A four-gene transcript score to predict metastatic-lethal progression in men treated for localized prostate cancer: Development and validation studies

Anqi Cheng, Shanshan Zhao, Liesel M. FitzGerald, Jonathan L. Wright, Suzanne Kolb, Robert Jeffrey Karnes, Robert Brian Jenkins, Elai Davicioni, Elaine A. Ostrander, Ziding Feng, Jian Bing Fan, James Y. Dai, Janet L. Stanford

Research output: Contribution to journalArticle

Abstract

Background: Molecular studies have tried to address the unmet need for prognostic biomarkers in prostate cancer (PCa). Some gene expression tests improve upon clinical factors for prediction of outcomes, but additional tools for accurate prediction of tumor aggressiveness are needed. Methods: Based on a previously published panel of 23 gene transcripts that distinguished patients with metastatic progression, we constructed a prediction model using independent training and testing datasets. Using the validated messenger RNAs and Gleason score (GS), we performed model selection in the training set to define a final locked model to classify patients who developed metastatic-lethal events from those who remained recurrence-free. In an independent testing dataset, we compared our locked model to established clinical prognostic factors and utilized Kaplan-Meier curves and receiver operating characteristic analyses to evaluate the model's performance. Results: Thirteen of 23 previously identified gene transcripts that stratified patients with aggressive PCa were validated in the training dataset. These biomarkers plus GS were used to develop a four-gene (CST2, FBLN1, TNFRSF19, and ZNF704) transcript (4GT) score that was significantly higher in patients who progressed to metastatic-lethal events compared to those without recurrence in the testing dataset (P = 5.7 × 10−11). The 4GT score provided higher prediction accuracy (area under the ROC curve [AUC] = 0.76; 95% confidence interval [CI] = 0.69-0.83; partial area under the ROC curve [pAUC] = 0.008) than GS alone (AUC = 0.63; 95% CI = 0.56-0.70; pAUC = 0.002), and it improved risk stratification in subgroups defined by a combination of clinicopathological features (ie, Cancer of the Prostate Risk Assessment-Surgery). Conclusion: Our validated 4GT score has prognostic value for metastatic-lethal progression in men treated for localized PCa and warrants further evaluation for its clinical utility.

Original languageEnglish (US)
Pages (from-to)1589-1596
Number of pages8
JournalProstate
Volume79
Issue number14
DOIs
StatePublished - Jan 1 2019

Fingerprint

Validation Studies
ROC Curve
Prostatic Neoplasms
Area Under Curve
Neoplasm Grading
Genes
Biomarkers
Confidence Intervals
Recurrence
Gene Expression
Messenger RNA
Datasets
Neoplasms

Keywords

  • biomarkers
  • metastatic-lethal
  • prognosis
  • prostate cancer
  • validation

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

A four-gene transcript score to predict metastatic-lethal progression in men treated for localized prostate cancer : Development and validation studies. / Cheng, Anqi; Zhao, Shanshan; FitzGerald, Liesel M.; Wright, Jonathan L.; Kolb, Suzanne; Karnes, Robert Jeffrey; Jenkins, Robert Brian; Davicioni, Elai; Ostrander, Elaine A.; Feng, Ziding; Fan, Jian Bing; Dai, James Y.; Stanford, Janet L.

In: Prostate, Vol. 79, No. 14, 01.01.2019, p. 1589-1596.

Research output: Contribution to journalArticle

Cheng, A, Zhao, S, FitzGerald, LM, Wright, JL, Kolb, S, Karnes, RJ, Jenkins, RB, Davicioni, E, Ostrander, EA, Feng, Z, Fan, JB, Dai, JY & Stanford, JL 2019, 'A four-gene transcript score to predict metastatic-lethal progression in men treated for localized prostate cancer: Development and validation studies', Prostate, vol. 79, no. 14, pp. 1589-1596. https://doi.org/10.1002/pros.23882
Cheng, Anqi ; Zhao, Shanshan ; FitzGerald, Liesel M. ; Wright, Jonathan L. ; Kolb, Suzanne ; Karnes, Robert Jeffrey ; Jenkins, Robert Brian ; Davicioni, Elai ; Ostrander, Elaine A. ; Feng, Ziding ; Fan, Jian Bing ; Dai, James Y. ; Stanford, Janet L. / A four-gene transcript score to predict metastatic-lethal progression in men treated for localized prostate cancer : Development and validation studies. In: Prostate. 2019 ; Vol. 79, No. 14. pp. 1589-1596.
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abstract = "Background: Molecular studies have tried to address the unmet need for prognostic biomarkers in prostate cancer (PCa). Some gene expression tests improve upon clinical factors for prediction of outcomes, but additional tools for accurate prediction of tumor aggressiveness are needed. Methods: Based on a previously published panel of 23 gene transcripts that distinguished patients with metastatic progression, we constructed a prediction model using independent training and testing datasets. Using the validated messenger RNAs and Gleason score (GS), we performed model selection in the training set to define a final locked model to classify patients who developed metastatic-lethal events from those who remained recurrence-free. In an independent testing dataset, we compared our locked model to established clinical prognostic factors and utilized Kaplan-Meier curves and receiver operating characteristic analyses to evaluate the model's performance. Results: Thirteen of 23 previously identified gene transcripts that stratified patients with aggressive PCa were validated in the training dataset. These biomarkers plus GS were used to develop a four-gene (CST2, FBLN1, TNFRSF19, and ZNF704) transcript (4GT) score that was significantly higher in patients who progressed to metastatic-lethal events compared to those without recurrence in the testing dataset (P = 5.7 × 10−11). The 4GT score provided higher prediction accuracy (area under the ROC curve [AUC] = 0.76; 95{\%} confidence interval [CI] = 0.69-0.83; partial area under the ROC curve [pAUC] = 0.008) than GS alone (AUC = 0.63; 95{\%} CI = 0.56-0.70; pAUC = 0.002), and it improved risk stratification in subgroups defined by a combination of clinicopathological features (ie, Cancer of the Prostate Risk Assessment-Surgery). Conclusion: Our validated 4GT score has prognostic value for metastatic-lethal progression in men treated for localized PCa and warrants further evaluation for its clinical utility.",
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T1 - A four-gene transcript score to predict metastatic-lethal progression in men treated for localized prostate cancer

