Reply to ‘It May be Time to Abandon Urine Tests for Bladder Cancer’

Authors: Hideki Furuya PhD 1 and Charles J. Rosser MD, MBA 1
View More View Less
  • 1 University of Hawaii Cancer Center, Clinical and Translational Research Program

“…for whom the bell tolls, It tolls for thee.”

- John Donne

The article, “It May be Time to Abandon Urine Tests for Bladder Cancer”1 reinforces what is widely known within urology: that current urine-based assays for the diagnosis of bladder cancer are subpar. Briefly, the FDA has approved 4 urine-based assays for bladder cancer detection (UroVysion for initial evaluation and tumor surveillance, ImmunoCyt for tumor surveillance, BTA stat for initial evaluation and tumor surveillance, NMP-22 for initial evaluation and tumor surveillance). We have shown that BTA stat is a surrogate for hematuria2 and NMP-22 identifies states of cellular proliferation,3 and thus it is no wonder one can have positive BTA stat or NMP-22 test results in the face of a benign condition. The lack of robustness is also well documented with ImmunoCyt and UroVysion.4 Voided urinary cytology (VUC), the gold standard for noninvasive monitoring, lacks sensitivity, especially in low-grade and low-stage disease. Although VUC is recommended in the American Urological Association (AUA) guidelines for the evaluation of bladder cancer, it is used in <10% of these evaluations.5 The use of these urine-based assays continues to decline each year. Accordingly, current urine tests for bladder cancer are “dead.”

As is evident in most cancers, single biomarkers have inadequate predictive power, and thus the concept that the presence or absence of a single molecular biomarker will aid diagnostic or prognostic evaluation has not proved to be the case. This makes sense when one analyzes the complex interactions between various molecules within a single pathway, the cross-talk between molecular pathways, the redundancy of some pathways, and the oligoclonality of many tumors. Thus, we previously proposed a paradigm shift from single biomarker research to a more global assessment of bladder cancer looking for molecular signatures associated with the disease. Other disease sites have embraced this notion and now have assays in clinical use (eg, Oncotype Dx Colon, MammoPrint, and Genomic Prostate Score).

Although Fantony and Inman1 reinforce these points, little information is given about promising new leads. Several groups are on the precipice of potentially bringing such a multiplex assay to the clinic. For example, in a large multicenter study of 789 subjects, Ribal et al6 recently reported that their 5-gene expression signature consisting of ANXA10, DAB2, HYAL2, SPOCD1, and MAP4K1 possessed a sensitivity and specificity of 81% and 91%, respectively. At the 2016 AUA meeting in San Diego, in a large cohort of 803 subjects, Lotan et al7 reported a 4-gene-expression signature consisting of CDC2, MDK, IGFBP5, and HOXA13, which possessed a sensitivity and negative predictive value of 93% and 97%, respectively. Furthermore, our group previously reported on a multiplex panel of protein biomarkers consisting of ANG, APOE, A1AT, CA9, IL8, MMP9, MMP10, PAI-1, SDC1, and VEGF.8 After review of pooled data from 999 subjects, meta-analysis showed that the combination of 10 biomarkers possessed a higher log odds ratio (3.61; 95% CI, 2.90–4.32) than any single biomarker (H.F. and C.J.R., unpublished data; 2017). Subsequently, we launched a multicenter prospective trial to test the assay in patients with hematuria (gross and microscopic, n=1,600) and those undergoing surveillance for bladder cancer (n=400). Thus, several groups may be within 5 years of having a new validated multiplex assay available for effective cancer risk assessment, early detection, and early diagnosis of bladder cancer, ushering in a new era in bladder cancer diagnosis.

Call for Correspondence

JNCCN is committed to providing a forum to enhance collaboration between academic medicine and the community physician. We welcome comments about the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), articles published in the journal, or any other topic relating to cancer prevention, detection, treatment, supportive care, or survivorship.

Please submit correspondence to JNCCN.edmgr.com or to JNCCN@nccn.org.

Letters should be no more than 400 words, with no more than 5 references if included. Please include the full names, degrees, and affiliations of all letter authors and a phone number or e-mail address for contact.

Letters are considered for publication as space allows. NCCN reserves the right not to publish correspondence for any reason it deems appropriate. All letters are subject to editing and/or abridgment.

References

  • 1.

    Fantony JJ, Inman BA. It may be time to abandon urine tests for bladder cancer. J Natl Compr Canc Netw 2015;13:11631166.

  • 2.

