Pertuzumab

About: Pertuzumab is a research topic. Over the lifetime, 1453 publications have been published within this topic receiving 73219 citations. The topic is also known as: 2C4 Antibody & MOAB 2C4.

Role for HER2/neu and HER3 in fulvestrant-resistant breast cancer.

Abstract: Tamoxifen resistance is common for estrogen receptor alpha (ERalpha) positive breast cancer. Second-line therapies include aromatase inhibitors or fulvestrant. We have shown previously that fulvestrant reversed 17beta-estradiol-induced tumor regression of tamoxifen-stimulated MCF-7 xenografts (MCF-7TAMLT) treated for >5 years with tamoxifen in athymic mice and paradoxically stimulated growth. We investigated mechanisms responsible for growth by fulvestrant in the presence of physiologic estradiol and therapeutic strategies in vivo. The results demonstrated that only estradiol increased expression of the estrogen-responsive genes, c-myc, igf-1, cathepsin D, and pS2 mRNAs, in MCF-7E2 and MCF-7TAMLT tumors. Tamoxifen or fulvestrant decreased the estradiol-induced increase of these mRNAs in both tumor models. However, tyrosine-phosphorylated HER2/ neu, HER3, phospho-extracellular-regulated kinase-1/2 (ERK-1/2), and phospho-glycogen synthetase kinase 3alpha (GSK3alpha) and beta proteins were increased in MCF-7TAMLT tumors treated with fulvestrant compared to estradiol, control, or tamoxifen. Phospho-HER2/neu interacted with HER3 protein in MCF-7TAMLT tumors. In order to determine whether the functional interaction of HER2/neu with HER3 is critical for growth of fulvestrant-stimulated MCF-7TAMLT tumors, pertuzumab (an antibody that blocks HER2/neu-HER3 interaction) was used in an in vivo xenograft growth assay. Only growth of fulvestrant-treated MCF-7TAMLT xenografts was decreased significantly by 37.2% in response to pertuzumab (P=0.004). Pertuzumab specifically decreased the interaction of HER2/neu protein with HER3 in fulvestrant-stimulated MCF-7TAMLT tumors. These results suggested growth of MCF-7TAMLT tumors by tamoxifen or fulvestrant is potentially independent of ERalpha transcriptional activity as evidenced by lack of induction of four estrogen-responsive genes. The results suggested that growth of MCF-7TAMLT tumors treated with fulvestrant in the presence of physiologic estradiol is in part mediated through enhanced signaling from the HER2/neu-HER3 pathway as pertuzumab partially inhibited growth and the interaction of HER2/neu with HER3 in vivo.

Population pharmacokinetic and covariate analysis of pertuzumab, a HER2‑targeted monoclonal antibody, and evaluation of a fixed, non‑weight‑based dose in patients with a variety of solid tumors

Abstract: To characterize the population pharmacokinetics (PK) of pertuzumab across clinical trials in a variety of solid tumors, evaluate the potential impact of patient characteristics on PK, and confirm the appropriateness of the fixed (non-weight-based) dose Pertuzumab concentration data collected following intravenous administration during eleven phase I/II studies and the pivotal phase III trial CLEOPATRA were analyzed using nonlinear mixed-effects modeling The potential impact of patient and laboratory characteristics and HER2 target-related variables on pertuzumab PK were investigated in a covariate analysis The final model was used to confirm selection of fixed, non-weight-based dosing of pertuzumab, and to compare pertuzumab PK in CLEOPATRA with the other studies The analysis included 4,525 serum concentration measurements from 481 patients with solid tumors Pertuzumab PK in the 2–25 mg/kg dose range was described by a two-compartment linear model with first-order elimination The elimination clearance and central compartment volume were 0235 L/day, and 311 L, respectively, and the terminal elimination half-life was 180 days Baseline serum albumin and lean body weight had statistically significant effects on pertuzumab clearance; however, simulations showed that the magnitude of their effects on pertuzumab exposure was minimal compared with overall variability and was not clinically relevant Thus, variations in these factors do not require dose adjustments The fixed, non-weight-based dosing of pertuzumab, 840 mg loading dose followed by a 420 mg maintenance dose every 3 weeks, in patients with the solid tumors in this analysis is well supported by the population pharmacokinetic modeling and simulation results

HER-2-positive metastatic breast cancer: trastuzumab and beyond

Abstract: Background: The recognition achieved in the late 1980s of human epidermal growth factor receptor 2 as an appealing therapeutic target for breast cancer has led to the development of targeted therapies for patients with human epidermal growth factor receptor 2-overexpressing breast tumors. Objectives: The aim of the present review is to address the standard treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer patients, which is currently based on the humanized monoclonal antibody trastuzumab and to describe the new treatment options available for patients progressing on trastuzumab-based therapies. Methods: A broad literature research was performed in order to review treatments, starting from the developmental phase of trastuzumab to the most recent biologic agents being tested in human epidermal growth factor receptor 2-positive disease. Results: Trastuzumab combined with a taxane represents the first therapeutic option for human epidermal growth factor receptor 2-positi...

The war on cancer: are we winning?

Abstract: Of all the diseases affecting humankind, cancer is one of the most difficult to treat and cure. One of the main reasons for this difficulty relates to the fact that cancer is not a single disease but consists of hundreds of different types. Furthermore, cancers exhibit considerable genetic complexity with more than 400 different genes implicated in their development. In addition, cancers display major inter- and intratumor heterogeneity. Despite these complexities, several successes have been achieved in recent years. Most of these successes relate to the specific targeting of driver genes involved in cancer development. These successes include imatinib for the treatment of chronic myeloid leukemia, anti-HER2 therapies (trastuzumab, pertuzumab, and lapatinib) to treat breast cancer, anti-EGFR tyrosine kinase inhibitors (gefitinib and erlotinib) to treat non-small cell lung cancer, and anti-BRAF agents (vemurafenib and dabrafenib) to treat melanoma. Although the war on cancer has not yet been won, neither has it been lost. With continued basic and clinical research, cancer is being transformed into a chronic disease in which patients have increased survival rates and better quality of life.

Targeting HER2 in prostate cancer: where to next?

Abstract: 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