Urothelial Bladder Cancer

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

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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

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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

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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.