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International Journal of Urology (2014) 21, 1209–1214
doi: 10.1111/iju.12571
Original Article: Clinical Investigation
PTEN loss in biopsy tissue predicts poor clinical outcomes in prostate cancer Prabhakar Mithal,1,4 Emma Allott,2,4 Leah Gerber,2 Julia Reid,3 William Welbourn,3 Eliso Tikishvili,3 Jimmy Park,3 Adib Younus,3 Zaina Sangale,3 Jerry S Lanchbury,3 Steven Stone3 and Stephen J Freedland2,4 1
University of Massachusetts Medical School, Worcester, Massachusetts, 2Duke University, Durham, North Carolina, 3Myriad Genetics, Salt Lake City, Utah, and 4Surgery Department, Durham VA Medical Center, Durham, North Carolina, USA
Abbreviations & Acronyms ADT = androgen deprivation therapy BCR = biochemical recurrence CRPC = castration-resistant prostate cancer PC = prostate cancer PCSM = prostate cancer specific mortality PSA = prostate-specific antigen RP = radical prostatectomy TURP = transurethral resection of the prostate Correspondence: Stephen J Freedland M.D., Departments of Surgery and Pathology, Duke University Medical Center, DUMC Box 2626, Suite 457, MSRB-I, 571 Research Drive, Durham, NC 27710, USA. Email: [email protected] Received 17 December 2013; accepted 17 June 2014. Online publication 5 August 2014
© 2014 The Japanese Urological Association
Objectives: To determine whether PTEN status in prostate biopsy represents a predictor of intermediate and long-term oncological outcomes after radical prostatectomy, and whether PTEN status predicts response to androgen deprivation therapy. Methods: In a retrospective analysis of 77 men treated by radical prostatectomy who underwent diagnostic biopsy between 1992–2006, biopsy samples were stained for PTEN expression by the PREZEON assay with >10% staining reported as positive. Cox proportional hazards and log–rank models were used to assess the correlation between PTEN loss and clinical outcomes. Results: During a median follow-up period after radical prostatectomy of 8.8 years, 39 men (51%) developed biochemical recurrence, four (5%) had castration-resistant prostate cancer, two (3%) had metastasis and two (3%) died from prostate cancer. PTEN loss was not significantly associated with biochemical recurrence (hazard ratio 2.1, 95% confidence interval 0.9–5.1, P = 0.10), but significantly predicted increased risk of castration-resistant prostate cancer, metastasis and prostate cancer-specific mortality (all log–rank, P < 0.0001), and time from androgen deprivation therapy to castration-resistant prostate cancer (log–rank, P = 0.003). No patient without PTEN loss developed metastases or died from prostate cancer. Conclusions: PTEN loss at the time of biopsy seems to predict time to development of metastasis, prostate cancer-specific mortality and, for the first time, castration-resistant prostate cancer and response to androgen deprivation therapy after radical prostatectomy. If confirmed by larger studies, this would support the use of PTEN loss as an early marker of aggressive prostate cancer.
Key words: biochemical recurrence, castration-resistant prostate cancer, prostate cancer, PTEN, prostate cancer-specific mortality.
Introduction The need for better risk stratification in PC is well established. Despite the use of PSA, Gleason score and clinical staging, a substantial number of men with PC continue to be both under-and overtreated.1 Thus, in order to better differentiate aggressive from indolent PC, clinicians are in need of more reliable molecular markers. A growing body of evidence suggests that the PTEN gene, a tumor suppressor that regulates the PI3K/p-AKT pathway, is one of the most commonly deleted genes in PC.2–12 In animal models, complete PTEN loss recapitulates the major hallmarks of aggressive human PC – local tumor invasion, metastases and castration resistance.13 The role of PTEN in human PC progression is supported by multiple studies showing PTEN loss is more frequent in metastatic CRPC compared with localized PC.6,11,12,14,15 However, it is unknown whether PTEN loss in localized tumor can help identify which men are at increased risk of future CRPC development. To understand the prognostic significance of PTEN, multiple studies have examined RP tissue and have shown that PTEN loss in the RP specimen is prognostic for BCR, an intermediate end-point.3,5,10,11,16,17 However, given the marked tumor heterogeneity in PC, it is unclear whether using the more limited amount of tissue available in biopsy samples can yield similar prognostic information. The one study to date that examined this found no significant association between PTEN loss and BCR.18 1209
P MITHAL ET AL.
