Protein Kinase A RI-α Predicts for Prostate Cancer Outcome: Analysis of Radiation Therapy Oncology Group Trial 86-10
Received 11 October 2007; accepted 6 December 2007. published online 02 May 2008.
Purpose
The RI-α regulatory subunit of protein kinase A type 1 (PKA) is constitutively overexpressed in human cancer cell lines and is associated with active cell growth and neoplastic transformation. This report examined the association between PKA expression and the endpoints of biochemical failure (BF), local failure (LF), distant metastasis (DM), cause-specific mortality (CSM), and overall mortality in men treated with radiotherapy, with or without short-term androgen deprivation in Radiation Therapy Oncology Group trial 86-10.
Methods and Materials
Pretreatment archival diagnostic tissue samples from 80 patients were stained for PKA by immunohistochemical methods from a parent cohort of 456 cases. PKA intensity was scored manually and by image analysis. The Cox proportional hazards model for overall mortality and Fine and Gray's regression models for CSM, DM, LF and BF were then applied to determine the relationship of PKA expression to the endpoints.
Results
The pretreatment characteristics of the missing and determined PKA groups were not significantly different. On univariate analyses, a high PKA staining intensity was associated with BF (image analysis, continuous variable, p = 0.022), LF (image analysis, dichotomized variable, p = 0.011), CSM (manual analysis, p = 0.037; image analysis, continuous, p = 0.014), and DM (manual analysis, p = 0.029). On multivariate analyses, the relationships to BF (image analysis, continuous, p = 0.03), LF (image analysis, dichotomized, p = 0.002), and DM remained significant (manual analysis, p = 0.018). In terms of CSM, a trend toward an association was seen (manual analysis, p = 0.08; image analysis, continuous, p = 0.09).
Conclusion
PKA overexpression was significantly related to patient outcome and is a potentially useful biomarker for identifying high-risk prostate cancer patients who might benefit from a PKA knockdown strategy.
∗Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA
†Radiation Therapy Oncology Group, American College of Radiology, Philadelphia, PA
‡Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA
§Department of Pathology, LDS Hospital, Intermountain Health Care, Salt Lake City, UT
¶Department of Pathology, Indiana University, Indianapolis, IN
‖Department of Radiation, LDS Hospital, Salt Lake City, UT
#Department of Radiation Oncology, UCLA Medical Center, Los Angeles, CA
∗∗Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY
††Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI
Reprint requests to: Alan Pollack, M.D., Ph.D., Department of Radiation Oncology, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111. Tel: (215) 728-2940; Fax: (215) 728-2868
Supported in part by Grants CA-006927, CA-101984-01, CA-21661, and CA-32115 from the National Cancer Institute and grants from Varian Medical Systems, Palo Alto, CA and the Pennsylvania Department of Health.
The contents are solely the responsibility of the authors and do not necessarily represent the official views of the supporting organizations.
ABSTRACT