Prospective Validation of an mRNA-based Urine Test for Surveillance of Patients with Bladder Cancer

F. Johannes P.van Valenberg; Andrew M. Hiar; Ellen Wallace; Julia A. Bridge; Donna J. Mayne; Safedin Beqaj; Wade J. Sexton; Yair Lotan; Alon Z. Weizer; Godfrey K. Jansz; Arnulf Stenzl; John F. Danella; Barry Shepard; Kevin J. Cline; Michael B. Williams; Scott Montgomery; Richard D. David; Richard Harris; Eric W. Klein; Timothy J. Bradford; Fred N. Wolk; Karl R. Westenfelder; Andrew F. Trainer; Timothy A. Richardson; Russell B. Egerdie; Bernard Goldfarb; Joseph A. Zadra; Sijian Ge; Suling Zhao; Iris M. Simon; Scott A. Campbell; Brian Rhees; Michael P. Bates; Russell G. Higuchi; J. Alfred Witjes

doi:10.1016/j.eururo.2018.11.055

Prospective Validation of an mRNA-based Urine Test for Surveillance of Patients with Bladder Cancer

F. Johannes P.van Valenberg, Andrew M. Hiar, Ellen Wallace, Julia A. Bridge, Donna J. Mayne, Safedin Beqaj, Wade J. Sexton, Yair Lotan, Alon Z. Weizer, Godfrey K. Jansz, Arnulf Stenzl, John F. Danella, Barry Shepard, Kevin J. Cline, Michael B. Williams, Scott Montgomery, Richard D. David, Richard Harris, Eric W. Klein, Timothy J. BradfordFred N. Wolk, Karl R. Westenfelder, Andrew F. Trainer, Timothy A. Richardson, Russell B. Egerdie, Bernard Goldfarb, Joseph A. Zadra, Sijian Ge, Suling Zhao, Iris M. Simon, Scott A. Campbell, Brian Rhees, Michael P. Bates, Russell G. Higuchi, J. Alfred Witjes

Research output: Contribution to journal › Article › peer-review

66 Scopus citations

Abstract

Background: A fast, noninvasive test with high sensitivity (SN) and a negative predictive value (NPV), which is able to detect recurrences in bladder cancer (BC) patients, is needed. A newly developed urine assay, Xpert Bladder Cancer Monitor (Xpert), measures five mRNA targets (ABL1, CRH, IGF2, UPK1B, and ANXA10) that are frequently overexpressed in BC. Objective: To validate Xpert characteristics in patients previously diagnosed with non-muscle-invasive BC. Design, setting, and participants: Voided precystoscopy urine samples were prospectively collected at 22 sites. Xpert, cytology, and UroVysion were performed. If cystoscopy was suspicious for BC, a histologic examination was performed. Additionally, technical validation was performed and specificity was determined in patients without a history or clinical evidence of BC. Outcome measurements and statistical analysis: Test characteristics were calculated based on cystoscopy and histology results, and compared between Xpert, cytology, and UroVysion. Results and limitations: Of the eligible patients, 239 with a history of BC had results for all assays. The mean age was 71 yr; 190 patients were male, 53 never smoked, and 64% had previous intravesical immunotherapy (35%) or chemotherapy (29%). Forty-three cases of recurrences occurred. Xpert had overall SN of 74% (95% confidence interval [CI]: 60–85) and 83% (95% CI: 64–93) for high-grade (HG) tumors. The NPV was 93% (95% CI: 89–96) overall and 98% (95% CI: 94–99) for HG tumors. Specificity was 80% (95% CI: 73–85). Xpert SN and NPV were superior to those of cytology and UroVysion. Specificity in non-BC individuals (n = 508) was 95% (95% CI: 93–97). Conclusions: Xpert has an improved NPV compared with UroVysion and cytology in patients under follow-up for BC. It represents a promising tool for excluding BC in these patients, reducing the need for cystoscopy. Patient summary: Xpert is an easy-to-perform urine test with good performance compared with standard urine tests. It should help optimize the follow-up of recurrent bladder cancer patients. The Xpert test is a mRNA-based urine assay for bladder cancer detection. In recurrent bladder cancer patients, its test characteristics compare favorably with those of UroVysion and cytology. It represents a promising tool for excluding cancer, thus reducing the need for cystoscopy.

