The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti–HER-2 Therapy

[Hopeful]

http://theoncologist.alphamedpress.o.../full/14/4/320

Hopeful

[eric]

Thanks, this is a very good article.

[Rich66]

I found this part especially informative:

Trastuzumab–Lapatinib Combinations and Other Targeted Therapies

Trastuzumab Plus Lapatinib
A number of clinical trials are examining the potential synergy of using both trastuzumab and lapatinib for HER-2–positive breast cancer in the neoadjuvant, adjuvant, and metastatic disease settings. Data from the ALTTO, Neo-ALTTO, and CHERLOB trials are not yet mature, and efficacy data are currently not available to assess the impact of combining HER-2–targeted agents [336, 338, 339]. In a recent interim report, testing the efficacy of the combination of trastuzumab and lapatinib compared with lapatinib alone in a heavily pretreated population of HER-2–positive MBC patients who progressed on trastuzumab-based regimens, significant synergy, as measured by the progression-free survival duration, was shown [351].

Trastuzumab Plus Bevacizumab
The BEvacizumab and Trastuzumab Adjuvant Therapy in HER-2-Positive Breast Cancer trial is a multicenter phase III randomized adjuvant trial comparing chemotherapy plus trastuzumab with chemotherapy plus trastuzumab and the anti-VEGF ligand bevacizumab [352]. No efficacy data are available at this time. In an ongoing neoadjuvant trastuzumab–bevacizumab trial, to date, the addition of bevacizumab has not resulted in a higher rate of pCR [353]. However, in a recent interim report of the combination in a trial of locally advanced disease treated in the neoadjuvant setting, early evidence of synergistic efficacy was noted [354].

Trastuzumab Plus Everolimus
As documented in a preclinical study, one of the strategies for overcoming the resistance of PTEN-deficient breast cancers to trastuzumab is the targeting of the Akt pathway using a mammalian target of rapamycin (mTOR) inhibitor [355]. RAD001 (everolimus) is an inhibitor of mTOR currently in clinical trials for the treatment of HER-2–positive breast cancer in combination with trastuzumab. In an ongoing clinical trial, early efficacy data suggest the possibility of significant synergism from the addition of everolimus to a trastuzumab and taxane regimen in the metastatic disease setting [356].

Trastuzumab Plus Heat Shock Protein 90 Inhibitors
Inhibition of the chaperone protein heat shock protein 90 (HSP90) results in increased degradation of HER-2 ECD [357, 358]. Two anti-HSP90 agents that have been combined with trastuzumab in early-stage clinical trials are geldanamycin and tenespimycin (17-AAG; Kosan Biosciences, Hayword, CA). Reports of a trial of tenespimycin combined with trastuzumab in advanced pretreated MBC have shown good safety and tolerability [359] and early indications of significant clinical activity in HER-2–positive disease [360].


Duration of Anti–HER-2 Targeted Therapy
A number of recent reviews have summarized the lack of standardization of the duration of treatment with anti–HER-2 targeting agents in HER-2–positive breast cancer [361–364]. Although the current recommended duration of trastuzumab treatment is 1 year in the adjuvant setting, different treatment durations, from 9 weeks to 2 years, have been studied with, to date, no optimal duration of treatment achieving consensus among investigators [265]. In the lapatinib plus capecitabine registration trial, oral lapatinib therapy was maintained until the time of disease progression or based on adverse events [331, 332]. In a recent study, a higher efficacy but similar toxicity were found when trastuzumab was continued beyond progression and second-line chemotherapy with capecitabine was initiated [365]. However, there is increasing evidence that continuation of anti–HER-2 therapy after progression on trastuzumab confers clinical benefit. In a recent review by the NCCN, it was noted that 74% of patients with MBC who had progressed after first-line trastuzumab-based therapy continued to receive trastuzumab in a second-line protocol [366]. Currently, no specific biomarkers appear to be capable of preselecting an individual patient for a short-term or long-term treatment regimen. A variety of markers, including serum-based assays and imaging studies, have been proposed to guide the cessation or continuance of treatment with these drugs, but, to date, no clear consensus on what tests should be selected and how they should be used has emerged.
Novel Anti–HER-2 Targeted Therapies

HER-2 Vaccines
A novel approach toward the treatment of HER-2–positive breast cancer has been the use of vaccines and adoptive immunotherapy targeting HER-2 ECD [367–371]. HER-2–specific vaccines have been tested in human clinical trials that have shown that significant levels of durable T-cell HER-2 immunity can be generated with active immunization. No significant autoimmunity directed against normal tissues has been encountered [368]. Moreover, active anti–HER-2 immunization could facilitate the ex vivo expansion of HER-2–specific T cells for use in adoptive immunotherapy for the treatment of established metastatic disease [367]. In addition, early data from trials examining the potential use of HER-2–based vaccines in the adjuvant setting to prevent the relapse of breast cancer in high-risk patients have shown promising results [371]. Future approaches include the development and testing of multiepitope vaccines [370].

