expression profiles generated by GenomeDx Biosciences Decipher Genomics Resource Information Database (Decipher GRID ® ), a recent analysis showed that the genomic signature PAM50, normally applied to breast cancer patients to determine their risk of reappearance, can be used in prostate cancer as well for predicting which individual may take advantage from early initiation of post-operative androgen deprivation therapy (ADT), thus delivering a potential clinical tool to customize the treatment of prostate cancer. This personalized selection of patients will ameliorate treatment outcomes and prevent many patients from unnecessary risks of toxicity [78]. …”

Section: The Precision Neurology Paradigm In Alzheimer’s Diseasementioning

confidence: 99%

Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology

Hampel

Toschi

Babiloni

et al. 2018

JAD

131

113

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The Precision Neurology development process implements systems theory with system biology and neurophysiology in a parallel, bidirectional research path: a combined hypothesis-driven investigation of systems dysfunction within distinct molecular, cellular and large-scale neural network systems in both animal models as well as through tests for the usefulness of these candidate dynamic systems biomarkers in different diseases and subgroups at different stages of pathophysiological progression. This translational research path is paralleled by an “omics”-based, hypothesis-free, exploratory research pathway, which will collect multimodal data from progressing asymptomatic, preclinical and clinical neurodegenerative disease (ND) populations, within the wide continuous biological and clinical spectrum of ND, applying high-throughput and high-content technologies combined with powerful computational and statistical modeling tools, aimed at identifying novel dysfunctional systems and predictive marker signatures associated with ND. The goals are to identify common biological denominators or differentiating classifiers across the continuum of ND during detectable stages of pathophysiological progression, characterize systems-based intermediate endophenotypes, validate multi-modal novel diagnostic systems biomarkers, and advance clinical intervention trial designs by utilizing systems-based intermediate endophenotypes and candidate surrogate markers. Achieving these goals is key to the ultimate development of early and effective individualized treatment of ND, such as Alzheimer’s disease (AD). The Alzheimer Precision Medicine Initiative (APMI) and cohort program (APMI-CP), as well as the Paris based core of the Sorbonne University Clinical Research Group “Alzheimer Precision Medicine” (GRC-APM) were recently launched to facilitate the passageway from conventional clinical diagnostic and drug development towards breakthrough innovation based on the investigation of the comprehensive biological nature of aging individuals. The APMI movement is gaining momentum to systematically apply both systems neurophysiology and systems biology in exploratory translational neuroscience research on ND.

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“…Before tissue sampling for the clinical Decipher assay, a histologic review of the submitted FFPE block was performed by a pathologist. Details regarding pathology procedures, including microarray preprocessing and normalization, have been previously described . Notably, an attempt was made to identify all available FFPE blocks (including lymph node blocks); the block containing the dominant Gleason tumor was selected for RNA isoloation .…”

Section: Methodsmentioning

confidence: 99%

Genomic and clinical characterization of stromal infiltration markers in prostate cancer

Mahal

Alshalalfa

Zhao

et al. 2020

Cancer

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Background The progression of prostate cancer is a complex, multistep process that involves molecular alterations in cells of the tumor and the microenvironment, with associated interactions between the stroma and epithelium. Genomic expression analyses of stromal infiltration markers were performed to determine the significance thereof in prostate cancer. Methods Genome‐wide expression profiles of formalin‐fixed, paraffin‐embedded radical prostatectomy samples were evaluated from a prospective registry cohort (n = 5239) and 3 retrospective institutional cohorts (n = 1135). Two independent stromal gene expression signatures implied stromal infiltration. Cox proportional hazards regression defined the association between stromal infiltration expression and metastasis‐free survival (MFS). Results Stromal expression scores were correlated with stromal signature genes and with other key stromal markers (CAV1, VIM, and TAGLN), basal activity, and CD3 and CD4 immune biomarkers (r > 0.5 for all). The top decile of stromal expression was associated with high genomic risk scores (Decipher ≥ 0.6) , high Cancer of the Prostate Risk Assessment–Postsurgical scores, Gleason 9 to 10 disease, and a higher risk for metastasis (hazard ratio, 2.35; 95% CI, 1.37‐4.02; P = .001). A higher stromal infiltration score was also associated with decreased expression of DNA repair genes and higher radiation sensitivity genomic scores. Postoperative radiation therapy (RT) was associated with an MFS benefit for patients with high stromal scores, but not for patients with low stromal scores (Pinteraction = .02). Conclusions Expression of stromal infiltration markers is correlated with prostate cancer aggressiveness/progression and may be predictive of a response to RT. Stromal infiltration markers should be studied and considered for incorporation into clinical prognostication and decision making.

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Associations of Luminal and Basal Subtyping of Prostate Cancer With Prognosis and Response to Androgen Deprivation Therapy

Cited by 238 publications

References 48 publications

Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor

Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor

Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology

Genomic and clinical characterization of stromal infiltration markers in prostate cancer

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