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JU INSIGHT Urinary Analysis of FGFR3 and TERT Gene Mutations Enhances Performance of Cxbladder Tests and Improves Patient Risk Stratification
By: Yair Lotan, MD, University of Texas Southwestern, Dallas; Jay D. Raman, MD, Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania; Badrinath Konety, MD, Allina Health Cancer Institute, Minneapolis, Minnesota; Siamak Daneshmand, MD, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles; Florian Schroeck, MD, White River Junction Veteran Affairs Medical Center, Vermont; Shahrokh F. Shariat, MD, Comprehensive Cancer Center, Medical University of Vienna, Austria, Weill Cornell Medical College, New York, New York, University of Texas Southwestern, Dallas, Charles University, Prague, Czech Republic, Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Jordan; Peter Black, MD, University of British Columbia, Vancouver, Canada; Michel de Lange, PhD, Pacific Edge Ltd, Dunedin, New Zealand; Scott Asroff, MD, New Jersey Urology, Mount Laurel Township; Evan Goldfischer, MD, Premier Medical Group, Poughkeepsie, New York; Mitchell Efros, MD, Accumed Research Associates, Garden City, New York; Kian Tai Chong, MD, Surgi-TEN Specialists, Farrer Park Hospital, Singapore, PanAsia Surgery, Mount Elizabeth Novena Specialist Centre, Singapore; Eugene Huang, MD, KK Women’s and Children’s Hospital, Singapore; Hong Liang Chua, MD, KK Women’s and Children’s Hospital, Singapore; Qing Hui Wu, MD, National University Hospital, Singapore; Siying Yeow, MD, Khoo Teck Puat Hospital, Singapore; Weida Lau, MD, Khoo Teck Puat Hospital, Singapore; Jin Yong, MD, Singapore General Hospital, Singapore; Molly Eng, MD, Khoo Teck Puat Hospital, Singapore | Posted on: 20 Apr 2023
Lotan Y, Raman JD, Konety B, et al. Urinary analysis of FGFR3 and TERT gene mutations enhances performance of Cxbladder tests and improves patient risk stratification. J Urol. 2023;209(4):762-772.
Study Need and Importance
Most bladder cancer patients have hematuria but few hematuria patients have cancer, resulting in many evaluations with normal cystoscopy. Noninvasive tests with high negative predictive value could spare patients unnecessary discomfort and cost of cystoscopy. We hypothesized that adding DNA single nucleotide polymorphisms to the mRNA genomic markers of current Cxbladder urinary tests Triage and Detect resulting in an enhanced Cxbladder-Triage (CxbT+) and enhanced Cxbladder-Detect (CxbD+) would improve their accuracy and ability to risk stratify hematuria patients for bladder cancer risk.
What We Found
In 804 patients, CxbT+ had significantly improved specificity (78% vs 63%; P < .001) and CxbD+ had significantly improved sensitivity (97% vs 74%; P < .001) and specificity (90% vs 82%; P < .001) compared with the respective first-generation tests (see Table). The negative predictive value for CxbD+ was 99.7% and the only 2 false-negative tests were in patients with low-grade Ta tumors (see Table). Eighty-three percent of patients were CxbD+-negative and could therefore have been spared cystoscopy. The incidence of bladder cancer was 44% in CxbD+-positive patients in the pooled cohort, compared with 7.7% of patients who were at intermediate or high risk based on the American Urological Association hematuria guidelines.
Table. Comparison of Diagnostic Performance Characteristics of Enhanced Cxbladder-Triage and Enhanced Cxbladder-Detect Compared With the First-generation Cxbladder-Triage and Cxbladder-Detect Tests
| Parameter | U.S. cohort (n=344) | Singaporean cohort (n=460) | Pooled cohort (n=804) | |||
|---|---|---|---|---|---|---|
| Cxbladder-Triage | CxbT | CxbT+ | CxbT | CxbT+ | CxbT | CxbT+ |
| Sensitivity, % (95% CI) | 93 (77-99) | 97 (82-100) | 84 (67-95) | 94 (79-99) | 89 (78-95) | 95 (86-99) |
| CxbT+ vs CxbT incremental difference, % | +4 | +10 | +6 | |||
| Specificity, % (95% CI) | 38 (33-44) | 58 (53-64) | 81 (77-84) | 93 (90-95) | 63 (59-66) | 78 (75-81) |
| CxbT+ vs CxbT incremental difference, % | +20 | +12 | +15 | |||
| Rule-out rate, % (95% CI) | 35 (30-41) | 54 (48-59) | 76 (72-80) | 87 (83-90) | 59 (55-62) | 73 (69-76) |
| CxbT+ vs CxbT incremental difference, % | +19 | +11 | +14 | |||
| Cxbladder-Detect | CxbD | CxbD+ | CxbD | CxbD+ | CxbD | CxbD+ |
| Sensitivity, % (95% CI) | 69 (49-85) | 97 (82-100) | 78 (60-91) | 97 (84-100) | 74 (61-84) | 97 (89-100) |
| CxbD+ vs CxbD incremental difference, % | +28 | +19 | +23 | |||
| Specificity, % (95% CI) | 74 (69-79) | 85 (81-89) | 88 (85-91) | 94 (91-96) | 82 (79-85) | 90 (88-92) |
| CxbD+ vs CxbD incremental difference, % | +11 | +6 | +8 | |||
| Rule-out rate, % (95% CI) | 70 (65-75) | 78 (73-82) | 84 (80-87) | 87 (84-90) | 78 (75-81) | 83 (81-86) |
| CxbD+ vs CxbD incremental difference, % | +8 | +3 | +5 | |||
| Abbreviations: CI, confidence interval; CxbD, first-generation Cxbladder-Detect; CxbD+, enhanced Cxbladder-Detect; CxbT, first-generation Cxbladder-Triage; CxbT+, enhanced Cxbladder-Triage. | ||||||
Limitations
Pooled data sets from different countries were used, with differences in patient demographics and clinical characteristics, as well as differences in test performance. The results may have been affected by referral and selection bias, and some of the study samples had also been used during the development of the enhanced Cxbladder tests. External validation is needed and ongoing.
Interpretation for Patient Care
The enhanced Cxbladder tests were analytically validated in an ethnically diverse population of hematuria patients. Use of these tests may improve risk stratification and allow more patients without cancer to avoid cystoscopy.
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