Prediction of response to combined immunotherapy with interferon-alpha and low-dose interleukin-2 in metastatic renal cell carcinoma: expression patterns of potential molecular markers in radical nephrectomy specimens.
OBJECTIVE
To evaluate the expression levels of multiple molecular markers in radical nephrectomy specimens from patients with metastatic renal cell carcinoma (RCC) who received combined immunotherapy with interferon-alpha (IFN-alpha) and low-dose interleukin-2 (IL-2) and to identify factors predicting susceptibility to this therapy.


METHODS
This study included 40 patients with metastatic clear cell RCC undergoing combined immunotherapy with IFN-alpha and low-dose IL-2 following radical nephrectomy. Expression levels of 10 markers, including Aurora-A, Bcl-2, clusterin, heat shock protein 27, heat shock protein 90, Ki-67, matrix metalloproteinase-2, matrix metalloproteinase-9, p53 and vascular endothelial growth factor, in RCC specimens were measured using immunohistochemical staining.


RESULTS
In this series, one, 10, 15 and 16 patients were diagnosed as showing complete response, partial response, stable disease and progressive disease, respectively. Expression levels of Bcl-2 and Ki-67 had significant impacts on the response to this therapy. Furthermore, cancer-specific survival was significantly associated with the expression levels of Ki-67 and Bcl-2 in addition to performance status, presence of metastases at diagnosis, metastatic organ and C-reactive protein on univariate analysis. Only the presence of metastases at diagnosis and Ki-67 expression level appeared to be independent predictors of cancer-specific survival on multivariate analysis.


CONCLUSIONS
It would be useful to consider the expression levels of potential molecular markers, particularly Ki-67, in addition to clinical parameters, such as the presence of metastases at diagnosis, to select metastatic RCC patients likely to benefit from combined immunotherapy.
Miyake
Hideaki
H
Division of Urology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan. hideakimiyake@hotmail.com
Sakai
Iori
I
Muramaki
Mototsugu
M
Kurahashi
Toshifumi
T
Takenaka
Atsushi
A
Fujisawa
Masato
M
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D003131:Combined Modality Therapy; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage; D016898:Interferon-alpha / Q000008:administration & dosage*; D007376:Interleukin-2 / Q000008:administration & dosage*; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009392:Nephrectomy / Q000401:mortality; D011237:Predictive Value of Tests; D011379:Prognosis
D015415:Biomarkers; D014408:Biomarkers, Tumor; D007155:Immunologic Factors; D016898:Interferon-alpha; D007376:Interleukin-2