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External Validation of a Biomarker-Based Preoperative Nomogram Predicts Biochemical Recurrence After Radical Prostatectomy

Shahrokh F. Shariat, Jochen Walz, Claus G. Roehrborn, Alexandre R. Zlotta, Paul Perrotte, Nazareno Suardi, Fred Saad, Pierre I. Karakiewicz

From the Cancer Prognostics and Health Outcomes Unit, University of Montreal, Montreal, Quebec; and Department of Urology, Mount Sinai and Princess Margaret Hospitals, University of Toronto, Toronto, Ontario, Canada; Department of Urology, University Medical Centre Eppendorf, Hamburg, Germany; and the Department of Urology, University of Texas Southwestern Medical Centre, Dallas, TX

Corresponding author: Shahrokh F. Shariat, MD, Department of Urology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9110; e-mail: shahrokh.shariat{at}utsouthwestern.edu

	ABSTRACT

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Purpose Biomarker signatures currently are used in several malignancies to guide clinical decision making. Recently, preoperative plasma levels of transforming growth factor-β1 (TGF-β1) and interleukin-6 soluble receptor (IL6-SR) have improved the accuracy of a clinical nomogram that predicted biochemical recurrence after radical prostatectomy. However, this model was never externally validated. We tested the accuracy of this nomogram in an independent, external cohort.

Patients and Methods Preoperative plasma levels of TGF-β1 and IL6-SR were measured in 423 consecutive men who underwent radical prostatectomy and bilateral lymphadenectomy and were used, along with preoperative prostate-specific antigen levels, biopsy Gleason sum, and clinical stage to determine nomogram-derived probabilities of biochemical recurrence–free survival at 5 years after radical prostatectomy. The accuracy of predictions was quantified with the area under the curve (AUC) and calibration plots that graphically displayed the nomogram's performance characteristics. The statistical significance of the difference between the biomarker nomogram and a model designed on the basis of clinical variables alone was tested by using the Mantel-Haenszel statistic.

Results Biochemical recurrence–free survival at 5 years was 77.0% (95% CI, 72.0% to 82.0%). The biomarker-based nomogram was 87.9% accurate versus 71.1% for the nomogram designed on the basis of clinical variables alone (16.8% difference; P < .001). The performance characteristics of the biomarker-based nomogram were superior to those of the clinical nomogram.

Conclusion We confirm that plasma levels of TGF-β1 and IL6-SR considerably enhance the accuracy of the standard preoperative nomogram for the prediction of biochemical recurrence after radical prostatectomy. This model further refines our ability to identify patients at a high risk of biochemical recurrence after radical prostatectomy.

	INTRODUCTION

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In recent years, several nomograms to predict prostate cancer stage and outcomes after definitive therapy have been introduced.^1-6 These predictive models represent the most widely used tools in clinical practice to improve patient counseling and management. Moreover, nomograms to date represent the only truly individualized prediction tools, as they neither average nor group individual patients. Although nomograms are more accurate than tree-regression models, neural networks, and look-up tables, they do not predict with perfect accuracy.⁷ For example, the preoperative nomograms that predict biochemical recurrence–free survival at 5 and 10 years after radical prostatectomy are only 75% and 79% accurate, respectively.^1,4 Inclusion of additional clinical variables, such as the percent of high-grade prostate cancer or the cancer volume at radical prostatectomy, failed to substantially increase nomograms‘ accuracy.^8,9 On the basis of preliminary data, it might be postulated that predictors specifically associated with prostate cancer biologic behavior might further improve the accuracy of existing tools.^10,11 More accurate nomograms could improve the identification of patients who are likely to fail definitive local therapy and who are best suited for adjuvant therapy or clinical trials of early systemic intervention.^12,13