T2 - Development and validation studies

AU - Cheng, Anqi

AU - Zhao, Shanshan

AU - FitzGerald, Liesel M.

AU - Wright, Jonathan L.

AU - Kolb, Suzanne

AU - Karnes, Robert Jeffrey

AU - Jenkins, Robert Brian

AU - Davicioni, Elai

AU - Ostrander, Elaine A.

AU - Feng, Ziding

AU - Fan, Jian Bing

AU - Dai, James Y.

AU - Stanford, Janet L.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Molecular studies have tried to address the unmet need for prognostic biomarkers in prostate cancer (PCa). Some gene expression tests improve upon clinical factors for prediction of outcomes, but additional tools for accurate prediction of tumor aggressiveness are needed. Methods: Based on a previously published panel of 23 gene transcripts that distinguished patients with metastatic progression, we constructed a prediction model using independent training and testing datasets. Using the validated messenger RNAs and Gleason score (GS), we performed model selection in the training set to define a final locked model to classify patients who developed metastatic-lethal events from those who remained recurrence-free. In an independent testing dataset, we compared our locked model to established clinical prognostic factors and utilized Kaplan-Meier curves and receiver operating characteristic analyses to evaluate the model's performance. Results: Thirteen of 23 previously identified gene transcripts that stratified patients with aggressive PCa were validated in the training dataset. These biomarkers plus GS were used to develop a four-gene (CST2, FBLN1, TNFRSF19, and ZNF704) transcript (4GT) score that was significantly higher in patients who progressed to metastatic-lethal events compared to those without recurrence in the testing dataset (P = 5.7 × 10−11). The 4GT score provided higher prediction accuracy (area under the ROC curve [AUC] = 0.76; 95% confidence interval [CI] = 0.69-0.83; partial area under the ROC curve [pAUC] = 0.008) than GS alone (AUC = 0.63; 95% CI = 0.56-0.70; pAUC = 0.002), and it improved risk stratification in subgroups defined by a combination of clinicopathological features (ie, Cancer of the Prostate Risk Assessment-Surgery). Conclusion: Our validated 4GT score has prognostic value for metastatic-lethal progression in men treated for localized PCa and warrants further evaluation for its clinical utility.

AB - Background: Molecular studies have tried to address the unmet need for prognostic biomarkers in prostate cancer (PCa). Some gene expression tests improve upon clinical factors for prediction of outcomes, but additional tools for accurate prediction of tumor aggressiveness are needed. Methods: Based on a previously published panel of 23 gene transcripts that distinguished patients with metastatic progression, we constructed a prediction model using independent training and testing datasets. Using the validated messenger RNAs and Gleason score (GS), we performed model selection in the training set to define a final locked model to classify patients who developed metastatic-lethal events from those who remained recurrence-free. In an independent testing dataset, we compared our locked model to established clinical prognostic factors and utilized Kaplan-Meier curves and receiver operating characteristic analyses to evaluate the model's performance. Results: Thirteen of 23 previously identified gene transcripts that stratified patients with aggressive PCa were validated in the training dataset. These biomarkers plus GS were used to develop a four-gene (CST2, FBLN1, TNFRSF19, and ZNF704) transcript (4GT) score that was significantly higher in patients who progressed to metastatic-lethal events compared to those without recurrence in the testing dataset (P = 5.7 × 10−11). The 4GT score provided higher prediction accuracy (area under the ROC curve [AUC] = 0.76; 95% confidence interval [CI] = 0.69-0.83; partial area under the ROC curve [pAUC] = 0.008) than GS alone (AUC = 0.63; 95% CI = 0.56-0.70; pAUC = 0.002), and it improved risk stratification in subgroups defined by a combination of clinicopathological features (ie, Cancer of the Prostate Risk Assessment-Surgery). Conclusion: Our validated 4GT score has prognostic value for metastatic-lethal progression in men treated for localized PCa and warrants further evaluation for its clinical utility.

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