Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study

Abstract

SUMMARY Background Optimal management of clinically localized prostate cancer presents unique challenges because of its highly variable and often indolent natural history. To predict disease aggressiveness, clinicians combine clinical parameters to create prognostic models, but the accuracy of current models is very limited. There is significant clinical need for biomarkers that improve our ability to predict disease outcome. Methods Using quantitative RT-PCR on RNA from formalin fixed paraffin-embedded tumour samples, we measured the expression level of 31 genes involved in cell cycle progression (CCP genes), created a predefined score and evaluated its ability to predict disease outcome. The signature was tested in a retrospective cohort of 366 patients from the U.S. who had undergone radical prostatectomy, and in a retrospective cohort of 337 men with clinically localized prostate cancer diagnosed by a transurethral resection (TURP) in the UK and managed conservatively. Findings The cell cycle progression signature was a highly significant predictor of outcome in both cohorts. After prostatectomy the CCP score predicted biochemical recurrence in univariate (Hazard ratio (HR) for a one unit change in CCP (doubling) = 1.89; 95% CI (1.54, 2.31) χ2 = 34·0, 1df, p = 5·6 × 10−9) and multivariate analysis (HR = 1.74; 95% CI (1.39, 2.17) χ2 = 21·65, 1df, p = 3·3 ×10−6). The CCP score and PSA were the dominant variables in the best predictive model and were much more significant than any other clinical measure. In the TURP cohort, the CCP score was the dominant variable for predicting death from prostate cancer in both univariate (HR= 2.92; 95% CI (2.38, 3.57) χ2 = 92·7, 1df, p = 6.1 × 10−22) and multivariate analyses (χ2 = 42·2, p = 8·2 × 10−11), where it was much stronger than all other prognostic factors. In no case 4 was there significant evidence for heterogeneity in the hazard ratio for the CCP score across any clinical parameter. Interpretation The CCP score provides a substantial amount of independent information about the risk of recurrence after radical prostatectomy and the risk of death in conservatively managed prostate cancer diagnosed by TURP. Taken together, these studies provide strong evidence that the CCP score is a highly robust prognostic marker which, after additional validation, could have a central role in determining appropriate treatment for prostate cancer patients. Funding Study funded by Cancer Research UK, the Orchid Appeal, US National Institutes of Health (SPORE CA92629), and the Koch Foundation. Molecular testing performed at Myriad Genetics.

Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence

“…Finally, we made an attempt to compare the performance of SigMuc1NW to Prolaris (cell cycle progression/CPC) (Cuzick et al ., 2011) in predicting BCR. The basis for this comparison was the similarities between SigMuc1NW to CPC: (a) like CPC, SigMuc1NW affects cell cycle progression (Table S2A and S2C; also see Discussion), and (b) similar to CPC, SigMuc1NW predicts BCR.…”

“…Between two commercially available multigene panels, Oncotype DX (12 genes plus 5 reference genes) and Prolaris (31 genes), there are no overlapping genes (Cuzick et al ., 2011; Knezevic et al ., 2013). This suggests the coexistence of different genesets with predictive values toward PC recurrence, which might be attributable to the complex mechanisms involved in disease progression.…”

“…Both the 17‐gene Oncotype DX and the 31‐gene Prolaris improve risk stratification of patients with high risk of PC recurrence at time of diagnosis (Albala et al ., 2016; Cuzick et al ., 2011; Klein et al ., 2014; Knezevic et al ., 2013; Oderda et al ., 2017) and after radical prostatectomy (RP) (Cooperberg et al ., 2013; Cullen et al ., 2015). The 22‐gene Decipher predicts metastasis following RP (Erho et al ., 2013; Karnes et al ., 2013; Klein et al ., 2016).…”

Cancer/testis antigens: novel tools for discerning aggressive and non-aggressive prostate cancer

“…In fact, there has already been some success in the identification of subtypes of prostate cancer based on derived sets of signature gene clusters. 44,45 Numerous studies reviewed here strongly suggest that CTAs are good candidates to establish a gene signature that can predict prostate cancer progression as a result of their advanced stage specific and coordinate expression pattern. In the future, CTA gene signatures might complement clinicopathological factors in the molecular differential diagnosis of aggressive and indolent prostate cancer.…”

Clinical Utility of Biomarkers in Localized Prostate Cancer

“…This gene signature was initially derived from a set of 126 candidate genes associated with CCP pathways and narrowed down based on analyses of correlation among the candidate genes. The CCP signature has been evaluated in formalin-fixed paraffin-embedded (FFPE) PCa specimens derived from both radical prostatectomy and prostate biopsy specimens [31]. In clinical validation studies, the CCP signature has demonstrated favorable performance for the prediction of downstream oncologic endpoints.…”