811PD - Met tumor expression and mutational analysis in bladder cancer patients (pts) receiving cabozantinib

Date 29 September 2014
Event ESMO 2014
Session Genitourinary tumours, non prostate
Topics Anti-Cancer Agents & Biologic Therapy
Urothelial Cancers
Translational Research
Presenter Andrea Apolo
Citation Annals of Oncology (2014) 25 (suppl_4): iv280-iv304. 10.1093/annonc/mdu337
Authors A.B. Apolo1, D.P. Bottaro2, M.J. Merino3, L. Xi3, Y.H. Lee2, B.A. Weinberg4, J.J. Wright4, W.L. Dahut4, H.L. Parnes4, M. Raffeld3
  • 1Genitourinary Malignancies Branch, National Cancer Institute, 20892 - Bethesda/US
  • 2Urologic Oncology Branch, National Cancer Institute, Bethesda/US
  • 3Laboratory Of Pathology, National Cancer Institute, Bethesda/US
  • 4Genitourinary Malignancies Branch, National Cancer Institute, Bethesda/US

Abstract

Aim

Met receptor tyrosine kinase abundance correlates with poor prognosis in many tumors including urothelial carcinoma; Met can promote tumor growth, angiogenesis and metastasis. Cabozantinib is an oral kinase inhibitor primarily targeting Met and VEGFR2. Tumor Met content and mutation status were assessed in bladder cancer pts receiving cabozantinib in a phase II clinical trial.

Methods

Formalin-fixed paraffin-embedded (FFPE) primary and metastatic tumor samples were collected at baseline from consenting pts. Met content was assessed by immunohistochemistry (IHC) using the SP44 monoclonal antibody (Ventana Medical Systems). Met IHC scores were defined as: 3+ (strong staining for tumor cells); 2+ (moderate staining); 1+ (weak intensity); or 0 (no staining). Cases were reviewed by 2 pathologists. IHC score of 0-1+ was negative and 2-3+ was positive for Met content. Mutation detection was performed on 20ng of FFPE tissue DNA using Ampliseq (Life Technologies), which covers 2800 COSMIC hotspot mutations in 50 cancer genes.

Results

43 specimens from 30 cabozantinib treated pts (27 urothelial carcinoma, 1 small cell, 1 squamous cell carcinoma, 1 sarcomatoid of the bladder or upper tract) were analyzed. IHC scores were 0 (4/43, 9%); 1 (17/43, 40%); 2 (14/43, 33%); 3 (8/43, 18%). 12 pts had at least 2 different tissue samples from primary vs. metastatic site or different metastatic sites. 2/12 matched pt specimens had the same IHC score, and 7/12 (58%) were positive for MET (IHC score of 2-3+).8 pts with 12 specimens were responders (3 partial responses, 2 bone responses, 3 stable disease >8 mos.), and 16 pts with 23 specimens progressed at first restaging (non-responders). Met staining was positive (IHC score 2-3+) in 9/12, 75% of responders vs. 8/23, 35% of non-responders. The most common mutations found were EGFR 6%; FGFR3 13%; KRAS 13%; HRAS 13%, PIK3CA 25%; RB1 6% and TP53 56%. MET mutations were not found.

Conclusions

Met expression was higher in bladder cancer pts that responded to cabozantinib treatment vs. pts that did not respond. IHC scores differed in specimens from different organ sites within the same pt. The frequency of mutations found is consistent with reports from The Cancer Genome Atlas.

Disclosure

All authors have declared no conflicts of interest.