Background: In cancers with variable natural history, prognostic biomarkers are needed for selecting patients for therapeutic intervention. This is particularly true for prostate cancer, where many screen-detected cases are indolent and predicting adverse outcomes is difficult. Therefore, we developed an expression signature composed of genes involved in cell cycle progression (CCP) and tested its utility in prostate cancer.
Methods: We developed a 46-gene prognostic RNA signature that is based on measuring the expression of CCP genes. The expression score (CCP score) is derived as the normalized mean expression all CCP genes in the signature.
Results: The prognostic utility of the CCP score has been tested in both multiple clinical settings and patient populations. First, it was tested in a post-prostatectomy cohort from the U.S. where the CCP score predicted biochemical recurrence in univariate (χ2 = 34.0, 1df, p = 5·6 × 10-9) and multivariate analysis (χ2 = 21.65, 1df, p = 3.3 × 10-6). CCP score and PSA were the dominant variables in the best predictive model and were much more significant than any other clinical measure. Second, it was tested in a conservatively managed TURP cohort from the UK where the CCP score was the dominant variable for predicting death from prostate cancer in both univariate (χ2 = 92.7, 1df, p = 6.1 × 10-22) and multivariate analyses (χ2 = 42.2, p = 8.2 × 10-11). Third, it was tested in a conservatively managed needle biopsy cohort from the UK where the CCP score was a better univariate predictor of prostate cancer death than any other variable (χ2 = 37·6, 1df, p = 8.6 × 10-10). The best multivariate model from this study included Gleason and PSA, but CCP dominated (HR for one unit increase = 1.65, 95% CI (1.31, 2.09) χ2 = 17.7, P = 3 × 10-5) with Gleason score (χ2 = 12.1, P = 5 × 10-4) and baseline PSA (χ2 = 5.7, P = 0.017) providing significant, but smaller additional contributions.
Conclusions: A CCP expression signature is prognostic in prostate cancer patients at diagnosis and after prostatectomy. It consistently provides information beyond clinical and pathological variables to help differentiate aggressive from indolent disease. Studies aimed at expanding the clinical utility of this signature are warranted and ongoing.
Citation Format: Steven Stone, On behalf of the Transatlantic Prostate Group, Jack Cuzick, Dan Berney, Julia Reid, Gabrielle Fisher, Jerry Lanchbury, Alexander Gutin, Greg Swanson. Cell cycle progression genes differentiate indolent from aggressive prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA6.