(a)
(b)
Fig. 1 Images taken at 20× magnification of biopsy samples stained by the PREZEON assay (Myriad Genetics). (a) PTEN-negative prostate biopsy tissue. (b) PTEN-positive prostate biopsy tissue.
Furthermore, although BCR is an end-point linked with later outcomes,19 not all men with BCR progress. As such, it is noteworthy that the two prior studies that examined the association of PTEN loss with clinical outcomes beyond BCR found that PTEN loss in the primary resected tumor predicted the development of metastatic disease among high-risk, but not PCSM in lower-risk men.8,9 However, this has never been tested using biopsy tissue. Collectively, the prior studies leave open two key unanswered questions: (i) Can PTEN loss in the biopsy tissue predict clinical outcomes? and (ii) Can PTEN loss predict outcomes beyond BCR? To address these questions, we carried out a pilot study using an immunohistochemistry technique previously shown to be reliable, sensitive and specific for PTEN loss to assess whether PTEN status in diagnostic prostate biopsy tissue samples is associated with clinical outcomes in PC.20 Furthermore, given that a recent study in mice with early-stage disease and PTEN loss suggested that ADT might actually accelerate disease progression,21 we tested whether PTEN status predicted responses to ADT.
carry out radiographic imaging was at the attending physician’s discretion. CRPC was defined using the Prostate Cancer Working Group 2 criteria: a 25% PSA increase from the nadir and an increase of ≥2 ng/mL. PCSM was defined as death in any patient with metastasis showing progression after ADT. All information relevant to study variables was ascertained from medical records.
Statistical analysis
A retrospective analysis was carried out in 77 men who underwent a diagnostic biopsy between 1992 and 2006 and were subsequently treated by RP at the Veterans Affairs Medical Center in Durham, North Carolina, USA. The entry criteria for the present study included treatment between 1992 and 2006, treatment
International Journal of Urology (2014) 21, 1209–1214
doi: 10.1111/iju.12571
Original Article: Clinical Investigation
PTEN loss in biopsy tissue predicts poor clinical outcomes in prostate cancer Prabhakar Mithal,1,4 Emma Allott,2,4 Leah Gerber,2 Julia Reid,3 William Welbourn,3 Eliso Tikishvili,3 Jimmy Park,3 Adib Younus,3 Zaina Sangale,3 Jerry S Lanchbury,3 Steven Stone3 and Stephen J Freedland2,4 1
University of Massachusetts Medical School, Worcester, Massachusetts, 2Duke University, Durham, North Carolina, 3Myriad Genetics, Salt Lake City, Utah, and 4Surgery Department, Durham VA Medical Center, Durham, North Carolina, USA
Abbreviations & Acronyms ADT = androgen deprivation therapy BCR = biochemical recurrence CRPC = castration-resistant prostate cancer PC = prostate cancer PCSM = prostate cancer specific mortality PSA = prostate-specific antigen RP = radical prostatectomy TURP = transurethral resection of the prostate Correspondence: Stephen J Freedland M.D., Departments of Surgery and Pathology, Duke University Medical Center, DUMC Box 2626, Suite 457, MSRB-I, 571 Research Drive, Durham, NC 27710, USA. Email: [email protected] Received 17 December 2013; accepted 17 June 2014. Online publication 5 August 2014
© 2014 The Japanese Urological Association
Objectives: To determine whether PTEN status in prostate biopsy represents a predictor of intermediate and long-term oncological outcomes after radical prostatectomy, and whether PTEN status predicts response to androgen deprivation therapy. Methods: In a retrospective analysis of 77 men treated by radical prostatectomy who underwent diagnostic biopsy between 1992–2006, biopsy samples were stained for PTEN expression by the PREZEON assay with >10% staining reported as positive. Cox proportional hazards and log–rank models were used to assess the correlation between PTEN loss and clinical outcomes. Results: During a median follow-up period after radical prostatectomy of 8.8 years, 39 men (51%) developed biochemical recurrence, four (5%) had castration-resistant prostate cancer, two (3%) had metastasis and two (3%) died from prostate cancer. PTEN loss was not significantly associated with biochemical recurrence (hazard ratio 2.1, 95% confidence interval 0.9–5.1, P = 0.10), but significantly predicted increased risk of castration-resistant prostate cancer, metastasis and prostate cancer-specific mortality (all log–rank, P < 0.0001), and time from androgen deprivation therapy to castration-resistant prostate cancer (log–rank, P = 0.003). No patient without PTEN loss developed metastases or died from prostate cancer. Conclusions: PTEN loss at the time of biopsy seems to predict time to development of metastasis, prostate cancer-specific mortality and, for the first time, castration-resistant prostate cancer and response to androgen deprivation therapy after radical prostatectomy. If confirmed by larger studies, this would support the use of PTEN loss as an early marker of aggressive prostate cancer.
