Imaging, Diagnosis, Prognosis The Importance of Protein Kinase A in Prostate Cancer: Relationship to Patient Outcome in Radiation Therapy Oncology Group Trial 92-02

Purpose: Wepreviously reported that protein kinase A type I (PKARIα) overexpressionwas predictive of outcome in prostate cancer patients treated with radiotherapy (RT) ± shortterm androgen deprivation (STAD) on Radiation Therapy Oncology Group (RTOG) protocol 86-10. Here, we attempt to verify our prior findings and test the hypothesis that the relationship of the length of AD to patient outcome is affected by PKARIα overexpression. Experimental Design: Therewere 313 cases in theRTOG92-02 study cohortwith available tissue and suitable staining by immunohistochemistry. Median follow-up was 10.1 years. The intensity of PKARIα staining intensity was quantified manually and by image analysis. Multivariate analysesweredone foroverallmortality usingCoxproportional hazardsmodels and for local failure, biochemical failure, distant metastasis, and cause-specific mortality using Fine and Gray's regression models. Results: The expression levels of PKARIα, determined bymanual and image analysis, were strongly correlated (P < 0.0001). In themultivariate analyses,manual-quantified and image analysis–quantified PKARIα staining intensities were independent predictors of distant metastasis (P < 0.01), local failure (P < 0.05), and biochemical failure (P ≤ 0.01). Furthermore, the benefit of long-term AD over STAD was much less when PKARIα expression was high. Conclusions: PKARIα overexpression has been shown in two RTOG trials to be associated withan increased riskof failureafterAD+RT. In this seriesof contemporaryhigh-riskpatients, PKARIα overexpression was associated with diminished response to LTAD + RT relative to STAD + RT, suggesting that such patients would be ideal for a PKARIα knockdown strategy. (Clin Cancer Res 2009;15(17):5478–84) The protein kinase A (PKA) protein belongs to a family of cyclic AMP–dependent holoenzymes that is related to cell proliferation and malignant transformation (1). Preliminary results (2) indicate that PKA type I (PKARIα) knockdown using an antisense strategy significantly inhibits prostate cancer cell growth in vitro and in vivowhen combined with androgen deprivation (AD) and radiation. Thus, PKARIα is a therapeutic target with the potential to enhance response in high-risk men treated with AD and radiation, which currently represents the standard of care for men with high-risk disease. A knockdown approachmay bemost beneficial for prostate cancers that overexpress PKARIα, if such overexpression were associated with worse patient outcome. PKA overexpression has been associated with poor patient outcome for colorectal, breast, and lung cancers (3–5). Recently, we reported that the intensity of PKARIα expression quantified by manual or image analysis methods was significantly related to a higher rate of distant metastasis (DM) in men treated with radiotherapy (RT) alone or RT + short-term AD (STAD) on Radiation Therapy Oncology Group (RTOG) trial 86-10. In this analysis, we attempt to validate and extend our findings in an independent cohort of men treated with RT + STAD or RT + long-term AD (LTAD) as part of RTOG trial 92-02. Our results Authors' Affiliations: Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida; Department of Statistics, Radiation Therapy Oncology Group; Department of Pathology, Drexel University College of Medicine; Department of Pathology, Fox Chase Cancer Center; Department of Radiation Oncology, Albert Einstein Medical Center, Philadelphia, Pennsylvania; Department of Pathology, LDS Hospital, Salt Lake City, Utah; Department of Radiation Oncology, University of Western Ontario, London, Ontario, Canada; Department of Radiation Oncology, Zablocki VA Medical Center, Milwaukee, Wisconsin; Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts; and Department of RadiationOncology,UniversityofMichiganMedicalCenter,AnnArbor,Michigan Received 10/17/08; revised 6/19/09; accepted 6/19/09; published OnlineFirst 8/25/09. Grant support: National Cancer Institute grants CA-006927 and CA-10198401 and Pennsylvania Department of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute and Pennsylvania Department of Health. Requests for reprints: Alan Pollack, Department of Radiation Oncology, University of Miami, Sylvester Cancer Center, 1475 Northwest 12th Avenue, Suite 1500 (D-31), Miami, FL 33136. Phone: 305-243-4916; Fax: 305-2434363; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-2704 5478 Clin Cancer Res 2009;15(17) September 1, 2009 www.aacrjournals.org Research. on May 2, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst August 25, 2009; DOI: 10.1158/1078-0432.CCR-08-2704