Pertuzumab-more good news about targeted treatment?

[Ellie F]

Just read news about Roche applying for American and European approval of pertuzumab later this year.

I know this combo has been in trials at my onc centre but was wondering if any sisters on the board had been on a trial of this therapy and had a positive response??

This seems to be another step forward using targeted treatments rather than more chemos.

Ellie

[chrisy]

Link to press release last night with CLEOPATRA (paclitaxol/herceptin/+/-Pertuzumab) Phase III results!

http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=13547

There is a lot of interest in this as a blockade of multiple Her-family signalling pathways. Very good news, I think, if this is approved quickly

[pibikay]

Thanks Ellie and chrisy.I hope it will be available here soon

[Jackie07]

This is a full-text link via NCBI:

http://www.smw.ch/content/smw-2011-13231/

Breast cancer is the most commonly diagnosed malignancy and one of the major causes of death among women. Breast cancer is also one of the most investigated diseases but whose biological features are still not well understood, several effective treating strategies having been explored in dealing with different types of advanced breast cancer, such as endocrine therapy and molecular targeted therapy. Trastuzumab is the first approved targeted anti-cancer agent to show an attractive response rate and outcomes in treating HER-2 positive metastatic breast cancer patients. However, primary or acquired trastuzumab resistance usually occurs some time into the use of trastuzumab and leads to treatment resistance or tumour progression. The promising results with trastuzumab targeted therapy encouraged further investigations in this area exploring several novel targeted agents aiming to overcome the resistance drawback of trastuzumab. In this review we discuss the major newly developed targeted agents in breast cancer treatment, including the novel anti-HER-2 monoclonal antibody pertuzumab or ertumaxomab, small molecular tyrosine inhibitor lapatinib, selective PARP1 inhibitor olaparib, mTOR inhibitor rapamycin analogues, and sheddase inhibitors. Many of these novel targeted drugs or molecules showed additional or complementary effects to trastuzumab therapy that need further and wider investigation.
Breast cancer as a heterogeneous disease presents a wide range of pathological characteristics and clinical features. Breast cancer is the most commonly diagnosed cancer type and one of the major causes of death among women worldwide [1 (http://www.smw.ch/index.php?id=833#REF01)]. Breast cancer mortality has been falling steadily since the 1990s, as a result of the successful promotion of earlier breast cancer screening techniques and the improvement of therapeutic strategies. For instance, over half of breast cancer cases are in hormone receptor positive patients, most of whom show a high response rate to endocrine therapy. However, primary and secondary resistance to hormone therapy decreases its efficacy in advanced breast cancers and finally leads to tumour progression.
Tumorigenesis is a multistep process involving several sequential or overlapping abnormal alternations in cellular physiology, briefly categorised as self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of programmed cell death (apoptosis), unlimited replicative potential, sustained angiogenesis, and tissue invasion [2 (http://www.smw.ch/index.php?id=833#REF02)]. The emerging studies reveal the molecular and genetic mechanisms of neoplastic transformation, including local progression and remote metastasis leading scientists into individualised therapeutic perspectives such as taking single or several aberrant molecules or mutated genes as key initiators or promoters in cancer progress in order to develop precise targeted therapy. These perspectives theoretically offer a more effective and less detrimental way of dealing with malignant diseases. Based on several specific biomolecular features of breast cancer, such as breast cancer susceptibility gene type 1, 2 (BRCA1/BRCA2) mutations [3 (http://www.smw.ch/index.php?id=833#REF03)], human epidermal growth factor receptor-2 (HER-2) overexpression [4 (http://www.smw.ch/index.php?id=833#REF04)], and vascular endothelial growth factor (VEGF) receptor activation [5 (http://www.smw.ch/index.php?id=833#REF05)], some targeted agents aiming at these genetic or molecular alterations have been developed to expand the beneficiary groups and augment treatment efficacy. In a more comprehensive perspective, several novel endocrine therapies targeting endocrine receptors, such as G-protein coupled receptor 30 (GPR30), should be included in targeted therapy. However, endocrine therapy is not the main focus of this review, in which several newly established or under-evaluating targeted therapies besides hormone receptor related therapy will be discussed.
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Pertuzumab
Pertuzumab (OmnitargTM; Genentech/Roche, South San Francisco, CA) is a humanised monoclonal antibody that targets the extracellular domain of HER-2. However, the structure and function analysis demonstrated that pertuzumab binds to a quite distinct site of the HER-2 extracellular part from that of trastuzumab and is considered to serve as a HERs dimerisation inhibitor [23 (http://www.smw.ch/index.php?id=833#REF23)]. Receptor dimerisation can occur between two different EGFR family members (heterodimerisation) or between two symmetric EGFR receptors (homodimerisation). The intercellular tyrosine kinase of one receptor can only be phosphorylated and activated through dimerisation. This mechanism is quite important for HER-2/HER-3 dimers as the HER-3 receptor which lacked active tyrosine kinase domain and disabled to form the homodimers. Different investigations suggested that HER-2/HER-3 can act as an oncogenic unit, which initiates activation of the PI3K/Akt signal pathway to enhance tumour progression [24 (http://www.smw.ch/index.php?id=833#REF24)]. Pertuzumab is designed to bind to the junction part of HER-2 extracellular domain and thereby ultimately block the formation of HER-2 related homo- and hetero-dimerisation as well as their downstream signal transduction. The good tolerance and antitumour activity of pertuzumab has been identified in several completed phase I and phase II studies [25 (http://www.smw.ch/index.php?id=833#REF25)]. Pertuzumab showed a compensating anti-HER-2 efficacy after use in trastuzumab refractory metastatic breast cancer patients, which meant that it could partially reverse trastuzumab resistance [26 (http://www.smw.ch/index.php?id=833#REF26)]. A recently published phase II trial reported a 24.2% objective response rate and 50% clinical benefit rate in the regimen consisting of pertuzumab plus trastuzumab in advanced breast cancer patients with HER-2 overexpression and patients whose disease progresses aftertrastuzumab-based therapy. The promising results strongly demonstrate a synergistic efficacy of the two combined antibodies [27 (http://www.smw.ch/index.php?id=833#REF27)]. Two randomised phase III studies with pertuzumab that can increase knowledge of it are currently ongoing. The CLinical Evaluation of PErtuzumab and TRAstuzumab, sponsored by a Genentech (CLEOPATRA) study aims to compare the efficacy and safety of docetaxel plus trastuzumab with or without the combination of pertuzumab in previously untreated breast cancer patients. The neoadjuvant treatment with herceptin and pertuzumab, sponsored by a Hoffmann-LaRoche (NEOSPHERE) study recruits patients with locally advanced, inflammatory, or early-stage HER-2 positive breast cancer to evaluate the complete pathological response rate of the combination of trastuzumab, pertuzumab, and docetaxel. The first clinical data shows that pertuzumab and trastuzumab plus docetaxel given in a neoadjuvant setting prior to surgery significantly improved the pathological complete response rate as compared with trastuzumab plus docetaxel (San Antonio Breast Cancer Symposium, SABCS 2010).
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