Topic
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.
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TL;DR: It is concluded that HER3 mRNA is down-regulated by both heregulin-β1 and epidermal growth factor activation, which suggests that in some tumors, low Her3 mRNA expression is driven by, or dependent on, growth factor.
Abstract: This study was designed to evaluate the expression of HER receptors as a marker of sensitivity to the humanized anti-HER2 monoclonal antibody pertuzumab in ovarian cancer cells. In a recent clinical trial, low levels of HER3 mRNA have been shown to associate with pertuzumab response when combined with gemcitabine. We sought to define how pertuzumab modulated HER expression levels in ovarian cancer using cell line models to better understand differential and dynamic receptor expression in therapeutic response. Changes in HER3 mRNA expression were also assessed in pertuzumab-treated xenografts. HER3 mRNA and, to a lesser extent, HER2, were down-regulated after stimulation both with heregulin-β1 and epidermal growth factor in a range of ovarian cancer cell lines either growth sensitive or growth resistant to pertuzumab. Pertuzumab reversed this down-regulation and the magnitude of the reversal correlated with pertuzumab sensitivity. The change in HER3 mRNA expression correlated inversely to how much the extracellular signal-regulated kinase and phosphoinositide 3-kinase pathways were dynamically activated with stimulation. Finally, up-regulation of HER3 mRNA was found in cancer xenografts treated with pertuzumab. We conclude that HER3 mRNA is down-regulated by both heregulin-β1 and epidermal growth factor activation. This suggests that in some tumors, low HER3 mRNA expression is driven by, or dependent on, growth factor. HER3 mRNA expression is effectively reversed in pertuzumab-sensitive tumors. These data are consistent with low HER3 mRNA identifying a pertuzumab-sensitive phenotype.
39 citations
TL;DR: Several strategies to overcome resistance to anti-HER2 treatment are in different phases of development and include treatment with pertuzumab, T-DM1 and mammalian target of rapamycin (mTOR) inhibitors.
Abstract: Human epidermal growth factor receptor (HER)-2 overexpression or amplification occurs in about 20% of all breast cancers and results in a worse prognosis. Nevertheless, anti-HER2 treatments have recently been developed, resulting in dramatic improvements in the clinical outcome of patients with HER2-positive breast cancer. Trastuzumab has shown efficacy in early and advanced breast cancer treatment and lapatinib is currently approved for the treatment of advanced disease. Other anti-HER2 agents are being investigated. Mechanisms of resistance to trastuzumab treatment include crosstalk with heterologous receptors and amplification of HER2 signalling; amplification of the phosphoinositide 3-kinase (PI3K)/AKT pathway; alteration in binding of trastuzumab to HER2; and loss of HER2 expression. Proposed mechanisms of resistance to lapatinib involve derepression and/or activation of compensatory survival pathways through increased PI3K/AKT or estrogen receptor (ER) signalling. Several strategies to overcome resistance to anti-HER2 treatment are in different phases of development and include treatment with pertuzumab, T-DM1 and mammalian target of rapamycin (mTOR) inhibitors.
39 citations
TL;DR: In MARIANNE, biomarkers related to the HER2 pathway did not have predictive value for PFS when comparing T-DM1 (with or without pertuzumab) with trastuzuab plus taxane, however, HER2 mRNA level and PIK3CA mutation status showed prognostic value.
Abstract: Following publication of the original article [1], the authors reported the following errors in the article.
38 citations
TL;DR: The results show that the exposure of T-DM1 and DM1 was comparable with that reported by historical single-agent studies in patients with HER2-positive MBC, and the risk of TP-DI appears to be low when T- DM1 and pertuzumab are given together.
Abstract: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprised of trastuzumab and the cytotoxic agent DM1 (derivative of maytansine) linked by a stable linker N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC). T-DM1 targets an epitope located at subdomain IV of human epidermal growth factor receptor 2 (HER2). Pertuzumab is a monoclonal antibody that targets an epitope located at subdomain II of HER2, distinct from the epitope recognized by T-DM1. The pharmacokinetics (PK), safety, and efficacy of T-DM1 combined with pertuzumab were studied in a phase 1b/2 trial in 67 patients with HER2-positive, locally advanced or metastatic breast cancer (MBC). The therapeutic protein-drug interaction (TP-DI) potential of T-DM1 plus pertuzumab was evaluated. The PK of T-DM1-related analytes and pertuzumab were compared with historical PK data. The results show that the exposure of T-DM1 and DM1, as estimated by noncompartmental analyses, was comparable with that reported by historical single-agent studies in patients with HER2-positive MBC. T-DM1 clearance and volume of distribution in the central compartment, as estimated by population PK analysis, were also comparable between this study and historical single-agent studies in patients with HER2-positive MBC. Summary statistics of pertuzumab trough and maximal exposure (concentrations at predose and 15-30 minutes after the end of infusion at cycle 1 and at steady state) were similar with those observed in a representative historical single-agent study with the same dosing regimen. The visual predictive check plot by population simulation further confirmed that T-DM1 did not alter pertuzumab PK. Based on these data and the PK and pharmacodynamic properties of T-DM1 and pertuzumab, the risk of TP-DI appears to be low when T-DM1 and pertuzumab are given together.
38 citations
TL;DR: Pertuzumab monotherapy is active against HER2-positive breast cancer which has progressed during trastuzumAB-based therapy and the combination of the two antibodies appears to be more active than either antibody alone.
Abstract: 1022 Background: Pertuzumab binds to the dimerization epitope of the HER2 receptor, inhibits HER dimerization and signal transduction, and induces ADCC. In 2 cohorts of pts (n = 66) with HER2-positive metastatic breast cancer which had progressed during trastuzumab therapy after ≤3 lines of chemotherapy with or without trastuzumab, pertuzumab plus trastuzumab has been shown to be active (CR 7.6%, PR 16.7%, SD ≥6/12 25.8%) (Gelmon et al. ASCO 2008, Abs 1026). To assess the activity of pertuzumab monotherapy in this clinical setting, the protocol was amended to include a 3rd cohort of pts. Methods: Pt selection was not changed except that ≥1 month between the last dose of trastuzumab and study start was required. Pts received pertuzumab monotherapy. If the tumor failed to respond or responded and then progressed, trastuzumab could be added to pertuzumab. 27 pts were to be recruited to ensure that ≥24 were fully evaluable for objective response and stabilization of disease ≥6 months. Standard 21-day schedule...
38 citations