Original language	English (US)
Pages (from-to)	853-860
Number of pages	8
Journal	European urology
Volume	75
Issue number	5
DOIs	https://doi.org/10.1016/j.eururo.2018.11.055
State	Published - May 2019

Keywords

Bladder cancer
Cystoscopy
Diagnostic test
Non-muscle-invasive bladder cancer
Recurrence
Sensitivity
Specificity
Urine test
mRNA

ASJC Scopus subject areas

Urology

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10.1016/j.eururo.2018.11.055

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Valenberg, F. J. P. V., Hiar, A. M., Wallace, E., Bridge, J. A., Mayne, D. J., Beqaj, S., Sexton, W. J., Lotan, Y., Weizer, A. Z., Jansz, G. K., Stenzl, A., Danella, J. F., Shepard, B., Cline, K. J., Williams, M. B., Montgomery, S., David, R. D., Harris, R., Klein, E. W., ... Witjes, J. A. (2019). Prospective Validation of an mRNA-based Urine Test for Surveillance of Patients with Bladder Cancer. European urology, 75(5), 853-860. https://doi.org/10.1016/j.eururo.2018.11.055

Valenberg, FJPV, Hiar, AM, Wallace, E, Bridge, JA, Mayne, DJ, Beqaj, S, Sexton, WJ, Lotan, Y, Weizer, AZ, Jansz, GK, Stenzl, A, Danella, JF, Shepard, B, Cline, KJ, Williams, MB, Montgomery, S, David, RD, Harris, R, Klein, EW, Bradford, TJ, Wolk, FN, Westenfelder, KR, Trainer, AF, Richardson, TA, Egerdie, RB, Goldfarb, B, Zadra, JA, Ge, S, Zhao, S, Simon, IM, Campbell, SA, Rhees, B, Bates, MP, Higuchi, RG & Witjes, JA 2019, 'Prospective Validation of an mRNA-based Urine Test for Surveillance of Patients with Bladder Cancer', European urology, vol. 75, no. 5, pp. 853-860. https://doi.org/10.1016/j.eururo.2018.11.055

@article{845f1c43ae8c41e6b97c057789af1579,

title = "Prospective Validation of an mRNA-based Urine Test for Surveillance of Patients with Bladder Cancer",

abstract = "Background: A fast, noninvasive test with high sensitivity (SN) and a negative predictive value (NPV), which is able to detect recurrences in bladder cancer (BC) patients, is needed. A newly developed urine assay, Xpert Bladder Cancer Monitor (Xpert), measures five mRNA targets (ABL1, CRH, IGF2, UPK1B, and ANXA10) that are frequently overexpressed in BC. Objective: To validate Xpert characteristics in patients previously diagnosed with non-muscle-invasive BC. Design, setting, and participants: Voided precystoscopy urine samples were prospectively collected at 22 sites. Xpert, cytology, and UroVysion were performed. If cystoscopy was suspicious for BC, a histologic examination was performed. Additionally, technical validation was performed and specificity was determined in patients without a history or clinical evidence of BC. Outcome measurements and statistical analysis: Test characteristics were calculated based on cystoscopy and histology results, and compared between Xpert, cytology, and UroVysion. Results and limitations: Of the eligible patients, 239 with a history of BC had results for all assays. The mean age was 71 yr; 190 patients were male, 53 never smoked, and 64% had previous intravesical immunotherapy (35%) or chemotherapy (29%). Forty-three cases of recurrences occurred. Xpert had overall SN of 74% (95% confidence interval [CI]: 60–85) and 83% (95% CI: 64–93) for high-grade (HG) tumors. The NPV was 93% (95% CI: 89–96) overall and 98% (95% CI: 94–99) for HG tumors. Specificity was 80% (95% CI: 73–85). Xpert SN and NPV were superior to those of cytology and UroVysion. Specificity in non-BC individuals (n = 508) was 95% (95% CI: 93–97). Conclusions: Xpert has an improved NPV compared with UroVysion and cytology in patients under follow-up for BC. It represents a promising tool for excluding BC in these patients, reducing the need for cystoscopy. Patient summary: Xpert is an easy-to-perform urine test with good performance compared with standard urine tests. It should help optimize the follow-up of recurrent bladder cancer patients. The Xpert test is a mRNA-based urine assay for bladder cancer detection. In recurrent bladder cancer patients, its test characteristics compare favorably with those of UroVysion and cytology. It represents a promising tool for excluding cancer, thus reducing the need for cystoscopy.",

