Elsevier

The Lancet Oncology

Volume 13, Issue 11, November 2012, Pages 1105-1113
The Lancet Oncology

Articles
A whole-blood RNA transcript-based prognostic model in men with castration-resistant prostate cancer: a prospective study

https://doi.org/10.1016/S1470-2045(12)70263-2Get rights and content

Summary

Background

Survival for patients with castration-resistant prostate cancer is highly variable. We assessed the effectiveness of a whole-blood RNA transcript-based model as a prognostic biomarker in castration-resistant prostate cancer.

Methods

Peripheral blood was prospectively collected from 62 men with castration-resistant prostate cancer on various treatment regimens who were enrolled in a training set at the Dana-Farber Cancer Institute (Boston, MA, USA) from August, 2006, to June, 2008, and from 140 patients with castration-resistant prostate cancer in a validation set from Memorial Sloan-Kettering Cancer Center (New York, NY, USA) from August, 2006, to February, 2009. A panel of 168 inflammation-related and prostate cancer-related genes was assessed with optimised quantitative PCR to assess biomarkers predictive of survival.

Findings

A six-gene model (consisting of ABL2, SEMA4D, ITGAL, and C1QA, TIMP1, CDKN1A) separated patients with castration-resistant prostate cancer into two risk groups: a low-risk group with a median survival of more than 34·9 months (median survival was not reached) and a high-risk group with a median survival of 7·8 months (95% CI 1·8–13·9; p<0·0001). The prognostic utility of the six-gene model was validated in an independent cohort. This model was associated with a significantly higher area under the curve compared with a clinicopathological model (0·90 [95% CI 0·78–0·96] vs 0·65 [0·52–0·78]; p=0·0067).

Interpretation

Transcriptional profiling of whole blood yields crucial prognostic information about men with castration-resistant prostate cancer. The six-gene model suggests possible dysregulation of the immune system, a finding that warrants further study.

Funding

Source MDX.

Introduction

Castration-resistant prostate cancer is a strikingly heterogeneous disease state that affects patients with varying metastatic burden and symptoms.1 As a result of this heterogeneity, the overall survival of patients with castration-resistant prostate cancer can be extremely variable, ranging from several months to several years. The ability to accurately predict prognosis in men with castration-resistant prostate cancer is crucial to assist with patient counselling and to optimise clinical-trial design and patient stratification.

Several studies have correlated clinical and laboratory variables, including age, functional status, extent of bone and other metastases, prostate-specific antigen (PSA), alkaline phosphatase, and lactate dehydrogenase, with survival in patients with castration-resistant prostate cancer.2, 3, 4 Additionally, points-based nomograms have been developed combining these variables.5, 6 While such nomograms have improved the ability to individualise prognosis, they offer only moderate predictive discrimination, highlighting the need for improved models.

Interactions between blood cells and the peripheral tissue through which blood circulates, including neoplastic tissue, might alter the gene expression of blood cells. Indeed, recent studies have shown that gene-expression profiling of peripheral blood cells could yield diagnostic and prognostic information regarding various disease states.7, 8, 9, 10 Expression profiling of blood offers several practical advantages compared with expression profiling of tumour tissue, including the minimally invasive nature of sample acquisition, relative ease of standardisation of sampling protocols, and the ability to obtain repeated samples over time. In this study, we tested the hypothesis that transcriptional profiling of whole blood could yield prognostic information in men with astration-resistant prostate cancer.

Section snippets

Patient population

The training set comprised 62 patients with castration-resistant prostate cancer, with or without the presence of radiographic metastases, and on various treatment regimens, enrolled at the Dana-Farber Cancer Institute from August, 2006, to June, 2008, on a genitourinary oncology clinical database and biorepository protocol. Whole-blood samples were prospectively collected in PAXgene Blood RNA tubes (PreAnalytiX, Hombrechtikon, Switzerland) from patients in this cohort. The validation set

Results

The baseline characteristics of patients in the training set and validation set were similar, though a slightly higher proportion of patients in the validation set had received previous chemotherapy (table 1).

Blood samples were available from all 62 patients in the training set for gene-expression profiling. As of June 20, 2008, a total of 47 patients in the training set were alive and 15 (24%) had died. All 168 target genes and all pairs of these genes were entered directly as predictors in

Discussion

The prognosis of patients with castration-resistant prostate cancer is extremely heterogeneous and the ability to predict prognosis has been limited by models with only moderate predictive discrimination. We postulated that gene-expression profiling of whole blood, which might be influenced by neoplastic tissue through which blood circulates, could provide insights into the behaviour of malignant disease. Indeed, the peripheral-blood six-gene model was capable of predicting survival in patients

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  • Cited by (0)

    RWR and MG contributed equally to this report

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