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NOXA and PUMA Expression Add to Clinical Markers in Predicting Biochemical Recurrence of Prostate Cancer Patients in a Survival Tree Model

Authors' Affiliations: ¹ Centre de Recherche du Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal, ² Department of Pathology, McGill University Health Centre, ³ Service d'Anatomopathologie, Hôpital du Sacré-Coeur de Montréal, ⁴ Département de Médecine, and ⁵ Département d'Urologie, Université de Montréal, Montréal, Québec, Canada

Requests for reprints: Fred Saad, Centre de Recherche du Centre Hospitalier de l'Université de Montréal/Hôpital Notre-Dame/Institut du Cancer de Montréal, 1560 rue Sherbrooke est, Montréal, Québec, Canada, H2L 4M1. Phone: 514-890-8000, ext. 27466; Fax: 514-412-7620; E-mail: fred.saad.chum{at}ssss.gouv.qc.ca.

Purpose: To assess the expression of proapoptotic NOXA and PUMA in prostate tissues and delineate their association with prostate cancer (PCa) recurrence.

Experimental Design: Normal, prostatic intraepithelial neoplasia (PIN), hormone-sensitive (HS) PCa, and hormone-refractory (HR) PCa tissues were used to build tissue microarrays encompassing a total of 135 patients. Two observers assessed the intensity of NOXA and PUMA immunohistochemical staining using a composite color scale. One hundred and eighty recursive partitioning and regression tree (RPART) models were generated to predict biochemical recurrence (BCR) within HS cancer patients using NOXA, PUMA, and clinical parameters. Models were then ranked according to the integrated Brier score (IBS).

Results: Increasing NOXA expression was associated with PCa progression, reaching the highest levels in HR PCa. Increased NOXA expression was observed in 68% of HS cancer patients and was predictive of BCR (LR = 8.64; P = 0.003). In contrast, PUMA expression was highest in HS cancer, and although 70% of HS cancer patients exhibited increased PUMA expression, PUMA alone could not predict the onset of BCR. Interestingly, the top-ranking RPART model generated [IBS = 0.107; 95% confidence interval (95% CI), 0.065-0.128] included surgical margin status and NOXA and PUMA expression, although recurrent prognostic classification schemes obtained in the top 10 models favored a survival tree model containing margin status, NOXA expression, and preoperative prostate-specific antigen (PSA) (IBS = 0.114; 95% CI, 0.069-0.142).

Conclusion: We conclude that NOXA and PUMA expression may be linked to PCa progression and propose further validation of a survival tree model including surgical margin status, NOXA expression, and preoperative PSA for predicting BCR.