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Targeting HER2 in Prostate Cancer: Where to Next?

Department of Medicine, the Human Oncology and Pathogenesis Program and Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY

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 receptor- and receptor-like transmembrane proteins that are activated in some human tumors.^1,2 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.^3,4 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 homo- and heterodimerization.^5,6 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.^7,8 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.⁹

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).^4,10-13 Lapatinib, a HER2 kinase inhibitor, has also recently demonstrated promising activity in patients with breast cancer.¹⁴ Given that HER2 was found to be overexpressed in some prostate cancers,¹⁵ trastuzumab was also tested for activity in this disease, but failed to demonstrate meaningful activity.^16-18 Clinical trials of gefitinib and erlotinib were also negative in patients with prostate cancer.^19,20

In this issue of the Journal of Clinical Oncology, de Bono et al²¹ report the results of a phase II trial of the second-generation anti-HER2 antibody pertuzumab in patients with hormone-refractory prostate cancer. Pertuzumab and trastuzumab bind to different epitopes of the HER2 extracellular domain.²² Specifically, pertuzumab binds to the HER2 dimerization domain and thus prevents HER2 dimerization with the other HER kinase family members.^22,23 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.²⁴ 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.²⁴ 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.²⁴

In contrast to the results reported in ovarian cancer, in the trial by de Bono et al,²¹ 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 sites.²⁵ Alternatively, the level of target inhibition required to induce cell cycle arrest or apoptosis may differ in mutant cells, which are oncogene addicted to the target compared with those that are not. Inadequate target inhibition could have been excluded if pre- and post-treatment tumor tissue had been collected for pharmacodynamic studies. Such studies were not attempted, however, likely due to the difficulty of collecting such samples in patients with prostate cancer.

Alternatively, the lack of efficacy of trastuzumab, pertuzumab, and erlotinib in prostate cancer may be an indication that EGFR and HER2 do not have a primary pathogenic role in this disease. HER2 is overexpressed in many prostate cancers,¹⁵ but trastuzumab is most (if not exclusively) effective in breast cancers in which HER2 overexpression is mediated by gene amplification.²⁶ In prostate cancer, HER2 amplification is a rare event, if it occurs at all, and thus the target may not be as important in this disease.

The situation for EGFR is somewhat more complex. EGFR mutations occur at significant frequency in lung cancer and in glioblastoma, and tumors with these mutations are often sensitive to EGFR inhibitors.^25,27,28 However, the activity of the anti-EGFR antibody cetuximab in colon cancer is not associated with known EGFR mutations or correlated with the level of EGFR expression or amplification.^10,29 Furthermore, EGFR tyrosine kinase inhibitors are believed to be of some benefit in lung cancer patients in whose tumors EGFR is neither mutated or amplified.^13,30 Thus, wild-type EGFR clearly is necessary for some feature of the growth of some tumors. However, in fairly large studies, none of the antibody or small-molecule inhibitors of HER kinase function have shown significant activity in prostate cancer.^16-19,31 These results suggest that these targets may not be of primary importance in this disease, or that they are of primary importance in only a minority of prostate cancers.

Even if HER kinase inhibitors alone have little or no activity in prostate cancer, they may prove useful in combination with other agents. Craft et al³² and Mellinghoff et al³³ have shown in model systems that activation of the HER2 kinase signaling cascade can constitutively activate androgen receptor and render prostate cancer cells refractory to androgen receptor inhibition. However, if such tumors exist in nature, inhibiting HER2 alone might not be sufficient to inhibit their growth. As pointed out by de Bono et al,²¹ inhibition might cause tumor cells to revert to androgen dependence. This model thus suggests that administering a HER kinase inhibitor together with an antiandrogen may prove more useful.

PTEN loss is a common event in advanced prostate and other cancers, and results in activation of PI3 kinase/AKT signaling.³⁴ In several model systems, PTEN loss is strongly associated with EGFR inhibitor resistance.^35-37 Mellinghoff et al³⁸ recently showed that, in glioblastoma, PTEN loss predicted for resistance to EGFR inhibition. Patients whose tumors had EGFRvIII mutations and wild-type PTEN, but not those with mutated PTEN, were sensitive to gefitinib and erlotinib.³⁸ Moreover, PTEN loss has also been associated with resistance to trastuzumab in breast tumor model systems.³⁹ Therefore, it is quite likely that the significant number of prostate tumors with PTEN loss will not respond to monotherapy with HER kinase inhibitors. However, such tumors may respond to combinations of HER kinase and PI3 kinase/AKT pathway inhibitors, but the testing of such combinations will need to await the development of the latter agents in the clinic.

The take-home lesson is that there remains little evidence for a significant role for HER2 or EGFR as the primary driver of prostate cancers. Given the lack of efficacy seen with these agents, the use of HER kinase inhibitors in multidrug combinations in prostate cancer patients should be based on strong hypotheses and preclinical data. To maximize the likelihood for success, the studies should be informed by molecular profiling and mutational analyses of the tumor. It took large, expensive clinical trials conducted for many years to show that lung tumors with RAS mutation were unlikely to respond to EGFR inhibition.^40,41 This ought to have been recognized as a likely outcome 10 years before these studies were initiated. Unfortunately, this situation continues to be repeated in other disease sites, with other agents. Studies of targeted agents in prostate cancer and other tumors continue to proceed without patient stratification or association of outcome with common mutations in RAS, BRAF, and PTEN that might affect drug efficacy. We recognize that such studies are particularly challenging in prostate cancer, given its long natural history (which makes archival tissue collected at diagnosis of limited value) combined with a lack of accessible tissue for biopsy at the time of recurrence. Therefore, to accelerate the identification of more effective therapies for prostate cancer, efforts must be made to develop novel minimally invasive technologies that will allow for genetic stratification of patients in future clinical trials in this disease.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: David B. Solit, Genentech; Neal Rosen, Genentech Research Funds: N/A Testimony: N/A Other: N/A

AUTHOR CONTRIBUTIONS

Conception and design: David B. Solit, Neal Rosen

Administrative support: David B. Solit, Neal Rosen

Manuscript writing: David B. Solit, Neal Rosen

Final approval of manuscript: David B. Solit, Neal Rosen

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