Biomarkers are used currently in several malignancies to assist with treatment decision making.^14-17 For a biomarker to be clinical useful, it must improve the predictive accuracy of established predictors.¹⁸ Despite numerous reports of promising new biomarkers in the urologic literature, only one study demonstrated a statistically significant improvement in predictive accuracy when biomarkers were added to established predictors of cancer control after radical prostatectomy.^14,15 In this report, Kattan et al¹⁴ developed and internally validated a prognostic model that incorporated plasma transforming growth factor-β1 (TGF-β1) and interleukin-6 soluble receptor (IL6-SR) with preoperative prostate-specific antigen (PSA), biopsy Gleason grade, and clinical stage to predict the probability of biochemical recurrence–free survival at 5 years after radical prostatectomy. The addition of biomarkers improved the prediction of biochemical recurrence by a statistically and prognostically substantial margin relative to clinical variables alone (ie, an increase in predictive accuracy from 75% to 83%). Before these encouraging findings can be used in routine clinical practice, they need to be validated in an independent external cohort, which represents the aim of the current study. Our goal was to assess the validity of the biomarker-based model and to quantify the difference in prediction accuracy when evaluation of pretreatment TGF-β1 and IL6-SR are added to standard clinical parameters.

	PATIENTS AND METHODS

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Patient Population
This study received institutional review board approval and was conducted according to Health Insurance Portability and Accountability Act guidelines. We measured preoperative plasma levels of TGF-β1 and IL6-SR in 423 consecutive patients who underwent radical prostatectomy and bilateral lymphadenectomy for clinically localized prostatic adenocarcinoma between July 1994 and November 1997. No patient received neoadjuvant therapy, and none had secondary cancers. Preoperative PSA levels were measured by the Hybritech Tandem-R assay (Hybritech Inc, San Diego, CA). The clinical stage was assigned by the urologic surgeon according to the 1992 TNM system.

Biomarker Measurements
Preoperative plasma levels of TGF-β1 and IL6-SR were measured according to previously published protocols.^10,19,20 Briefly, preoperative plasma samples were prospectively collected into sodium citrate Vacutainer CPT tubes (Becton Dickinson, Franklin Lakes, NJ), were centrifuged at room temperature for 20 minutes at 1,500 x g, and immediately were frozen and stored at –80°C. To quantitatively measure TGF-β1 and IL6-SR levels, we used quantitative immunoassays (R&D Systems, Minneapolis, MN).^10,20 An additional centrifugation step of the plasma was performed at 10,000 x g for 10 minutes at room temperature for complete platelet removal before assessment. Every sample was run in duplicate, and the calculated mean was used for data analysis. Differences between the two measurements were minimal, as shown by the intra-assay precision coefficient of variation of only 6.5% ± 7.3% and 8.6% ± 5.2% for TGF-β1 and IL6-SR, respectively.

Postoperative Follow-Up
Postoperatively, patients were observed to obtain serum PSA measurements every 3 months for the first year, semi-annually from the second through the fifth years, and annually thereafter. Biochemical recurrence was defined as a PSA level 0.2 ng/mL and rising, and the recurrence date was assigned to the first value 0.2 ng/mL. No patient received adjuvant therapy before biochemical recurrence.

Statistical Analysis
To graphically explore the effect of TGF-β1 and IL6-SR on the rate of biochemical recurrence–free survival, we used Kaplan-Meier plots and life-table analyses. For this purpose, quartile-derived cut-offs were used for TGF-β1 and IL6-SR, and the statistical significance of the survival differences across these strata were assessed with the log-rank test. Within the previously published biomarker-based nomogram, the predictor variables consisted of preoperative PSA levels, the primary and secondary biopsy Gleason grades, the clinical stage, preoperative TGF-β1-levels, and preoperative IL6-SR levels (Fig 1).¹⁴ This information was available for all patients. Conversely, the previously published clinical nomogram exclusively relied on preoperative PSA levels, on a combination of primary and secondary biopsy Gleason grades, and on clinical stage.¹ Both nomograms served to derive the 5-year predicted probabilities of biochemical recurrence–free survival. According to previously established methodology that we and others applied to several time-to-event nomograms, the nomogram-derived probabilities of biochemical recurrence at 5 years, obtained with either the biomarker-based nomogram or the clinical nomogram, were compared with the observed rate of biochemical recurrence at 5 years; accuracy was reported by using the area under the curve (AUC).^3,4,21-23 This method also may be applied to censored data, as described by Harrell et al.²⁴ The comparison between nomogram-predicted probabilities and the observed rate of biochemical recurrence at 5 years then were displayed graphically in the format of calibration plots. All statistical analyses were performed by using commercially available software (S-PLUS 2000 Professional; MathSoft Inc, Seattle, WA) with design and hmisc library functions.²⁵ All P values resulted from the use of two-sided statistical tests, and the significance level was set at .05.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Preoperative nomogram for predicting biochemical recurrence–free survival after radical prostatectomy. Preop., preoperative; PSA, prostate-specific antigen; Bx, biopsy; GG, Gleason grade; IL6SR, interleukin-6 soluble receptor; TGFβ1, transforming growth factor–β1.

