Urothelial Bladder Cancer

Reviewed on July 22, 2024

Introduction

  • Virtual Molecular Tumor Board
  • Patient: Urothelial bladder cancer
  • Carolinas HealthCare System/Levine Cancer Institute
  • Presented by: Dr. Earle Burgess

History- Part 1

  • 65-year-old male presented with gross hematuria in 2013.
    • Cystoscopic evaluation identified a large bladder tumor on the right lateral/posterior wall.
    • August 2013: Transurethral resection of bladder tumor identified high grade papillary urothelial carcinoma with extensive lamina propria invasion and focal muscularis propria invasion.
    • Staging studies negative, diagnosed with clinical stage T2N0M0 urothelial carcinoma of the bladder with right hydronephrosis.
  • Received 4 cycles of neoadjuvant gemcitabine and cisplatin.
  • February 2014: Robotic assisted radical cystoprostatectomy and bilateral pelvic lymph node dissection with ileal conduit urinary diversion
    • Pathology - Residual high grade, urothelial carcinoma with lamina propria invasion present and negative margins – pathologic stage ypT1 pN0.
  • February 2015:…

Introduction

  • Virtual Molecular Tumor Board
  • Patient: Urothelial bladder cancer
  • Carolinas HealthCare System/Levine Cancer Institute
  • Presented by: Dr. Earle Burgess

History- Part 1

  • 65-year-old male presented with gross hematuria in 2013.
    • Cystoscopic evaluation identified a large bladder tumor on the right lateral/posterior wall.
    • August 2013: Transurethral resection of bladder tumor identified high grade papillary urothelial carcinoma with extensive lamina propria invasion and focal muscularis propria invasion.
    • Staging studies negative, diagnosed with clinical stage T2N0M0 urothelial carcinoma of the bladder with right hydronephrosis.
  • Received 4 cycles of neoadjuvant gemcitabine and cisplatin.
  • February 2014: Robotic assisted radical cystoprostatectomy and bilateral pelvic lymph node dissection with ileal conduit urinary diversion
    • Pathology - Residual high grade, urothelial carcinoma with lamina propria invasion present and negative margins – pathologic stage ypT1 pN0.
  • February 2015: Surveillance imaging identified right ureteral lesion, which was identified as urothelial carcinoma via ureteroscopic biopsy.

Pathology- Part 1

Enlarge  Figure 1-1: August 2013: Bladder, TURBT - Papillary urothelial carcinoma, high grade, with lamina propria and muscularis propria invasion.
Figure 1-1: August 2013: Bladder, TURBT - Papillary urothelial carcinoma, high grade, with lamina propria and muscularis propria invasion.
Enlarge  Figure 1-2: August 2013: Bladder, TURBT - Higher magnification demonstrating muscularis propria invasion.
Figure 1-2: August 2013: Bladder, TURBT - Higher magnification demonstrating muscularis propria invasion.

History- Part 2

  • 4/17/15: Right robotic assisted laparoscopic radical nephroureterectomy
    • Pathology
    • Renal pelvis – high grade, urothelial carcinoma with lamina propria invasion, negative margins, pT1Nx
    • Mid ureter – high grade, urothelial carcinoma with lamina propria invasion, negative margins, pT1Nx
    • Distal ureter – high grade, urothelial carcinoma with lamina propria invasion, negative margins, pT1Nx
  • 8/18/15: CT A/P with new right pelvic side wall adenopathy, worrisome for metastatic disease.
  • 11/24/15: CT A/P with increasing pelvic mass, worrisome for recurrence as well as new pulmonary nodule.
  • 12/7/15: Biopsy of right pelvic sidewall mass confirms metastatic urothelial carcinoma.
  • December 2015-March 2016: Received palliative gemcitabine and carboplatin x4 cycles followed by progression
  • Received weekly docetaxel x1 cycle followed by clinical and radiographic progression.
  • Received palliative radiotherapy to bilateral acetabular regions, completed May 2016
  • Tumor molecular testing identified FGFR3 R248C mutation.

Pathology-Part 2

Enlarge  Figure 1-3: December 2015: Right pelvic sidewall mass, core biopsy - Metastatic urothelial carcinoma. Specimen submitted for biomarker testing.
Figure 1-3: December 2015: Right pelvic sidewall mass, core biopsy - Metastatic urothelial carcinoma. Specimen submitted for biomarker testing.

History- Part 3

  • 5/26/16: Enrolled on clinical trial with a pan-fibroblast growth factor receptor (FGFR) inhibitor.
  • 6/1/16: Dramatic clinical improvement observed.
  • Continued on clinical trial until progression, November 2016.
  • Due to clinical deterioration, this patient elected to forgo additional therapy and to enroll in hospice.

Imaging

Enlarge  Figure 1-7: On study imaging: 5/20/16
Figure 1-7: On study imaging: 5/20/16
Enlarge  Figure 1-8: Best response: 8/17/16
Figure 1-8: Best response: 8/17/16

Discussion

  • Fibroblast growth factor receptors are protein tyrosine kinases, consisting of 4 family member (FGFR1-4).1
  • FGFR signaling leads to activation of MAPK and PI3-K/Akt pathways.
  • FGFR aberrations are present in approximately 20% of advanced urothelial carcinomas.2,3
  • Phase I study of pan FGFR inhibitor JNJ-42756493: 3 patients with heavily pretreated urothelial carcinoma and FGFR aberrations demonstrated partial responses.4
  • Phase I study of selective FGFR 1-3 inhibitor BGJ398: Of 8 patients with FGFR3 mutated urothelial cancers treated at doses >= 100mg, 6 experienced stable disease or partial responses.5
  • This patient’s case illustrates the potential utility of targeting pathogenic FGFR aberrations in urothelial cancers.
  • This patient had exhausted standard cytotoxic therapies and subsequently derived a meaningful clinical benefit and 6 month progression free interval with the use of a FGFR inhibitor.
  • Although FGFR inhibitors are not available for routine clinical use in early 2017, clinical development is ongoing.

References

  • Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507:315-22, 2014
  • Nogova L, Sequist LV, Perez Garcia JM, et al: Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study. J Clin Oncol 35:157-165, 2017
  • Parker BC, Engels M, Annala M, et al: Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours. J Pathol 232:4-15, 2014
  • Ross JS, Wang K, Khaira D, et al: Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. Cancer 122:702-11, 2016
  • Tabernero J, Bahleda R, Dienstmann R, et al: Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors. J Clin Oncol 33:3401-8, 2015