Journal
BRITISH JOURNAL OF CANCER
Volume 99, Issue 9, Pages 1426-1432Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjc.6604706
Keywords
prostate cancer; platelet-derived growth factor receptor; docetaxel; survival
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Funding
- Novartis Pharmaceuticals
- National Cancer Institute [5-P50 CA090270-06]
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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.
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