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In Reply

Centre for Cancer Therapeutics, the Institute for Cancer Research, and the Royal Marsden Hospital National Health Service Foundation Trust, Surrey, United Kingdom

We would like to thank Menendez and Lupu for their comments on the potential role of human epidermal growth factor receptor (HER) 3 transactivation as a cause for the failure of drugs targeting the HER kinase family to achieve tumor responses in hormone refractory prostate cancer (HRPC). As argued by Solit and Rosen,¹ the failure to define HER2 status in our study could result in one missing important antitumor activity in a small subgroup of patients. However, more than 100 HRPC patients have now been treated in two separate phase II trials of pertuzumab and no definitive evidence of antitumor activity has been observed.^2,3 Tumor responses would be expected even if HER2 played a key oncogenic role in as few as 10% of HRPC patients. Moreover, in view of the several negative phase II HRPC trials with HER2-targeting drugs that have proven efficacy in breast, lung, and ovarian cancer, one must argue that the epidermal growth factor receptor and HER2 tyrosine kinase pathways are probably unlikely to play a major pathogenic role in HRPC in isolation of other oncogenic processes. Also, a recent study investigating pan-Erb blockade with lapatinib in 22 noncastrate hormone-sensitive prostate cancer patients reported no responses.⁴ Nonetheless, we agree with Drs Menendez and Lupu that it is possible that pertuzumab was [missing the target.] We are therefore currently completing a three-arm randomized phase II trial of the potent and irreversible erbB1 and erbB2 small molecule inhibitor BIBW, versus the small molecule multikinase inhibitor BIBF (targeting vascular endothelial growth factor/fibroblast growth factor receptor/platelet-derived growth factor receptor/C-kit/Src), versus the combination of BIBW and BIBF.

Furthermore, the initial observation by Craft et al⁵ that HER2 crosstalk with the androgen receptor (AR) -signaling cascade offered a mechanism for overcoming loss of ligand-dependent activation of AR must now be interpreted in the context of evidence that the level of androgens in HRPC tumors is sufficiently high to activate the AR.⁶ Moreover, we have recently reported that specific inhibition of CYP450c17, the key enzyme responsible for androgen biosynthesis, elicits biochemical and radiologic responses in approximately 60% of HRPC patients, confirming that a substantial proportion of HRPC tumors are indeed dependent on residual androgens.⁷ These data suggest that in hormone refractory patients, the role of crosstalk between the HER kinase family and AR signaling must at best be of limited relevance. We concur with Drs Mendoza and Lupu that phosphatidylinositol-3-OH kinase/AKT signaling could be an important mechanism for resistance and this is especially important in prostate cancer where loss of PTEN expression has been reported in a high proportion of tumors.⁸

We and other investigators have found the acquisition of HRPC tissue for molecular characterization challenging due to the inaccessibility of metastasis in most patients. Furthermore, the study of diagnostic tissue obtained several years before the development of hormone resistance is unlikely to offer useful insight into the driving role of HER2 or any other signaling pathway in the hormone-resistant tumor being treated. We and others are currently prospectively studying the potential role of the enumeration and molecular characterization of circulating tumor cells, isolated using Cell Search technology (Veridex, Warren, NJ) and evaluated by immunofluorescence or fluorescence in situ hybridization, to predict patient response to targeted therapies.⁹ Further validation of this technology is required but could allow patient selection on future clinical trials of targeted therapies in HRPC.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Solit DB, Rosen N: Targeting HER2 in prostate cancer: Where to next? J Clin Oncol 25:241-243, 2007[Free Full Text]

2. de Bono J, Bellmunt J, Attard G, et al: An open-label phase II study evaluating the efficacy and safety of two doses of pertuzumab in castrate chemotherapy-naïve patients with hormone-refractory prostate cancer. J Clin Oncol 25:257-262, 2007[Abstract/Free Full Text]

3. Agus DB, Sweeney CJ, Morris MJ, et al: Efficacy and safety of single-agent pertuzumab (rhuMAb 2C4), a human epidermal growth factor receptor dimerization inhibitor, in castration-resistant prostate cancer after progression from taxane-based therapy. J Clin Oncol 25:675-681, 2007[Abstract/Free Full Text]

4. Sridhar SS, Hotte, SJ, Chin JL, et al: A multicenter phase II study of lapatinib in hormone sensitive prostate cancer. GlaxoSmithKline, Prostate Cancer Symposium, February 22-24, 2007, Orlando, FL (abstr 261)

5. Craft N, Shostak Y, Carey M, et al: A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med 5:280-285, 1999[CrossRef][Medline]

6. Titus MA, Schell MJ, Lih FB, et al: Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res 11:4653-4657, 2005[Abstract/Free Full Text]

7. Attard G, Yap T, Reid A, et al: A phase I and pharmacokinetic (PK) study of abiraterone acetate, a novel, oral, selective and irreversible inhibitor of CYP450c17, in men with castration refractory prostate cancer (CRPC), incorporating steroid metabolite evaluation and tumor androgen levels to confirm inhibition of androgen synthesis and investigate progression. Cougar Biotechnology, Prostate Cancer Symposium, February 22-24, 2007 Orlando, FL (abstr 264)

8. Yoshimoto M, Cutz JC, Nuin PA, et al: Interphase FISH analysis of PTEN in histologic sections shows genomic deletions in 68% of primary prostate cancer and 23% of high-grade prostatic intra-epithelial neoplasias. Cancer Genet Cytogenet 169:128-137, 2006[CrossRef][Medline]

9. Attard G, Fong PC, Molife R, et al: Phase I trial involving the pharmacodynamic (PD) study of circulating tumour cells, of CP-751,871 (C), a monoclonal antibody against the insulin-like growth factor 1 receptor (IGF-1R), with docetaxel (D) in patients (p) with advanced cancer. J Clin Oncol 24:126s, 2006 (abstr 3023)

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