Targeting HER2 in prostate cancer: where to next?

Medical oncology is a young field. Historically, cancer chemotherapies have been developed by targeting processes such as cell proliferation, DNA synthesis, and purine or pyrimidine metabolism that are present in all cells and are required for their growth. Given that these cytotoxics often show broad-spectrum activity, it has been common practice in oncology to test empirically agents that show activity in one disease in all tumor types. The first human oncogenes were discovered 25 years ago, and the first therapies deliberately directed against the molecular aberrations required for cancer growth entered clinical trials much more recently. On the basis of historical practices, it is therefore not surprising that when therapies targeted to molecular lesions in specific tumors are successful in one cancer type, that these therapies are then tested in all cancers, especially if they have only modest toxicity. The broad testing of imatinib and all-trans-retinoic acid in tumors without the relevant mutations provide good examples of the limitations of this approach. The HER kinase family, which includes epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), are receptorand receptor-like transmembrane proteins that are activated in some human tumors. The gene encoding the HER2 protein is amplified in 20% to 25% of breast cancer patients and an anti-HER2 antibody, trastuzumab, has proven to be extremely useful in their treatment. Subsequently, intense effort was devoted to the testing of trastuzumab in other cancers and the development of other modalities for inhibiting both EGFR and HER2. Structural studies reveal that binding of ligand to EGFR or HER3 induces a conformational change within the receptor that facilitates receptor homoand heterodimerization. Dimerization leads to activation of the receptors’ intrinsic kinase activity followed by transphosphorylation of specific tyrosine residues located within the cytoplasmic tails. These tyrosine residues serve as docking sites and their phosphorylation regulates the activation of intracellular signaling cascades. HER2 is unique within the family in that it has a fixed open conformation. Because of this fixed conformation, ligand binding is not required for HER2 dimerization and HER2 is always available to dimerize with other ligand-bound HER kinase receptors, for which it serves as the preferred dimerization partner. Both EGFR and HER2 have been validated as therapeutic targets in several epithelial malignancies, including those of breast, lung, and colon origin. Clinical activity has been demonstrated with anti-HER2 (trastuzumab) and anti-EGFR (cetuximab and panitumumab) monoclonal antibodies and anti-EGFR kinase inhibitors (erlotinib and gefitinib). Lapatinib, a HER2 kinase inhibitor, has also recently demonstrated promising activity in patients with breast cancer. Given that HER2 was found to be overexpressed in some prostate cancers, trastuzumab was also tested for activity in this disease, but failed to demonstrate meaningful activity. Clinical trials of gefitinib and erlotinib were also negative in patients with prostate cancer. In this issue of the Journal of Clinical Oncology, de Bono et al report the results of a phase II trial of the second-generation anti-HER2 antibody pertuzumab in patients with hormonerefractory prostate cancer. Pertuzumab and trastuzumab bind to different epitopes of the HER2 extracellular domain. Specifically, pertuzumab binds to the HER2 dimerization domain and thus prevents HER2 dimerization with the other HER kinase family members. There may be a class of nonamplified, low-level HER2-expressing tumors in which HER2-containing heterodimers drive tumor growth or progression. Such tumors may be resistant to trastuzumab but sensitive to pertuzumab. Consistent with this hypothesis, pertuzumab was found to have activity in ovarian cancer in a recently reported phase II clinical trial. HER2 amplification has been reported in a small subset of ovarian tumors but was not detected in tumor samples derived from patients enrolled onto this trial. Notably, responses to pertuzumab correlated with HER2 activation (in tumors without HER2 gene amplification) in pretreatment samples as measure by an enzyme-linked immunosorbent assay. In contrast to the results reported in ovarian cancer, in the trial by de Bono et al, not a single patient with prostate cancer achieved the primary end point of a greater than 50% decline in prostate-specific antigen. Therefore, consistent with the experience of trastuzumab and the EGFR kinase inhibitors, the HER2 dimerization inhibitor pertuzumab as a single agent was found to be ineffective in patients with hormone-refractory prostate cancer. Why have HER-kinase inhibitors been so ineffective in prostate cancer? One possibility is that insufficient target inhibition was achieved at the dose levels studied. Though the activity of pertuzumab, trastuzumab, and erlotinib in ovarian, breast, and lung cancer, respectively, suggests that target inhibition was likely achieved with these agents in patients with prostate cancer, it is possible that the level of target inhibition required to induce an antitumor response may be different in these tumor types. Such a possibility could be explained by differences in drug-to-target affinity in mutant versus wild-type cells, as has been observed with gefitinib and EGFR, or differences in drug penetration to various JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 3 JANUARY 2