Key words: biochemical recurrence, castration-resistant prostate cancer, prostate cancer, PTEN, prostate cancer-specific mortality.
Introduction The need for better risk stratification in PC is well established. Despite the use of PSA, Gleason score and clinical staging, a substantial number of men with PC continue to be both under-and overtreated.1 Thus, in order to better differentiate aggressive from indolent PC, clinicians are in need of more reliable molecular markers. A growing body of evidence suggests that the PTEN gene, a tumor suppressor that regulates the PI3K/p-AKT pathway, is one of the most commonly deleted genes in PC.2–12 In animal models, complete PTEN loss recapitulates the major hallmarks of aggressive human PC – local tumor invasion, metastases and castration resistance.13 The role of PTEN in human PC progression is supported by multiple studies showing PTEN loss is more frequent in metastatic CRPC compared with localized PC.6,11,12,14,15 However, it is unknown whether PTEN loss in localized tumor can help identify which men are at increased risk of future CRPC development. To understand the prognostic significance of PTEN, multiple studies have examined RP tissue and have shown that PTEN loss in the RP specimen is prognostic for BCR, an intermediate end-point.3,5,10,11,16,17 However, given the marked tumor heterogeneity in PC, it is unclear whether using the more limited amount of tissue available in biopsy samples can yield similar prognostic information. The one study to date that examined this found no significant association between PTEN loss and BCR.18 1209
P MITHAL ET AL.
(a)
(b)
Fig. 1 Images taken at 20× magnification of biopsy samples stained by the PREZEON assay (Myriad Genetics). (a) PTEN-negative prostate biopsy tissue. (b) PTEN-positive prostate biopsy tissue.
Furthermore, although BCR is an end-point linked with later outcomes,19 not all men with BCR progress. As such, it is noteworthy that the two prior studies that examined the association of PTEN loss with clinical outcomes beyond BCR found that PTEN loss in the primary resected tumor predicted the development of metastatic disease among high-risk, but not PCSM in lower-risk men.8,9 However, this has never been tested using biopsy tissue. Collectively, the prior studies leave open two key unanswered questions: (i) Can PTEN loss in the biopsy tissue predict clinical outcomes? and (ii) Can PTEN loss predict outcomes beyond BCR? To address these questions, we carried out a pilot study using an immunohistochemistry technique previously shown to be reliable, sensitive and specific for PTEN loss to assess whether PTEN status in diagnostic prostate biopsy tissue samples is associated with clinical outcomes in PC.20 Furthermore, given that a recent study in mice with early-stage disease and PTEN loss suggested that ADT might actually accelerate disease progression,21 we tested whether PTEN status predicted responses to ADT.
carry out radiographic imaging was at the attending physician’s discretion. CRPC was defined using the Prostate Cancer Working Group 2 criteria: a 25% PSA increase from the nadir and an increase of ≥2 ng/mL. PCSM was defined as death in any patient with metastasis showing progression after ADT. All information relevant to study variables was ascertained from medical records.
Statistical analysis
A retrospective analysis was carried out in 77 men who underwent a diagnostic biopsy between 1992 and 2006 and were subsequently treated by RP at the Veterans Affairs Medical Center in Durham, North Carolina, USA. The entry criteria for the present study included treatment between 1992 and 2006, treatment
