Dynamic Change In Phosphorylated PDGFR In Peripheral Blood Leukocytes After Docetaxel Therapy Predicts Overall Survival In Prostate Cancer

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 01 Dec 2008 - 0:00 PST

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UroToday.com - Accurate molecular markers for targeted therapy that correlate with traditional clinical outcomes are not common. An online article from a distinguished group of researchers demonstrates how useful this approach may be.

As background, the combination of platelet-derived growth factor receptor (PDGFR) inhibition and taxane chemotherapy for CaP patients with bone metastasis has not demonstrated improved progression-free survival or overall survival benefit. However, there was high-frequency expression of phosphorylated PDGFR in bone metastasis and evidence of enhanced systemic inhibition of PDGFR phosphorylation measured in peripheral blood leukocytes. In the British Journal of Cancer, a group of investigators from Houston and Boston reported on the association of PDGF isoform kinetics and PDGFR inhibition with progression-free survival (PFS) and overall survival.

Between 2003 and 2004, 116 patients with metastatic castration-resistant prostate cancer were randomized to docetaxel with either the PDGFR inhibitor imatinib (D+I) or placebo (D+P). Serial blood was obtained for monitoring phosphorylated PDGFR (p-PDGFR) and concentration of plasma PDGF ligands PDGF-AA, PDGF-BB and PDGF-AB. At baseline, there was no difference among the PDGF ligand dimer values. As variations in ligand kinetics may be uniquely dependent upon quantitative receptor inhibition, the investigators assessed plasma PDGF dimer kinetics in relation to variations in p-PDGFR in the control and imatinib arms. With the same cut-point of probability of decrease in pPDGFR [Pr(Decr-pPDGFR)] >0.5, at which rising plasma PDGF concentrations were observed, PFS outcomes were estimated. They found a large, statistically significant difference in PFS between patients with Pr(Decr-pPDGFR) <0.5 and those with Pr(Decr-pPDGFR) >0.5. The median PFS duration was 6.8 months in patients with Pr(Decr-pPDGFR) <0.5 and 3.3 months for those with Pr(Decr-pPDGFR) >0.5. However, no statistical significant differences were seen in the D+1 group with a median PFS duration of 4.2 months in both patients with Pr(Decr-pPDGFR) <0.5 and those with Pr(Decr-pPDGFR) >0.5. Kaplan-Meier curves indicate that the advantageous effect of Pr(Decr-pPDGFR) <0.5 vs. Pr(Decr-pPDGFR) >0.5 was greater than any treatment effect. Finally, the relation of Pr(Decr-pPDGFR) >0.5 in the D+P group was associated with a median overall survival of 20 months vs. >30 months when Pr(Decr-pPDGFR) was <0.5. These data suggest that dynamic alterations I PDGFR activation in peripheral blood predict docetaxel efficacy.

Mathew P, Thall PF, Wen S, Bucana C, Jones D, Horne E, Oh WK, Morris MJ, Lee YC, Logothetis CJ, Lin SH, Fidler IJ
Br J Cancer. 2008 Nov 4;99(9):1426-32
doi:10.1038/sj.bjc.6604706

Written by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS

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