Sunitinib in urothelial cancer: Clinical, pharmacokinetic, and immunohistochemical study of predictors of response Journal Article

  


Authors: Gallagher, D. J.; Al-Ahmadie, H.; Ostrovnaya, I.; Gerst, S. R.; Regazzi, A.; Garcia Grossman, I.; Riches, J.; Gounder, S. K.; Flaherty, A. M.; Trout, A.; Milowsky, M. I.; Bajorin, D. F.
Article Title: Sunitinib in urothelial cancer: Clinical, pharmacokinetic, and immunohistochemical study of predictors of response
Abstract: Background: Sunitinib has activity in patients with metastatic urothelial cancer (UC), but most patients do not respond. Objective: To identify predictors of response to sunitinib. Design, setting, and participants: Seventy-seven patients with advanced UC received sunitinib on one of two schedules at a single institution. Blood pressure (BP), immunohistochemistry (IHC), and pharmacokinetic (PK) results were correlated with response to sunitinib. Measurements: BP was assessed on day 1 and 28 of each cycle and on day 14 of cycle 1. IHC was performed on 55 samples from 38 cases using mammalian target of rapamycin and hypoxia-inducible factor (HIF) pathway marker antibodies. Blood samples for PK analysis were collected from 15 patients at three time points. Response was assessed using Response Evaluation Criteria in Solid Tumors criteria. Results and limitations: Sunitinib-induced hypertension predicted improved response when hypertension was categorized as a discrete (p = 0.02) or continuous variable (p = 0.005 [systolic BP] and p = 0.007 [diastolic BP]). The odds ratio of response was 12.5 (95% confidence interval, 1.95-246.8) for grade 3/4 hypertension compared with grade 0. Response was associated with low HIF-1α expression in primary (p = 0.07) tissue. A nonstatistically significant trend was seen for an association between greater drug concentration and best response. A correlation between expression markers within the same pathways was identified, phosphorylated-4EBP1 and phosphorylated-S6 (p = 6.5 × 10-9), and vascular endothelial growth factor receptor 2 and HIF-1α (p = 0.008). Results are limited by small numbers. Conclusions: Clinical and molecular biomarkers of response to sunitinib may have clinical relevance and require prospective validation. There is an urgent need for predictive biomarkers to guide the management of UC. © 2011 European Association of Urology.
Keywords: immunohistochemistry; human tissue; protein expression; treatment response; major clinical study; sunitinib; hypertension; biomarkers; metastasis; multiple cycle treatment; vasculotropin receptor 2; urogenital tract cancer; blood sampling; mammalian target of rapamycin; initiation factor 4e binding protein 1; diastolic blood pressure; systolic blood pressure; blood pressure; drug blood level; hypoxia inducible factor 1alpha; transitional cell carcinoma; urothelial cancer; predictive; protein s6
Journal Title: European Urology
Volume: 60
Issue: 2
ISSN: 0302-2838
Publisher: Elsevier Science, Inc.  
Date Published: 2011-08-01
Start Page: 344
End Page: 349
Language: English
DOI: 10.1016/j.eururo.2011.05.034
PROVIDER: scopus
PUBMED: 21645967
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-79959571422&partnerID=40&md5=b9ca78210636e37f657c2afc5c03f26d
Notes: --- - "Export Date: 17 August 2011" - "CODEN: EUURA" - "Source: Scopus"
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MSK Authors
  1. Irina Ostrovnaya
    196 Ostrovnaya
  2. Dean Bajorin
    657 Bajorin
  3. Matthew I Milowsky
    76 Milowsky
  4. Scott R Gerst
    48 Gerst
  5. Alisa Trout
    14 Trout
  6. Hikmat Al-Ahmadie
    660 Al-Ahmadie
  7. Ashley Regazzi
    89 Regazzi
  8. Annemarie Flaherty
    10 Flaherty
  9. Jamie C Riches
    27 Riches
  10. Ilana Rebecca Garcia-Grossman
    27 Garcia-Grossman
  11. Sivaraman Gounder
    1 Gounder
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