keywords = "Bladder cancer, Cystoscopy, Diagnostic test, Non-muscle-invasive bladder cancer, Recurrence, Sensitivity, Specificity, Urine test, mRNA",

author = "Valenberg, {F. Johannes P.van} and Hiar, {Andrew M.} and Ellen Wallace and Bridge, {Julia A.} and Mayne, {Donna J.} and Safedin Beqaj and Sexton, {Wade J.} and Yair Lotan and Weizer, {Alon Z.} and Jansz, {Godfrey K.} and Arnulf Stenzl and Danella, {John F.} and Barry Shepard and Cline, {Kevin J.} and Williams, {Michael B.} and Scott Montgomery and David, {Richard D.} and Richard Harris and Klein, {Eric W.} and Bradford, {Timothy J.} and Wolk, {Fred N.} and Westenfelder, {Karl R.} and Trainer, {Andrew F.} and Richardson, {Timothy A.} and Egerdie, {Russell B.} and Bernard Goldfarb and Zadra, {Joseph A.} and Sijian Ge and Suling Zhao and Simon, {Iris M.} and Campbell, {Scott A.} and Brian Rhees and Bates, {Michael P.} and Higuchi, {Russell G.} and Witjes, {J. Alfred}",

note = "Funding Information: Financial disclosures: F. Johannes P. van Valenberg certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Andrew M. Hiar, Ellen Wallace, Suling Zhao, Sijian Ge, Iris M. Simon, Scott A. Campbell, Brian Rhees, Michael P. Bates, and Russell G. Higuchi are employees of Cepheid. Franciscus Johannes P. van Valenberg, Julia A. Bridge, Wade J. Sexton, Alon Z. Weizer, John F. Danella, Barry Shepard, Kevin J. Cline, Michael B. Williams, Timothy J. Bradford, Fred N. Wolk, Andrew F. Trainer, Russell B. Egerdie, Bernard Goldfarb, Godfrey K. Jansz, Eric W. Klein, Donna J. Mayne, Karl R. Westenfelder, Joseph A. Zadra, J. Alfred Witjes: none. Yair Lotan: consultant for Pacific Edge, MDxHealth, PHotocure, and Cepheid; grant and research support from Abbott, Pacific Edge, MDxHealth, Genomedix, and Cepheid. Arnulf Stenzl: speaker for Janssen, Ipsen Pharma, Sanofi Aventis, CureVac, and Astellas; in advisory board of/consultant for Ipsen Pharma, Roche, Janssen, Alere; in the advisory board of Bristol-Myers Squibb; grant and research support from Johnson & Johnson, Roche, Cepheid, Amgen Inc, Bayer AG, CureVac, Immatics Biotechnologies GmbH, Novartis AG, and Karl Storz AG. Timothy A. Richardson: Bayer and Astellas. Publisher Copyright: {\textcopyright} 2018 European Association of Urology",

year = "2019",

month = may,

doi = "10.1016/j.eururo.2018.11.055",

language = "English (US)",

volume = "75",

pages = "853--860",

journal = "European urology",

issn = "0302-2838",

publisher = "Elsevier",

number = "5",

}

TY - JOUR

T1 - Prospective Validation of an mRNA-based Urine Test for Surveillance of Patients with Bladder Cancer

AU - Valenberg, F. Johannes P.van

AU - Hiar, Andrew M.

