Tamara Jamaspishvili1,2, Palak G Patel1,2, Yi Niu3,4, Thiago Vidotto1,5,6, Isabelle Caven1,2, Rachel Livergant1,2, Winnie Fu1,2, Atsunari Kawashima1,2,7, Nathan How1,2, John B Okello1,2, Liana B Guedes8, Veronique Ouellet9, Clarissa Picanço6, Madhuri Koti1,5,10, Rodolfo B Reis11, Fred Saad9,12, Anne-Marie Mes-Masson9,13, Tamara L Lotan8,14, Jeremy A Squire6, Yingwei P Peng3,15,16, D Robert Siemens10, David M Berman1,2,5. 1. Division of Cancer Biology & Genetics, Queen's Cancer Research Institute, Kingston, ON K7L 3N6, Canada. 2. Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada. 3. Division of Cancer Care and Epidemiology, Queen's Cancer Research Institute, Kingston, ON K7L 3N6, Canada. 4. School of Mathematical Sciences, Dalian University of Technology, Dalian, Liaoning 116024, China. 5. Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 2V7, Canada. 6. Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, Brazil. 7. Department of Urology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan. 8. Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA. 9. Institut du Cancer de Montréal and Centre de Recherche du Centre hospitalier de l, 'Université de Montréal, Montréal, Québec H2X 0A9, Canada. 10. Urology, Queen's University, Kingston, ON K7L 2V7, Canada. 11. Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14048-900, Brazil. 12. Department of Surgery, Université de Montréal, Montréal, Québec H2X 0A9, Canada. 13. Department of Medicine, Université de Montréal, Montréal, Québec H3C 3J7, Canada. 14. Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA. 15. Department of Public Health Sciences, Queen's University, Kingston, ON K7L 3N6, Canada. 16. Mathematics and Statistics, Queen's University, Kingston, ON K7L 3N6, Canada.
Abstract
BACKGROUND: Phosphatase and tensin homolog (PTEN) loss has long been associated with adverse findings in early prostate cancer. Studies to date have yet to employ quantitative methods (qPTEN) for measuring of prognostically relevant amounts of PTEN loss in postsurgical settings and demonstrate its clinical application. METHODS: PTEN protein levels were measured by immunohistochemistry in radical prostatectomy samples from training (n = 410) and validation (n = 272) cohorts. PTEN loss was quantified per cancer cell and per tissue microarray core. Thresholds for identifying clinically relevant PTEN loss were determined using log-rank statistics in the training cohort. Univariate (Kaplan-Meier) and multivariate (Cox proportional hazards) analyses on various subpopulations were performed to assess biochemical recurrence-free survival (BRFS) and were independently validated. All statistical tests were two-sided. RESULTS: PTEN loss in more than 65% cancer cells was most clinically relevant and had statistically significant association with reduced BRFS in training (hazard ratio [HR] = 2.48, 95% confidence interval [CI] = 1.59 to 3.87; P < .001) and validation cohorts (HR = 4.22, 95% CI = 2.01 to 8.83; P < .001). The qPTEN scoring method identified patients who recurred within 5.4 years after surgery (P < .001). In men with favorable risk of biochemical recurrence (Cancer of the Prostate Risk Assessment - Postsurgical scores <5 and no adverse pathological features), qPTEN identified a subset of patients with shorter BRFS (HR = 5.52, 95% CI = 2.36 to 12.90; P < .001) who may be considered for intensified monitoring and/or adjuvant therapy. CONCLUSIONS: Compared with previous qualitative approaches, qPTEN improves risk stratification of postradical prostatectomy patients and may be considered as a complementary tool to guide disease management after surgery.
BACKGROUND: Phosphatase and tensin homolog (PTEN) loss has long been associated with adverse findings in early prostate cancer. Studies to date have yet to employ quantitative methods (qPTEN) for measuring of prognostically relevant amounts of PTEN loss in postsurgical settings and demonstrate its clinical application. METHODS:PTEN protein levels were measured by immunohistochemistry in radical prostatectomy samples from training (n = 410) and validation (n = 272) cohorts. PTEN loss was quantified per cancer cell and per tissue microarray core. Thresholds for identifying clinically relevant PTEN loss were determined using log-rank statistics in the training cohort. Univariate (Kaplan-Meier) and multivariate (Cox proportional hazards) analyses on various subpopulations were performed to assess biochemical recurrence-free survival (BRFS) and were independently validated. All statistical tests were two-sided. RESULTS:PTEN loss in more than 65% cancer cells was most clinically relevant and had statistically significant association with reduced BRFS in training (hazard ratio [HR] = 2.48, 95% confidence interval [CI] = 1.59 to 3.87; P < .001) and validation cohorts (HR = 4.22, 95% CI = 2.01 to 8.83; P < .001). The qPTEN scoring method identified patients who recurred within 5.4 years after surgery (P < .001). In men with favorable risk of biochemical recurrence (Cancer of the Prostate Risk Assessment - Postsurgical scores <5 and no adverse pathological features), qPTEN identified a subset of patients with shorter BRFS (HR = 5.52, 95% CI = 2.36 to 12.90; P < .001) who may be considered for intensified monitoring and/or adjuvant therapy. CONCLUSIONS: Compared with previous qualitative approaches, qPTEN improves risk stratification of postradical prostatectomy patients and may be considered as a complementary tool to guide disease management after surgery.
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