A. Karim Kader

M.D. Ph.D.

University of California, San Diego

Associate Professor

PLCO (Learn more about this study)

PLCO-14

Mar 5, 2013

Genetic Targeted Screening Prediction of Prostate Cancer Mortality

ABSTRACT SUMMARY
Prostate cancer (PCa) is the most common solid organ malignancy affecting American men with approximately 240,000 new cases in 2012. Despite aggressive PCa screening and treatment, over 30,000 deaths from PCa expected annually, making it the second leading cause of cancer related death.1
PCa screening entails regular rectal examinations and prostate specific antigen (PSA) blood testing. Unfortunately, PSA based screening has not led to a definitive improvement in mortality.2 Furthermore, due to the large number needed to screen to save one life and concern regarding overtreatment, the U.S. Preventative Task Force has recommended against PSA-based PCa screening.3 Despite this, there may be some benefit to the early detection and treatment of PCa.4-7 Taken together, this suggests that improved risk stratification prior to generalized PSA based screening may allow for aggressive screening of those men who would benefit the most.
Several genome wide association studies (GWAS) have identified dozens of single nucleotide polymorphisms (SNPs) associated with PCa risk. These are germ-line genetic markers available at any time in an individuals life. A test incorporating 33 PCa risk associated SNPs is highly correlated with PCa risk.8, 9 In a recent study examining a repeat prostate biopsy population, this test outperformed any existing baseline clinical variable for PCa risk prediction including PSA.9
Herein, we seek to evaluate the ability of this genetic test to identify those men at elevated risk for PCa specific mortality thus allowing for genetic targeted prostate cancer screening. The PLCO trial is the largest randomized PCa screening study of American men and is uniquely and perfectly suited to address this question. Furthermore, a nested case control study population already has been genotyped allowing for the direct testing of this hypothesis without further access to the specimens in the biorepository.

OVERALL DESIGN
The study design for this project is a nested case-control study based on the PLCO screening cohort. The case control was previously defined to incorporate high grade, low-grade cancer, and controls. The data contains previously obtained GWAS genetic information that will make up the genetic score. The Genetic score is mulitplication of the indivual odds ratios of 33 SNPS that have been previously associated with prostate cancer risk. Moreover, this data will be linked with the PLCO patient information regarding risk factors for prostate cancer and mortality data.

DATA MANAGEMENT AND SAMPLE SIZE
Once the database has been populated, statistical programs (either STATA or SPSS) will be used to compare groups using chi-square, t-test and ANOVA when appropriate. Multivariate analysis will include logistic regression and odds ratios comparing the groups.
Using the PLCO data with a mortality rate of prostate cancer at 2% (alpha 0.05, beta 80%), subjects at genetic high risk for prostate cancer have 3 times the odds of prostate caner death compared to low risk patients. In order to show this difference a sample size a minimum of 826 subjects are needed (413 vs. 413).

PRIMARY OBJECTIVE
The primary purpose of this study is to assess if men with an elevated genetic risk for developing prostate cancer have increased disease specific mortality as compared to men at low genetic risk.

SECONDARY OBJECTIVES
[1] to investigate associations with prostate cancer genetic risk and all cause mortality and specifically cardiovascular death.
[2] to asses the mean/median genetic score of prostate cancer deaths compared non-prostate cancer deaths.

PRIMARY HYPOTHESIS
Using the PLCO data with a mortality rate of prostate cancer, subjects at genetic high risk for prostate cancer have 3 times the odds of prostate caner death compared to low risk patients.

SECONDARY HYPOTHESIS
[1] There is no difference in the risk of death from competing causes (non-CaP) death between high-risk and low risk prostate cancer.
[2] The median genetic score is significantly higher in those who died of prostate cancer than those died of other causes.