	RESULTS

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View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier plots that demonstrate (A) the overall rate of biochemical recurrence–free survival, (B) the effects of preoperative levels of transforming growth factor-β1 (TGF-β1), and (C) interleukin-6 soluble receptor (IL6-SR) quartiles on the rate of biochemical recurrence after radical prostatectomy.

The external validation of the biomarker-based nomogram demonstrated 87.9% accuracy. Conversely, the external validation of the nomogram designed exclusively on the basis of clinical variables demonstrated 71.1% accuracy. The observed difference in accuracy was statistically significant (16.8%; P < .001).

Figures 3A and 3B show the calibration plots that compare nomogram-predicted probabilities of biochemical recurrence–free survival at 5 years after surgery with the observed rate of biochemical recurrence–free survival at 5 years. The dotted line represents the performance of an ideal nomogram, in which the predicted outcome would perfectly correspond to the actual outcome. The performance of the nomogram is plotted by the solid line. The biomarker-based nomogram overestimated the probability of biochemical recurrence–free survival by 20% in patients who had a low probability of biochemical recurrence–free survival. The nomogram designed on the basis of clinical variables alone exhibited a more pronounced overestimation compared with the biomarker-based nomogram (Fig 3B).

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Calibration plot of (A) the biomarker nomogram and (B) the clinical nomogram that predicts 5-year biochemical recurrence (BCR)–free survival after radical prostatectomy in the validation cohort.

	DISCUSSION

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We confirmed the strong predictive power of preoperative TGF-β1 and IL6-SR. The addition of preoperative TGF-β1 and IL6-SR to the standard preoperative nomogram improved its predictive accuracy for biochemical recurrence by a clinically and prognostically considerable margin (16.8%). The biomarker-based nomogram performed better in the current validation cohort than in the original development-cohort (predictive accuracy, 87.9% v 83% in the original report).¹⁴ The performance of the models under novel, external testing conditions is usually worse than their performance in the development data set. However, several previous studies also reported better accuracy than in original reports.^1,21,22 For example the preoperative biochemical recurrence–free survival nomogram reported by Kattan et al²² was 74% accurate in internal validation, and it achieved up to 83% accuracy in external validation. Therefore, this report is not the first to indicate better accuracy than in original development cohort.

In the original report, the choice to include TGF-β1 and IL6-SR in this biomarker nomogram was made on the basis of their robust, distinctive, and complimentary association with prostate cancer aggressiveness and metastases at early disease stages, before more obvious clinical evidence of progression occurs.^10,14,19 TGF-β1 and IL6-SR have been shown to play key roles in prostate cancer proliferation, chemotaxis, differentiation, immune response, and angiogenesis. In retrospective pilot studies that comprised 120 consecutive patients who underwent radical prostatectomy for clinically localized prostate cancer, Shariat et al^10,20 reported a strong association between TGF-β1 and IL6-SR and biochemical recurrence. On the basis of these promising findings, we conducted confirmatory retrospective clinical studies that involved larger cohorts of consecutive patients who had undergone prostatectomy to provide a reasonable assurance of the prognostic effectiveness of these biomarkers and to further elucidate the origin of the changes associated with different prostate cancer disease states.¹⁹ We found that, although both biomarkers were associated with frank metastatic disease to lymph nodes, there were definite distinctions in the biomarker associations with clinical and pathologic parameters of the local tumor. For example, preoperative TGF-β1 was associated with features of locally invasive disease, such as extraprostatic extension and seminal vesicle invasion, but was unrelated to the histologic grade of disease. On the other hand, preoperative IL6-SR was associated with a pathologic Gleason sum but not with extraprostatic extension or seminal vesicle invasion. Furthermore, preoperative IL6-SR was positively correlated with local tumor volume, whereas TGF-β1 levels were not. These data together suggest that blood levels of IL6-SR are produced primarily by tumor cells in the primary prostate cancer.^14,19 Furthermore, circulating levels of IL6-SR appear to be associated only with the potential of prostate cancer to metastasize but not with established metastases themselves. In contrast, it appears that circulating levels of TGF-β1 are more closely associated with the metastatic process, either because of direct release from foci of a metastatic tumor or because of the host's response to cancer invasion and dissemination.^14,19

