Poster Title

ABSTRACT #59ABSTRACT #59

Cell cycle progression genes differentiate indolent from aggressive prostate cancer.Steven Stone1Jack Cuzick2, Julia Reid1, David Mesher2, Henrik Møller3, V.O. Speights4, Gabrielle Fisher2, Jerry Lanchbury1, Alexander Gutin1, Greg Swanson5 and on behalf of the Transatlantic Prostate Group.

Myriad Genetics1, Cancer Research UK2, King’s College London3, Texas A&M School of Medicine4, and University of Texas Health Science Center San Antonio5

Prostate cancer is the most commonly diagnosed malignancy in men, but many patients have indolent disease that is unlikely to cause significant morbidity or mortality1. Biomarkers that accurately predict disease severity would enable physicians to more appropriately manage patient care. Data from previous studies indicated that cell cycle proliferation (CCP) were prognostic in some cancers 2-4. Here, we developed a CCP expression signature, and tested its utility to predict prostate cancer outcomes. After radical prostatectomy, CCP expression was a strong univariate (p-value = 5.6 x 10-9, HR = 1.89; 95% CI: 1.54, 2.31) and multivariate predictor of biochemical recurrence (p-value = 5.6 x 10-6, HR = 1.75). We also showed that CCP score predicts prostate cancer death in a conservatively managed cohort diagnosed with prostate cancer after TURP. The CCP score was the dominant variable in univariate analyses (p-value = 6.1 x 10-22; HR = 2.92; 95% CI: 2.38, 3.57). In multivariate analysis including PSA and Gleason score, CCP score remained highly significant (p-value = 2.5 x 10-8; HR= 2.40) and was the dominat prognostic factor.

OBJECTIVES

1) Evaluate whether CCP gene expression is prognostic in prostate cancer.

2) Determine if CCP expression levels add prognostic information beyond the clinical and pathological features typically used to predict disease outcome.

3) Determine if CCP is robust to patient composition and clinical setting.

CONCLUSION

A CCP expression signature is prognostic in prostate cancer patients at diagnosis and after prostatectomy. In both settings, it provided information beyond clinical and pathological variables and helped to differentiate aggressive from indolent disease.

REFERENCES

1) Jemal A et al., 2009, CA Cancer J Clin, 59 (4): 225.

2) Mosley J and Keri R, 2008, BMC Med Genomics, 1: 11.

3) Shedden K et al., 2008, Nat Med, 14(8): 822.

4) Zhang J et al., 2009. PLoS ONE, 4(7): e6274.

ABSTRACT

RESULTS

METHODS

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Using publically available expression data, we selected 126 candidate CCP genes for inclusion in our signature. Taqman assays for all 126 genes were run against 96 commercially obtained, anonymous FFPE prostate tumor samples without clinical data. Assays were ranked by Pearson's correlation coefficient (assuming they all measured the same process), and final gene selection was made from a ranked list. The expression score was derived as the mean of all selected genes.

The signature was tested in a retrospective cohort of 366 patients from the U.S. who had undergone radical prostatectomy (RP), 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.

Association with biochemical recurrence was evaluated using Cox PH models and likelihood ratio tests. All p-values are two-sided.

Figure 1 A) Kaplan-Meier plot of CCP score versus recurrence. B) Hazard Ratio of CCP score in subgroups determined by Gleason grade, baseline PSA, pathologic tumor stage, and surgical margins.

Variable Death (Prostate Cancer)

N Chi-sq [univariate]

p-value Hazard Ratio(95% CI)

CCP (continuous) 334 31.1 [92.5] 2.5 × 10-8 2.40 (1.77, 3.24)

Logarithm PSA (continuous) 334 32.3 [59.5] 1.3 × 10-8 1.76 (1.42, 2.18)

Gleason Score (continuous) 334 7.7 [92.7] 5.5 × 10-3 1.41 (1.10, 1.81)

VariableBiochemical Recurrence (N=353)

Hazard Ratio (95% CI) ChiSquared (1 df) p-value

CCP Score 1.75 (1.39, 2.21) 20.40 5.6 x 10-6

log(1+baseline PSA) 1.97 (1.47, 2.65) 20.07 7.1 x 10-6

Gleason Score

<7 1 (ref)

7 1.10 (0.71, 1.70) 2.52 0.11

>7 2.09 (1.05, 4.17)

pathological stage 1.15 (0.87, 1.51) 0.94 0.33

pathological grade 1.23 (0.88, 1.71) 1.45 0.23

surgical margins 1.97 (0.99, 3.91) 4.17 0.04

extracapsular extension 1.21 (0.55, 2.69) 0.22 0.64

bladder 2.03 (1.05, 3.90) 3.82 0.05

seminal vesicle 1.44 (0.67, 3.06) 0.86 0.36

lymph node 1.44 (0.66, 3.14) 0.80 0.37

age at surgery 1.02 (0.98, 1.05) 0.80 0.37

Table 1: Summary multivariate statistical analysis of RP cohort

Table 2: Summary of pre-planned multivariate statistical analysis of TURP cohort

Figure 2 A) Kaplan-Meier plot of CCP score versus prostate cancer death. B) Hazard Ratio of CCP score in subgroups determined by Gleason grade, baseline PSA, KI−67 levels, and extent of disease