    Miyake M, Goodison S, Rizwani W. Urinary BTA: indicator of bladder cancer or of hematuria. World J Urol 2012;30:869873.

  • 3.

    Miyake M, Goodison S, Giacoia EG. Influencing factors on the NMP-22 urine assay: an experimental model. BMC Urol 2012;12:23.

  • 4.

    Mbeutcha A, Lucca I, Mathieu R. Current status of urinary biomarkers for detection and surveillance of bladder cancer. Urol Clin North Am 2016;43:4762.

    • Search Google Scholar
    • Export Citation
  • 5.

    Elias K, Svatek RS, Gupta S, Ho R, Lotan Y. High-risk patients with hematuria are not evaluated according to guideline recommendations. Cancer 2010;116:29542959.

    • Search Google Scholar
    • Export Citation
  • 6.

    Ribal MJ, Mengual L, Lozano JJ. Gene expression test for the non-invasive diagnosis of bladder cancer: a prospective, blinded, international and multicenter validation study. Eur J Cancer 2016;54:131138.

    • Search Google Scholar
    • Export Citation
  • 7.

    Lotan Y, Raman J & Shariat S The development and clinical validation of a high sensitivity urine biomarker test for the determination of recurrence in urothelial carcinoma patients. Presented at American Urological Association 2016 Annual Meeting; May 6–10, 2016; San Diego, CA. Abstract PI-LBA07.

    • Search Google Scholar
    • Export Citation
  • 8.

    Shimizu Y, Furuya H, Bryant Greenwood P. A multiplex immunoassay for the non-invasive detection of bladder cancer. J Transl Med 2016;14:31.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1.

    Fantony JJ, Inman BA. It may be time to abandon urine tests for bladder cancer. J Natl Compr Canc Netw 2015;13:11631166.

  • 2.

    Miyake M, Goodison S, Rizwani W. Urinary BTA: indicator of bladder cancer or of hematuria. World J Urol 2012;30:869873.

  • 3.

    Miyake M, Goodison S, Giacoia EG. Influencing factors on the NMP-22 urine assay: an experimental model. BMC Urol 2012;12:23.

  • 4.

    Mbeutcha A, Lucca I, Mathieu R. Current status of urinary biomarkers for detection and surveillance of bladder cancer. Urol Clin North Am 2016;43:4762.

    • Search Google Scholar
    • Export Citation
  • 5.

    Elias K, Svatek RS, Gupta S, Ho R, Lotan Y. High-risk patients with hematuria are not evaluated according to guideline recommendations. Cancer 2010;116:29542959.

    • Search Google Scholar
    • Export Citation
  • 6.

    Ribal MJ, Mengual L, Lozano JJ. Gene expression test for the non-invasive diagnosis of bladder cancer: a prospective, blinded, international and multicenter validation study. Eur J Cancer 2016;54:131138.

    • Search Google Scholar
    • Export Citation
  • 7.

    Lotan Y, Raman J & Shariat S The development and clinical validation of a high sensitivity urine biomarker test for the determination of recurrence in urothelial carcinoma patients. Presented at American Urological Association 2016 Annual Meeting; May 6–10, 2016; San Diego, CA. Abstract PI-LBA07.

    • Search Google Scholar
    • Export Citation
  • 8.

    Shimizu Y, Furuya H, Bryant Greenwood P. A multiplex immunoassay for the non-invasive detection of bladder cancer. J Transl Med 2016;14:31.

  • 1.

    Gopalakrishna A, Longo TA, Fantony JJ. The diagnostic accuracy of urine-based tests for bladder cancer varies greatly by patient. BMC Urol 2016;16:30.

    • Search Google Scholar
    • Export Citation
  • 2.

    Gopalakrishna A, Fantony JJ, Longo TA. Anticipatory positive urine tests for bladder cancer [published online ahead of print January 10, 2017]. Ann Surg Oncol, doi: 10.1245/s10434-016-5763-5.

    • Search Google Scholar
    • Export Citation
  • 3.

    van der Aa MN, Steyerberg EW, Sen EF. Patients' perceived burden of cystoscopic and urinary surveillance of bladder cancer: a randomized comparison. BJU Int 2008;101:11061110.

    • Search Google Scholar
    • Export Citation
  • 4.

    Fantony JJ, Longo TA, Gopalakrishna A. Urinary NID2 and TWIST1 methylation to augment conventional urine cytology for the detection of bladder cancer [published online ahead of print January 13, 2017]. Cancer Biomark, doi: 10.3233/CBM-160261.

    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 131 40 7
PDF Downloads 33 27 8
EPUB Downloads 0 0 0