Despite these highly promising characteristics of TGF-β1 and IL6-SR, the clinical usefulness of these new biomarkers must be confirmed by their ability to add unique prognostic information to established predictors.¹⁸ To test this hypothesis, we previously explored the accuracy gain related to the inclusion of TGF-β1 and IL6-SR to the established, externally validated, preoperative nomogram that incorporated standard clinical predictors.^1,14 We found that the addition of preoperative plasma levels of TGF-β1 and IL6-SR increased the predictive accuracy of the standard clinical nomogram by a clinically and statically significant margin.¹⁴ In the current report, we corroborate the gain in predictive accuracy in an independent, external-validation cohort. This report confirms the usefulness of these biomarkers and, in our opinion, substantiates the indication for their use in routine clinical practice.

Our study is not devoid of limitations. First, the end point of the original and the validation study was defined as biochemical recurrence. Although this is a surrogate end point for clinical progression, not all patients with biochemical recurrence will progress to distant metastases and/or prostate cancer–related death.²⁶ Unfortunately, the protracted natural history of prostate cancer limits the availability of more definitive end points. Second, the brevity of follow-up and the relatively small sample size might have undermined the statistical significance and the ability of tested variables to predict the rate of biochemical recurrence. Despite these limitations, we were able to not only demonstrate a highly statistically significant relationship between the markers of interest but also show that these markers can predict with great accuracy the rate of biochemical recurrence. Third, our patients originated from a single institution. Inclusion of several institutions with diverse clinical, ethnic, and other variables could further strengthen the generalizability of our findings.²² Fourth, TGF-β1 and IL6-SR are not yet routinely used in daily practice. Therefore, application of these markers is limited to the centers in which the commercially available ELISA tests are made available for clinical use. The authors will gladly provide information about clinical implementation and cost, which may range from US $10 to $70 (dependent upon the number of used assays) and which is generally less than the cost of tissue samples or gene profiles.

In conclusion, we confirm that the addition of preoperative plasma TGF-β1 and IL6-SR levels to an evaluation increases the predictive accuracy of the standard clinical nomogram for biochemical recurrence after radical prostatectomy by a considerable margin. We therefore recommend adding these biomarkers in prognostic models and considering their use in the routine management of patients who present with clinically localized prostate cancer.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Shahrokh F. Shariat, Jochen Walz, Alexandre R. Zlotta, Fred Saad, Pierre I. Karakiewicz

Financial support: Shahrokh F. Shariat, Jochen Walz, Claus G. Roehrborn, Paul Perrotte, Fred Saad, Pierre I. Karakiewicz

Administrative support: Shahrokh F. Shariat, Claus G. Roehrborn, Paul Perrotte, Fred Saad, Pierre I. Karakiewicz

Provision of study materials or patients: Shahrokh F. Shariat, Claus G. Roehrborn

Collection and assembly of data: Shahrokh F. Shariat, Claus G. Roehrborn

Data analysis and interpretation: Jochen Walz, Shahrokh F. Shariat, Nazareno Suardi, Fred Saad, Pierre I. Karakiewicz

Manuscript writing: Shahrokh F. Shariat, Jochen Walz, Alexandre R. Zlotta, Nazareno Suardi, Pierre I. Karakiewicz

Final approval of manuscript: Shahrokh F. Shariat, Jochen Walz, Claus G. Roehrborn, Alexandre R. Zlotta, Paul Perrotte, Nazareno Suardi, Fred Saad, Pierre I. Karakiewicz

	NOTES

 
Supported in part by the University of Montreal Heath Center Urology Associates, Fonds de la Recherche en Santé du Québec, the University of Montreal Department of Surgery and the University of Montreal Health Center Foundation (P.I.K.); and by the grant of the Vereinigung Norddeutscher Urologen (J.W.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted May 4, 2007; accepted October 16, 2007.

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