Dataset Information

Longitudinal modeling of ultrasensitive and traditional prostate-specific antigen and prediction of biochemical recurrence after radical prostatectomy.

ABSTRACT: Ultrasensitive prostate-specific antigen (u-PSA) remains controversial for follow-up after radical prostatectomy (RP). The aim of this study was to model PSA doubling times (PSADT) for predicting biochemical recurrence (BCR) and to capture possible discrepancies between u-PSA and traditional PSA (t-PSA) by utilizing advanced statistical modeling. 555 RP patients without neoadjuvant/adjuvant androgen deprivation from the Turku University Hospital were included in the study. BCR was defined as two consecutive PSA values >0.2?ng/mL and the PSA measurements were log₂-transformed. One third of the data was reserved for independent validation. Models were first fitted to the post-surgery PSA measurements using cross-validation. Major trends were then captured using linear mixed-effect models and a predictive generalized linear model effectively identified early trends connected to BCR. The model generalized for BCR prediction to the validation set with ROC-AUC of 83.6% and 95.1% for the 1 and 3 year follow-up censoring, respectively. A web-based tool was developed to facilitate its use. Longitudinal trends of u-PSA did not display major discrepancies from those of t-PSA. The results support that u-PSA provides useful information for predicting BCR after RP. This can be beneficial to avoid unnecessary adjuvant treatments or to start them earlier for selected patients.

SUBMITTER: Laajala TD

PROVIDER: S-EPMC5090356 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Longitudinal modeling of ultrasensitive and traditional prostate-specific antigen and prediction of biochemical recurrence after radical prostatectomy.

Laajala Teemu D TD Seikkula Heikki H Seyednasrollah Fatemeh F Mirtti Tuomas T Boström Peter J PJ Elo Laura L LL

Scientific reports 20161102

Ultrasensitive prostate-specific antigen (u-PSA) remains controversial for follow-up after radical prostatectomy (RP). The aim of this study was to model PSA doubling times (PSADT) for predicting biochemical recurrence (BCR) and to capture possible discrepancies between u-PSA and traditional PSA (t-PSA) by utilizing advanced statistical modeling. 555 RP patients without neoadjuvant/adjuvant androgen deprivation from the Turku University Hospital were included in the study. BCR was defined as two ...[more]

PMID: 27805011

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Project description:Accurate estimation of recurrence risk is needed for optimal treatment of clinically localized prostate cancer (PCa) patients. We combined classical clinicopathological predictors of biochemical recurrence (BCR) and molecular markers into a new risk score for predicting BCR after radical prostatectomy (RP). A retrospective study which included 122 PCa patients who attended our department between 2000 and 2007 was conducted. Total RNA was isolated from formalin-fixed paraffin embedded PCa tissue. Gene expression patterns were analyzed in 21 selected samples from 7 localized, 6 locally advanced, and 8 metastatic PCa patients using Illumina microarrays. Expression levels of 41 genes were validated by quantitative PCR in an independent retrospective series of 101 patients with ≥ 10 years follow-up who underwent RP for clinically localized PCa. Univariate and multivariate logistic regression analysis were used to identify individual predictors of BCR. A risk score (RS) for predicting BCR including clinicopathological and gene expression data was developed and Kaplan-Meier curves were generated. Interaction networks between the genes of the model were built by GeneMANIA Cytoscape plugin. In a median follow-up of 120 months (range 3-190), 37 patients developed BCR (36.6%). Expression levels of 7,930 transcripts differed between clinically localized and locally advanced-metastatic PCa groups (FDR<0.1). A set of 41 genes were validated by quantitative PCR. Regression analysis showed that expression of ASF1B and MCL1 as well as Gleason score, extracapsular extension, seminal vesicle invasion and positive margins were independent prognostic factors of BCR. A RS generated using these gene expression and clinicopathological variables was able to discriminate between two groups of patients with a significantly different probability of BCR (HR 6.24; CI 3.23-12.4, p<0.01), improving the individual discriminative performance of each of these variables on their own. Direct interactions between the two genes of the model were not found. In conclusion, identification of new gene expression patterns associated with a high probability of BCR in clinically localized PCa patients treated with RP, and their combination with clinicopathological variables in a robust, easy-to-use and reliable classifier may contribute to improve PCa risk stratification and, consequently, to tailor treatment and surveillance strategies in these patients.

Project description:The objective of this study was to utilize a microarray platform to determine the microRNA (miRNA) expression profile in prostate cancer tissue from patients who underwent radical prostatectomy and were followed for an average of 47 months. The GeneChip® miRNA Array (Affymetrix) contains more than 46,000 probes, and more than 1,100 mature human miRNAs and transcripts. An expression level higher or lower than 1.1 with a p<0.05 were considered to be differentially expressed. When tumors with a GS<7 were compared with those with a GS≥7, five miRNAs were down-regulated and nine were up-regulated. In comparing tumors from patients with PSA <10 ng/mL vs. those with PSA ≥10 ng/mL, 21 miRNAs were down-regulated and 29 were overexpressed. There was decreased expression of 21 miRNAs and increased expression of 22 miRNAs when pT2 and pT3 tumors were compared. The comparison of the expression profiles of men with vs. without recurrent disease (PSA>0.2 ng/mL) revealed that 14 miRNAs were down-regulated and 17 were up-regulated. Considering the three prognostic factors and biochemical recurrence, miR-335 was overexpressed in pT3 tumors in patients with PSA>10 ng/mL, miR-1202 was overexpressed in recurrent tumors in which PSA >10 ng/mL, and miR-885 and miR-1226 were overexpressed in recurrent pT3 tumors. Six miRNAs (miR- 361, 378, 548, 574, 652 and 892) had decreased expression in pT3 tumors in patients with PSA >10 ng/mL. miR-16 was down-regulated in recurrent pT3 tumors. miR-92 and miR-450 exhibited decreased expression in recurrent tumors in patients with PSA > 10 ng/mL. miR-28 was down-regulated in pT3 adenocarcinomas with a GS ≥ 7. The differentially expressed miRNAs in recurrent tumors were validated using qRT-PCR in 74 additional specimens. miR-21 was overexpressed in recurrent tumors, and in the Cox model, expression levels higher than 0.64 were indicative of biochemical recurrence with a risk of 2.4. These results, which were based on clinical specimens from patients treated in a standardized way and followed for an average of 47 months, provide an initial understanding of the role of miRNAs in prostatecancer progression; the foremost representative is miR-21, which has been implicated in the progression of various human cancers.

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Dataset Information

Longitudinal modeling of ultrasensitive and traditional prostate-specific antigen and prediction of biochemical recurrence after radical prostatectomy.

Publications

Longitudinal modeling of ultrasensitive and traditional prostate-specific antigen and prediction of biochemical recurrence after radical prostatectomy.

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