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Prognostic Value of p16 in Locally Advanced Prostate Cancer: A Study Based on Radiation Therapy Oncology Group Protocol 9202

Arnab Chakravarti, Michelle DeSilvio, Min Zhang, David Grignon, Seth Rosenthal, Sucha O. Asbell, Gerald Hanks, Howard M. Sandler, Li-Yan Khor, Alan Pollack, William Shipley

From the Massachusetts General Hospital/Harvard Medical School, Boston, MA; American College of Radiology; Albert Einstein Medical Center; Fox Chase Cancer Center, Philadelphia, PA; Harper Hospital, Detroit; University of Michigan Medical Center, Ann Arbor, MI; and Radiological Associates of Sacramento, Sacramento, CA

Address reprint requests to Arnab Chakravarti, MD, Massachusetts General Hospital, Department of Radiation Oncology, 100 Blossom St, Cox 3, Boston, MA 02114; e-mail: achakravarti{at}partners.org

Purpose: Deregulation of the retinoblastoma (RB) pathway is commonly found in virtually all known human tumors. p16, the upstream regulator of RB, is among the most commonly affected member of this pathway. In the present study, we examined the prognostic value of p16 expression in men with locally advanced prostate cancer who were enrolled on Radiation Therapy Oncology Group protocol 9202.

Patients and Methods: RTOG 9202 was a phase III randomized study comparing long-term (LT) versus short-term (ST) androgen-deprivation therapy (AD). Of the 1,514 eligible cases, 612 patients had adequate tumor material for p16 analysis. Expression levels of p16 were determined by immunohistochemistry (IHC). IHC staining was scored quantitatively using an image analysis system.

Results: On multivariate analysis, intact p16 expression was significantly associated with decreased rate of distant metastases (P = .0332) when both STAD and LTAD treatment arms were considered together. For patients with intact (high levels of immunostaining) p16 (mean p16 index > 81.3%), LTAD plus radiotherapy (RT) significantly improved prostate cancer survival (PCS) compared with STAD plus RT (P = .0008) and reduced the frequency of distant metastasis (P = .0069) compared with STAD plus RT. In contrast, for patients with tumors demonstrating p16 loss (low levels of immunostaining, mean p16 index 81.3%), LTAD plus RT significantly improved biochemical no evidence of disease survival over STAD (P < .0001) primarily by decreasing the frequency of local progression (P = .02), as opposed to distant metastasis, which was the case in the high-p16 cohort.

Conclusion: Low levels of p16 on image analysis appear to be associated with a significantly higher risk of distant metastases among all study patients. p16 expression levels also appear to identify patients with locally advanced prostate cancer with distinct patterns of failure after LTAD.

This study was supported by RTOG U10CA21661, CCOP U10CA37422, Stat U10CA32115 from the National Cancer Institute to the Radiation Therapy Oncology Group, and the Pennsylvania Department of Health and R01 CA101984-01 (A.P.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.