Dynamic change in phosphorylated platelet-derived growth factor receptor in peripheral blood leukocytes following docetaxel therapy predicts progression-free and overall survival in prostate cancer Journal Article
| Authors: | Mathew, P.; Thall, P. F.; Wen, S.; Bucana, C.; Jones, D.; Horne, E.; Oh, W. K.; Morris, M. J.; Lee, Y. C.; Logothetis, C. J.; Lin, S. H.; Fidler, I. J. |
| Article Title: | Dynamic change in phosphorylated platelet-derived growth factor receptor in peripheral blood leukocytes following docetaxel therapy predicts progression-free and overall survival in prostate cancer |
| Abstract: | In a placebo-controlled randomised study of the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate and docetaxel in metastatic prostate cancer with bone metastases (n=116), no significant differences in progression-free and overall survival were observed. To evaluate pharmacodynamic correlates of outcomes, we assessed the association of plasma platelet-derived growth factor (PDGF) isoform kinetics and PDGFR inhibition with progression-free and overall survival by individual treatment arm. We found that in the docetaxel-placebo arm alone, the probability of decrease in PDGFR phosphorylation (Pr-Decr-pPDGFR) above 0.5 (vs ≤0.5) was associated with a sharp increase in all measured plasma PDGF isoforms (P=0.006 for AA, 0.002 for BB, 0.045 for AB); a decreased median progression-free survival of 3.3 months vs 6.8 months (hazard ratio (HR) 2.5; P=0.006 in log-rank test) and an inferior median overall survival of 20 months vs >30 months (HR 3.1; P=0.04 in log-rank test). By contrast, in the docetaxel plus imatinib arm, the association of Pr-Decr-pPDGFR >0.5 with a rise in plasma PDGF isoform concentrations and inferior survival was not observed. The data suggest that dynamic changes in PDGFR phosphorylation in peripheral blood leukocytes predict docetaxel efficacy. Rising plasma PDGF concentrations may explain and/or mark docetaxel resistance. Validation and mechanistic studies addressing these unexpected findings should anticipate a confounding influence of concurrent PDGFR inhibitor therapy. © 2008 Cancer Research. |
| Keywords: | survival; platelet derived growth factor; cancer survival; controlled study; protein phosphorylation; major clinical study; clinical trial; disease course; placebo; drug dose reduction; drug efficacy; antineoplastic agents; protein blood level; imatinib; controlled clinical trial; multiple cycle treatment; randomized controlled trial; combination chemotherapy; validation study; phosphorylation; docetaxel; prostate cancer; prostatic neoplasms; platelet-derived growth factor; dimerization; multivariate analysis; taxoids; leukocyte; receptors, platelet-derived growth factor; leukocytes; platelet-derived growth factor receptor; drug intoxication |
| Journal Title: | British Journal of Cancer |
| Volume: | 99 |
| Issue: | 9 |
| ISSN: | 0007-0920 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2008-10-04 |
| Start Page: | 1426 |
| End Page: | 1432 |
| Language: | English |
| DOI: | 10.1038/sj.bjc.6604706 |
| PUBMED: | 18841158 |
| PROVIDER: | scopus |
| PMCID: | PMC2579696 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 4" - "Export Date: 17 November 2011" - "CODEN: BJCAA" - "Source: Scopus" |
