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109 Expression of androgen and estrogen signalling components and stem cell markers is highly predictive cancer progression of metastatic prostate cancer
109
Expression of androgen and estrogen signalling components and stem cell markers is highly predictive cancer progression of metastatic prostate cancer Eur Urol Suppl 2014;13;e109
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Fujimura T.1 , Takahashi S. 2 , Urano T.3 , Takayama K. 3 , Sugihara T.1 , Obinata D.2 , Yamada Y. 1 , Kumagai J. 1 , Kume H.1 , Ouchi Y. 3 , Inoue S. 3 , Homma Y. 1 1 University
of Tokyo, Dept. of Urology, Tokyo, Japan, 2 Nihon University, Dept. of Urology, Tokyo, Japan, 3 University of Tokyo, Dept. of
Geriastric Medicine, Tokyo, Japan INTRODUCTION & OBJECTIVES: Androgen deprivation therapy (ADT) is effective but transitory prostate cancer (PC). Genes of androgen and estrogen signalling and stem cell (SC)-like cells have crucial roles in clinical progression of PC. This study aimed to predict clinical failure by estimating these PC-related genes. MATERIAL & METHODS: We developed a model to predict clinical failure based on gene analysis of biopsy samples from a training set of 46 men with bony metastatic PC and validated the model using an independent validation set of 30 patients. Serum PSA levels were 8.6– 13,700 ng/mL (mean, 219 ng/mL) and 5.8–8,428 ng/mL (mean, 498 ng/mL), respectively. Cancerous and stromal tissues were separately collected by laser-captured microdissection. The association between mRNA expression of the following genes and clinical failure was analysed: androgen receptor (AR) and its related genes (APP, FOX family, TRIM 36, Oct1, and ACSL 3), stem cell (SC)-like molecules (Klf4, c-Myc, Oct 3/4, and Sox2), estrogen receptor (ER), Her2, PSA, and CRP. RESULTS: In the training set, at the end of the follow-up period (mean follow-up: 1,650 ± 1,319 days) , 9 patients (19%) were alive without PSA relapse, whereas 15 (33%) were alive with biochemical or clinical recurrence, and 22 (48%) died of PC. Logistic regression analyses for predicting PSA recurrence using age, serum PSA levels, GS, T stage, N stage, and EOD showed relatively high AUCs (0.83); however, 11 patients (23%) were misclassified by discriminant analysis. In contrast, the AUCs for Sox2, Her2, and CRP mRNA expression in cancer cells; AR and ERα mRNA expression in stromal cells; and clinical parameters were 1.0 in men with PSA recurrence. Only 2 patients (4%) were misclassified by discriminant analysis. Thus, we selected 10 prognostic factors for cancer-specific survival (CSS): Oct1, TRIM36, Sox2, and c-Myc expression in cancer cells; AR, Klf4, and ERα expression in stromal cells; and PSA, Gleason score, and extent of disease. On the basis of these factors, patients were divided into favorable-, intermediate-, and poor-risk groups which had 0–3, 4–7, and 8–10 risk factors, respectively. Five-year CSS rates for the 3 groups were 90%, 32%, and 12%, respectively. In the independent validation cohort, at the end of the follow-up period (mean follow-up: 1,143 ± 1,226 days) 5 patients (16%) were alive without PSA relapse whereas 13 (43%) were alive with biochemical or clinical recurrence. Twelve patients (40%) died of PC.The model to predict PSA recurrence showed the reproducibility in the validation set. Risk classification using 10 prognostic factors were also highly predictive of clinical course. Five-year CSS rates for the 3 groups were 75%, 48%, and 0%, respectively. CONCLUSIONS: Expression levels of androgen and estrogen signalling components and SC markers are powerful prognostic tools. Men with bony metastatic PC, once identified as having intermediate or poor risk by these predictors, would be offered for adjuvant therapy in addition to ADT.
Expression of androgen and estrogen signalling components and stem cell markers is highly predictive cancer progression of metastatic prostate cancer Eur Urol Suppl 2014;13;e109
Print! Print!
Fujimura T.1 , Takahashi S. 2 , Urano T.3 , Takayama K. 3 , Sugihara T.1 , Obinata D.2 , Yamada Y. 1 , Kumagai J. 1 , Kume H.1 , Ouchi Y. 3 , Inoue S. 3 , Homma Y. 1 1 University
of Tokyo, Dept. of Urology, Tokyo, Japan, 2 Nihon University, Dept. of Urology, Tokyo, Japan, 3 University of Tokyo, Dept. of
Geriastric Medicine, Tokyo, Japan INTRODUCTION & OBJECTIVES: Androgen deprivation therapy (ADT) is effective but transitory prostate cancer (PC). Genes of androgen and estrogen signalling and stem cell (SC)-like cells have crucial roles in clinical progression of PC. This study aimed to predict clinical failure by estimating these PC-related genes. MATERIAL & METHODS: We developed a model to predict clinical failure based on gene analysis of biopsy samples from a training set of 46 men with bony metastatic PC and validated the model using an independent validation set of 30 patients. Serum PSA levels were 8.6– 13,700 ng/mL (mean, 219 ng/mL) and 5.8–8,428 ng/mL (mean, 498 ng/mL), respectively. Cancerous and stromal tissues were separately collected by laser-captured microdissection. The association between mRNA expression of the following genes and clinical failure was analysed: androgen receptor (AR) and its related genes (APP, FOX family, TRIM 36, Oct1, and ACSL 3), stem cell (SC)-like molecules (Klf4, c-Myc, Oct 3/4, and Sox2), estrogen receptor (ER), Her2, PSA, and CRP. RESULTS: In the training set, at the end of the follow-up period (mean follow-up: 1,650 ± 1,319 days) , 9 patients (19%) were alive without PSA relapse, whereas 15 (33%) were alive with biochemical or clinical recurrence, and 22 (48%) died of PC. Logistic regression analyses for predicting PSA recurrence using age, serum PSA levels, GS, T stage, N stage, and EOD showed relatively high AUCs (0.83); however, 11 patients (23%) were misclassified by discriminant analysis. In contrast, the AUCs for Sox2, Her2, and CRP mRNA expression in cancer cells; AR and ERα mRNA expression in stromal cells; and clinical parameters were 1.0 in men with PSA recurrence. Only 2 patients (4%) were misclassified by discriminant analysis. Thus, we selected 10 prognostic factors for cancer-specific survival (CSS): Oct1, TRIM36, Sox2, and c-Myc expression in cancer cells; AR, Klf4, and ERα expression in stromal cells; and PSA, Gleason score, and extent of disease. On the basis of these factors, patients were divided into favorable-, intermediate-, and poor-risk groups which had 0–3, 4–7, and 8–10 risk factors, respectively. Five-year CSS rates for the 3 groups were 90%, 32%, and 12%, respectively. In the independent validation cohort, at the end of the follow-up period (mean follow-up: 1,143 ± 1,226 days) 5 patients (16%) were alive without PSA relapse whereas 13 (43%) were alive with biochemical or clinical recurrence. Twelve patients (40%) died of PC.The model to predict PSA recurrence showed the reproducibility in the validation set. Risk classification using 10 prognostic factors were also highly predictive of clinical course. Five-year CSS rates for the 3 groups were 75%, 48%, and 0%, respectively. CONCLUSIONS: Expression levels of androgen and estrogen signalling components and SC markers are powerful prognostic tools. Men with bony metastatic PC, once identified as having intermediate or poor risk by these predictors, would be offered for adjuvant therapy in addition to ADT.