AU - Wallace, Ellen

AU - Bridge, Julia A.

AU - Mayne, Donna J.

AU - Beqaj, Safedin

AU - Sexton, Wade J.

AU - Lotan, Yair

AU - Weizer, Alon Z.

AU - Jansz, Godfrey K.

AU - Stenzl, Arnulf

AU - Danella, John F.

AU - Shepard, Barry

AU - Cline, Kevin J.

AU - Williams, Michael B.

AU - Montgomery, Scott

AU - David, Richard D.

AU - Harris, Richard

AU - Klein, Eric W.

AU - Bradford, Timothy J.

AU - Wolk, Fred N.

AU - Westenfelder, Karl R.

AU - Trainer, Andrew F.

AU - Richardson, Timothy A.

AU - Egerdie, Russell B.

AU - Goldfarb, Bernard

AU - Zadra, Joseph A.

AU - Ge, Sijian

AU - Zhao, Suling

AU - Simon, Iris M.

AU - Campbell, Scott A.

AU - Rhees, Brian

AU - Bates, Michael P.

AU - Higuchi, Russell G.

AU - Witjes, J. Alfred

N1 - Funding Information: Financial disclosures: F. Johannes P. van Valenberg certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Andrew M. Hiar, Ellen Wallace, Suling Zhao, Sijian Ge, Iris M. Simon, Scott A. Campbell, Brian Rhees, Michael P. Bates, and Russell G. Higuchi are employees of Cepheid. Franciscus Johannes P. van Valenberg, Julia A. Bridge, Wade J. Sexton, Alon Z. Weizer, John F. Danella, Barry Shepard, Kevin J. Cline, Michael B. Williams, Timothy J. Bradford, Fred N. Wolk, Andrew F. Trainer, Russell B. Egerdie, Bernard Goldfarb, Godfrey K. Jansz, Eric W. Klein, Donna J. Mayne, Karl R. Westenfelder, Joseph A. Zadra, J. Alfred Witjes: none. Yair Lotan: consultant for Pacific Edge, MDxHealth, PHotocure, and Cepheid; grant and research support from Abbott, Pacific Edge, MDxHealth, Genomedix, and Cepheid. Arnulf Stenzl: speaker for Janssen, Ipsen Pharma, Sanofi Aventis, CureVac, and Astellas; in advisory board of/consultant for Ipsen Pharma, Roche, Janssen, Alere; in the advisory board of Bristol-Myers Squibb; grant and research support from Johnson & Johnson, Roche, Cepheid, Amgen Inc, Bayer AG, CureVac, Immatics Biotechnologies GmbH, Novartis AG, and Karl Storz AG. Timothy A. Richardson: Bayer and Astellas. Publisher Copyright: © 2018 European Association of Urology

