The first and second authors contributed equally to this article.
Prognostic relevance of the mTOR pathway in renal cell carcinoma
Implications for molecular patient selection for targeted therapy
Article first published online: 17 APR 2007
Copyright © 2007 American Cancer Society
Volume 109, Issue 11, pages 2257–2267, 1 June 2007
How to Cite
Pantuck, A. J., Seligson, D. B., Klatte, T., Yu, H., Leppert, J. T., Moore, L., O'Toole, T., Gibbons, J., Belldegrun, A. S. and Figlin, R. A. (2007), Prognostic relevance of the mTOR pathway in renal cell carcinoma. Cancer, 109: 2257–2267. doi: 10.1002/cncr.22677
- Issue published online: 18 MAY 2007
- Article first published online: 17 APR 2007
- Manuscript Accepted: 8 FEB 2007
- Manuscript Revised: 5 FEB 2007
- Manuscript Received: 9 JAN 2007
- Wyeth Research and The Richard and Nancy Bloch Kidney Cancer Research Fund
The mammalian target of rapamycin (mTOR) pathway is up-regulated in many human cancers, and agents targeting the mTOR pathway are in various stages of clinical development. The goal of the study was to evaluate the potential and limitations of targeting the mTOR pathway in renal cell carcinoma (RCC).
Immunohistochemical analysis using antibodies against pAkt, PTEN, p27, and pS6 was performed on a tissue microarray constructed from paraffin-embedded specimens from 375 patients treated by nephrectomy for RCC. The expression was associated with pathological parameters and survival.
The mTOR pathway was more significantly altered in clear-cell RCC, high-grade tumors, and tumors with poor prognostic features. PS6 and PTEN showed the strongest associations with pathological parameters. Survival tree analysis regarding expression of cytoplasmic pAkt, nuclear pAkt, PTEN, cytoplasmic p27, and pS6 identified staining percentages of 40%, 10%, 75%, 7%, and 70%, respectively, as ideal cutoff values for stratification, with corresponding P-values of .03, .001, .02, .005, and <.0001, respectively. Interestingly, high nuclear pAkt expression was associated with a favorable prognosis, whereas high cytoplasmic pAkt expression was associated with a poor prognosis. In multivariate Cox regression analysis, ECOG PS, T classification, N classification, M classification, cytoplasmic Akt, nuclear pAkt, PTEN, and pS6 were independent prognostic factors of DSS.
Components of the mTOR pathway are significantly associated with pathological features and survival. Not all RCC tumor types seem to be equally amenable to mTOR targeted therapy. PTEN, pAkt, p27, and pS6 may serve as surrogate parameters for patient selection and predicting prognosis. Patients with a highly activated mTOR pathway should benefit most from this therapy. External validation of our results is recommended. Cancer 2007. © 2007 American Cancer Society.