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Loss of p16 Expression Is of Prognostic Significance in Locally Advanced Prostate Cancer: An Analysis From the Radiation Therapy Oncology Group Protocol 86–10

A. Chakravarti, K. Heydon, C.L. Wu, E. Hammond, A. Pollack, M. Roach, H. Wolkov, P. Okunieff, J. Cox, J. Fontanesi, R. Abrams, M. Pilepich, W. Shipley

From the Radiation Therapy Oncology Group (RTOG) Genitourinary Translational Research Program, representing: Massachusetts General Hospital/Harvard Medical School Department of Radiation Oncology; RTOG Headquarters, Massachusetts General Hospital/Harvard Medical School, Department of Pathology, Boston, MA; Latter-Day Saints Hospital Department of Pathology, Salt Lake City, UT; and the departments of radiation oncology of: Fox Chase Cancer Center, Philadelphia, PA; University of California, San Francisco, San Francisco, CA; Sutter Cancer Center, Sacramento, CA; University of Rochester, Rochester, NY; M.D. Anderson Cancer Center, Houston, TX; Harper Hospital, Detroit, MI; Johns Hopkins Hospital, Baltimore, MD; and St. Joseph Mercy Hospital, Ann Arbor, MI.

Address reprint requests to Arnab Chakravarti, MD; Massachusetts General Hospital, Deparment of Radiation Oncology, 100 Blossom Street, Founders House, Room 536, Boston, MA 02114; email: achakravarti{at}partners.org.

Purpose: The retinoblastoma (RB) cell cycle regulatory pathway is known to be deregulated in virtually all known human tumors. The protein product of the RB gene, pRB, and its upstream regulator, p16, are among the most commonly affected members of this pathway. We investigated the prognostic significance of both pRB and p16 expression in locally advanced prostate cancers, from patients treated on the Radiation Therapy Oncology Group (RTOG) protocol 86–10.

Materials and Methods: Sixty-seven cases from RTOG 86–10 had immunohistochemically stained slides, judged interpretable for both p16 and pRB, available for analysis. Median follow-up was 8.9 years (range, 6.0 to 11.8 years) for surviving patients. Staining for each marker was then correlated with overall survival, local progression, distant metastasis, and disease-specific survival.

Results: Loss of p16 expression, as defined by expression was significantly associated with reduced overall survival (P = .039), disease-specific survival (P = .006), and higher risk of local progression (P = .0007) and distant metastasis (P = .026) in the univariate analysis. In the multivariate analysis, loss of p16 was significantly associated with reduced disease-specific survival (P = .0078) and increased risk of local failure (P = .0035) and distant metastasis (P = .026). A borderline association with reduced overall survival (P = .07) was also evident. Loss of pRB was associated with improved disease-specific survival on univariate (P = .028) and multivariate analysis (P = .043), but carried no other significant outcome associations.

Conclusion: Loss of p16 is significantly associated with adverse clinical outcome in cases of locally advanced prostate cancer.

This study was supported by RTOG U10 CA21661, CCOP U10 CA37422, and Stat U10 CA32115 grants from the National Cancer Institute (NCI). The contents of this manuscript are the sole responsibility of the authors and do not necessarily represent the official views of the NCI.

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