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Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1332-1333 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.274
Platelet-Derived Growth Factor Receptor Inhibitor Imatinib Mesylate and Docetaxel: A Modular Phase I Trial in Androgen-Independent Prostate CancerBrigham and Women's Hospital, Harvard Medical School, Boston, MA To the Editor: We read with great interest the article by Mathew et al.1 Recent work by our group has attempted to characterize the expression of platelet-derived growth factor receptor beta (PDGFR-ß) in a wide range of clinically localized and hormone-refractory metastatic prostate cancers at both the transcriptional and protein levels.2 We concur with the finding of Mathew et al that PDGFR-ß is expressed in metastatic prostate cancer. However, in contrast to other reports,3,4 PDGFR-ß is still expressed only in a minority of both metastatic and clinically localized prostate cancers. The authors note that monotherapy with the PDGFR-ß inhibitor imatinib mesylate did not show a response. This finding would be consistent with our recent findings that PDGFR-ß is expressed in less than 5% of localized and 16% of hormone-refractory metastatic prostate cancers.2 Mathew et al suggest use of a combination therapy and suggest that this offers better results compared with two other previously reported studies using docetaxel alone.5,6 Given the infrequent expression of PDGFR-ß, an alternative explanation for the modest improvement in clinical outcomes as measured by prostate-specific antigen decline may have to do with the different study designs. Mathew et al use a combination therapy of imatinib mesylate plus docetaxel administration continuously for 4 weeks in 6-week intervals. Berry et al6 and Beer et al5 studied the monotherapy with docetaxel administered once for 6 weeks (Berry et al) or 4 weeks (Beer et al). The differences between 38% prostate-specific antigen decline of greater than 50% in the study using combined therapy by Mathew et al does not appear to be significantly different from the 41% and 46% decline reported by Berry et al6 and Beer et al,5 respectively. Determining the true expression of the activated form of PDGFR-ß is also hampered by important technical issues. In our recent study, we identified some technical difficulties in determining PDGFR-ß expression in formalin-fixed, paraffin-embedded samples. Not all of the antibodies that we tested gave membranous protein expression, as depicted in Figure 1, representing localized prostate cancer. The problem of cross-reactivity with PDGFR-ß antibodies currently available for immunohistochemistry is well known and extensive care must be taken not to over-interpret staining. For example, Figure 2C in Mathew et al1 appears to demonstrate nuclear and not membranous protein expression. We also identified serious technical problems in determining the status of activated phosphorylated form of PDGFR-ß, the form that would be amenable to imatinib mesylate treatment. Antibodies specific for the phosphorylated PDGFR-ß did not reliably distinguish between the phosphorylated and unphosphorylated form, as we demonstrated using stimulated cell lines fixed in formalin and embedded in paraffin.2
Therefore, although the addition of imatinib mesylate to the treatment regime may be beneficial, the low percentage of patients expressing the receptor and the technical difficulties in determining its status should be considered in the planning of future clinical trials. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Mathew P, Thall PF, Jones D, et al: Platelet-derived growth factor receptor inhibitor imatinib mesylate and docetaxel: A modular phase I trial in androgen-independent prostate cancer. J Clin Oncol 22:3323-3329, 2004 2. Hofer MD, Fecko A, Shen R, et al: Expression of the platelet-derived growth factor receptor in prostate cancer and treatment implications with tyrosine kinase inhibitors. Neoplasia 6:503-512, 2004[CrossRef][Medline]
3. Ko YJ, Small EJ, Kabbinavar F, et al: A multi-institutional phase II study of SU101, a platelet-derived growth factor receptor inhibitor, for patients with hormone-refractory prostate cancer. Clin Cancer Res 7:800-805, 2001
4. Chott A, Sun Z, Morganstern D, et al: Tyrosine kinases expressed in vivo by human prostate cancer bone marrow metastases and loss of the type 1 insulin-like growth factor receptor. Am J Pathol 155:1271-1279, 1999
5. Beer TM, Pierce WC, Lowe BA, et al: Phase II study of weekly docetaxel in symptomatic androgen-independent prostate cancer. Ann Oncol 12:1273-1279, 2001 6. Berry W, Dakhil S, Gregurich MA, et al: Phase II trial of single-agent weekly docetaxel in hormone-refractory, symptomatic, metastatic carcinoma of the prostate. Semin Oncol 28:8-15, 2001[CrossRef]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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