PY - 2019/5

Y1 - 2019/5

N2 - Background: A fast, noninvasive test with high sensitivity (SN) and a negative predictive value (NPV), which is able to detect recurrences in bladder cancer (BC) patients, is needed. A newly developed urine assay, Xpert Bladder Cancer Monitor (Xpert), measures five mRNA targets (ABL1, CRH, IGF2, UPK1B, and ANXA10) that are frequently overexpressed in BC. Objective: To validate Xpert characteristics in patients previously diagnosed with non-muscle-invasive BC. Design, setting, and participants: Voided precystoscopy urine samples were prospectively collected at 22 sites. Xpert, cytology, and UroVysion were performed. If cystoscopy was suspicious for BC, a histologic examination was performed. Additionally, technical validation was performed and specificity was determined in patients without a history or clinical evidence of BC. Outcome measurements and statistical analysis: Test characteristics were calculated based on cystoscopy and histology results, and compared between Xpert, cytology, and UroVysion. Results and limitations: Of the eligible patients, 239 with a history of BC had results for all assays. The mean age was 71 yr; 190 patients were male, 53 never smoked, and 64% had previous intravesical immunotherapy (35%) or chemotherapy (29%). Forty-three cases of recurrences occurred. Xpert had overall SN of 74% (95% confidence interval [CI]: 60–85) and 83% (95% CI: 64–93) for high-grade (HG) tumors. The NPV was 93% (95% CI: 89–96) overall and 98% (95% CI: 94–99) for HG tumors. Specificity was 80% (95% CI: 73–85). Xpert SN and NPV were superior to those of cytology and UroVysion. Specificity in non-BC individuals (n = 508) was 95% (95% CI: 93–97). Conclusions: Xpert has an improved NPV compared with UroVysion and cytology in patients under follow-up for BC. It represents a promising tool for excluding BC in these patients, reducing the need for cystoscopy. Patient summary: Xpert is an easy-to-perform urine test with good performance compared with standard urine tests. It should help optimize the follow-up of recurrent bladder cancer patients. The Xpert test is a mRNA-based urine assay for bladder cancer detection. In recurrent bladder cancer patients, its test characteristics compare favorably with those of UroVysion and cytology. It represents a promising tool for excluding cancer, thus reducing the need for cystoscopy.

AB - Background: A fast, noninvasive test with high sensitivity (SN) and a negative predictive value (NPV), which is able to detect recurrences in bladder cancer (BC) patients, is needed. A newly developed urine assay, Xpert Bladder Cancer Monitor (Xpert), measures five mRNA targets (ABL1, CRH, IGF2, UPK1B, and ANXA10) that are frequently overexpressed in BC. Objective: To validate Xpert characteristics in patients previously diagnosed with non-muscle-invasive BC. Design, setting, and participants: Voided precystoscopy urine samples were prospectively collected at 22 sites. Xpert, cytology, and UroVysion were performed. If cystoscopy was suspicious for BC, a histologic examination was performed. Additionally, technical validation was performed and specificity was determined in patients without a history or clinical evidence of BC. Outcome measurements and statistical analysis: Test characteristics were calculated based on cystoscopy and histology results, and compared between Xpert, cytology, and UroVysion. Results and limitations: Of the eligible patients, 239 with a history of BC had results for all assays. The mean age was 71 yr; 190 patients were male, 53 never smoked, and 64% had previous intravesical immunotherapy (35%) or chemotherapy (29%). Forty-three cases of recurrences occurred. Xpert had overall SN of 74% (95% confidence interval [CI]: 60–85) and 83% (95% CI: 64–93) for high-grade (HG) tumors. The NPV was 93% (95% CI: 89–96) overall and 98% (95% CI: 94–99) for HG tumors. Specificity was 80% (95% CI: 73–85). Xpert SN and NPV were superior to those of cytology and UroVysion. Specificity in non-BC individuals (n = 508) was 95% (95% CI: 93–97). Conclusions: Xpert has an improved NPV compared with UroVysion and cytology in patients under follow-up for BC. It represents a promising tool for excluding BC in these patients, reducing the need for cystoscopy. Patient summary: Xpert is an easy-to-perform urine test with good performance compared with standard urine tests. It should help optimize the follow-up of recurrent bladder cancer patients. The Xpert test is a mRNA-based urine assay for bladder cancer detection. In recurrent bladder cancer patients, its test characteristics compare favorably with those of UroVysion and cytology. It represents a promising tool for excluding cancer, thus reducing the need for cystoscopy.

KW - Bladder cancer

KW - Cystoscopy

KW - Diagnostic test

KW - Non-muscle-invasive bladder cancer

KW - Recurrence

KW - Sensitivity

KW - Specificity

KW - Urine test

KW - mRNA

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Prospective Validation of an mRNA-based Urine Test for Surveillance of Patients with Bladder Cancer

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