Molecular Markers and Death From Prostate Cancer

  1. John Concato, MD, MPH;
  2. Dhanpat Jain, MD;
  3. Edward Uchio, MD;
  4. Harvey Risch, MD, PhD;
  5. William W. Li, MD; and
  6. Carolyn K. Wells, MPH
  1. From Veterans Affairs Clinical Epidemiology Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut; Yale University School of Medicine, New Haven, Connecticut; and the Angiogenesis Foundation, Cambridge, Massachusetts.

    Abstract

    Background: Current methods to assess the prognosis of prostate cancer at the time of diagnosis are limited.

    Objective: To determine whether molecular markers of cell cycle regulation (bcl-2 and p53) and angiogenesis (β-3 integrin, vascular endothelial growth factor, and microvessel density) are associated with increased long-term risk for death among men with prostate cancer.

    Design: Observational cohort study from 1991 to 2006.

    Setting: The Veterans Affairs Healthcare System in New England.

    Patients: Among 64 545 veterans at least 50 years of age, 1313 patients who had incident prostate cancer from 1991 to 1995 were identified. Clinical data were available for 1270 men and complete for 1172 men.

    Measurements: Data were extracted from medical records, including patient age, race, and comorbid conditions, as well as tumor-related anatomical extent, histologic grade (Gleason score), prostate-specific antigen level, symptoms, and treatment. Immunohistochemical analyses of tissue obtained at diagnosis, which used antibodies against the selected markers, were also conducted. Proportional hazards analysis was used to evaluate the association of these factors with death from prostate cancer through 2006.

    Results: At diagnosis, the median age was 72 years, the median prostate-specific antigen level was 10.0 µg/L, and most tumors were moderately differentiated. During an 11- to 16-year follow-up, 71.8% (842 of 1172) of men died, with 21.5% (181 of 842) of deaths attributable to prostate cancer. Among 1007 men with results for all pertinent markers and after adjustment for age and clinical characteristics, bcl-2 (adjusted hazard ratio [HR] for positive vs. negative staining, 1.61 [95% CI, 1.01 to 2.57]; P = 0.045), p53 (adjusted HR for positive vs. negative staining, 1.48 [CI, 1.06 to 2.08]; P = 0.022), and microvessel density (adjusted HR for highest vs. lowest quartile, 3.20 [CI, 1.77 to 5.78]; P < 0.001) were associated with death from prostate cancer.

    Limitations: Results may be affected by residual confounding. Some patients were not included in complete case analyses because information was not available from clinical care records (7.5%) or tissue staining (12.6%).

    Conclusion: Immunohistochemical evidence of bcl-2, p53, or high microvessel density in prostate cancer biopsy specimens at diagnosis is associated with an increased long-term risk for death from prostate cancer.

    Primary Funding Source: Office of Research and Development, Veterans Health Administration.

    Article and Author Information

    • Acknowledgment: The authors thank K. Anderson, M. Aslan, D. Berlowitz, C. Bifulco, D. Blake, D. Cavaliere, P. Crutchfield, N. Cummings, M. de Asis, R. Feinn, G. Fincke, G. Froehlich, G. Gehr, M. Helie, V. Latvis, D. Orlando, M. Palmisano, P. Peduzzi, N. Raheb, M. Rathier, and G. Sullivan. The 9 VA medical centers were Bedford, Boston, Brockton/West Roxbury, Manchester, Newington, Northampton, Providence, West Haven, and White River Junction.

    • Grant Support: By the Clinical Science Research and Development Service, Merit Review Award Program, Office of Research and Development, Veterans Health Administration.

    • Potential Financial Conflicts of Interest: None disclosed.

    • Reproducible Research Statement: Study protocol, statistical code, and data set: Not available.

    • Requests for Single Reprints: John Concato, MD, MPH, Clinical Epidemiology Research Center, Mail Code 151B, Veterans Affairs Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516.

    • Current Author Addresses: Dr. Concato and Ms. Wells: Clinical Epidemiology Research Center, Veterans Affairs Connecticut Healthcare System, Mail Code 151B, 950 Campbell Avenue, West Haven, CT 06516.

    • Dr. Jain: Department of Pathology, Yale University School of Medicine, 20 York Street, EP2-609, New Haven, CT 06510.

    • Dr. Uchio: Division of Urology, Veterans Affairs Connecticut Healthcare System, Mail Code 112, 950 Campbell Avenue, West Haven, CT 06516.

    • Dr. Risch: Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College Street, New Haven, CT 06510.

    • Dr. Li: Angiogenesis Foundation, PO Box 382111, Cambridge, MA 02238.

    • Author Contributions: Conception and design: J. Concato, D. Jain, H. Risch, W.W. Li, C.K. Wells.

    • Analysis and interpretation of the data: J. Concato, D. Jain, E. Uchio, H. Risch, W.W. Li, C.K. Wells.

    • Drafting of the article: J. Concato, E. Uchio.

    • Critical revision of the article for important intellectual content: J. Concato, D. Jain, E. Uchio, H. Risch, W.W. Li, C.K. Wells.

    • Final approval of the article: J. Concato, D. Jain, E. Uchio, H. Risch, W.W. Li, C.K. Wells.

    • Provision of study materials or patients: D. Jain.

    • Statistical expertise: C.K. Wells.

    • Obtaining of funding: J. Concato.

    • Administrative, technical, or logistic support: D. Jain, E. Uchio, H. Risch, W.W. Li.

    • Collection and assembly of data: J. Concato, D. Jain, E. Uchio, H. Risch, C.K. Wells.

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    1. Ann Intern Med May 5, 2009 vol. 150 no. 9 595-603
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