Pertuzumab
Pertuzumab (rhuMab 2C4, Omnitarg^TM; Genentech Corp., South San Francisco, CA) is an anti–HER-1/HER-2 antibody that inhibits HER-1–HER-2 dimerization [372]. Pertuzumab does cause an ADCC reaction, but it does not block HER-2 shedding. Pertuzumab may have efficacy in breast cancers featuring low levels of HER-2 overexpression or in cases in which HER-2 protein levels are normal but HER-1 (EGFR) levels are elevated [372]. Clinical trials evaluating pertuzumab efficacy in MBC have not been successful to date [372, 373]. The observation that pertuzumab can elicit a metabolic response detected by position emission tomography scanning in HER-2–negative MBC has fueled continued interest in the development of the antibody in subsets of breast cancer patients [374]. In a more recent phase II study of trastuzumab and pertuzumab combination therapy in HER-2–positive metastatic disease, a 40% clinical benefit rate with multiple complete and partial responses was described [375].

Ertumaxomab
Ertumaxomab (Fresenius Biotech, Hamburg, Germany) is a trifunctional bispecific antibody targeting HER-2 on tumor cells and CD3 on T cells that has the capability to redirect T cells, macrophages, dendritic cells, and natural killer cells to the sites of tumor metastases [376, 377]. In a phase I trial, ertumaxomab treatment was associated with one complete response and several partial responses in heavily pretreated patients with MBC [376].

MDX-H210
MDX-H210, a bispecific antibody targeting HER-2 combined with G-CSF has been tested in early clinical trials with limited clinical response to date [378].

Trastuzumab Conjugates
Early attempts to conjugate HER-2–targeting antibodies with a toxin involved the use of Pseudomonas aeruginosa exotoxin [379]. More recently, trastuzumab was conjugated with the fungal toxin maytansine (DM-1) [380]. In a recent report of a phase I trial, objective responses to trastuzumab-DM1 (Genentech Corp., South San Francisco, CA) were seen below the maximal tolerated doses of the antibody conjugate [380]. Phase II trials of this agent are currently in progress, with a recent interim report finding a 40% response rate in a heavily pretreated patient cohort including prior trastuzumab and/or lapatinib therapy [381].

Novel Tyrosine Kinase Inhibitors
A number of tyrosine kinase inhibitors (TKIs) are in early-stage clinical development for the treatment of HER-2–positive breast cancer. Similar to lapatinib, HKI-272 (Wyeth Corp., Madison, NJ) is a HER-1/HER-2 dual kinase inhibitor that recently was shown to have efficacy and acceptable toxicity in an early-stage clinical trial for advanced MBC [382, 383]. A number of additional HER-1/HER-2 TKIs, pan-HER TKIs, and dual HER-2/VEGF TKIs are in various stages of preclinical and early clinical development.






Another overview of Her2/ERBB receptor issues:

ERBB Receptors and Cancer: The Complexity of Targeted Inhibitors

Nancy E. Hynes; Heidi A. Lane
Authors and Disclosures
Posted: 05/12/2005; Nat Rev Cancer. 2005;5(5):341-354. © 2005 Nature Publishing Group

http://www.medscape.com/viewarticle/504424

• Username: Her2support
• Password: Member

Bull Cancer. 2010 Feb 23. [Epub ahead of print]
[Management of metastatic HER2-positive breast cancer: present and future.]

[Article in French]
Guiu S, Coudert B, Favier L, Arnould L, Fumoleau P.
Département d'oncologie médicale, centre de lutte contre le cancer Georges-François-Leclerc, 1, rue Professeur-Marion, 21000 Dijon, France, Département d'anatomopathologie, centre de lutte contre le cancer Georges-François-Leclerc, 1, rue Professeur-Marion, 21000 Dijon, France.
HER2-positive breast cancer accounts for 20 to 25% of breast cancers. The surexpression of this tyrosine-kinase receptor is often associated with a poor prognosis. However, the management and the outcome of these patients have changed these last ten years with trastuzumab. Despite the encouraging results obtained with this humanized monoclonal antibody directed against the HER2-receptor, used alone or in association with chemotherapy in metastatic patients, progression under trastuzumab are usually observed and resistances to this treatment are described. Thus, many other monoclonal antibodies and tyrosine-kinase inhibitors emerged. These therapeutics, used alone or in association with chemotherapy or trastuzumab have variable properties: anti-HER2 and anti-EGFR such as lapatinib, pertuzumab and neratinib; anti-EGFR such as erlotinib and gefitinib; antiangiogenesis (bevacizumab, pazopanib); anti-mTOR pathway (temsirolimus, everolimus) or inhibitor of HSP90 (tanespimycine). In this paper, we present an overview on validated targeted therapies and those which are currently under investigation and seem promising in first line or after progression under trastuzumab. Data regarding cardiotoxicity and the use of trastuzumab under particular clinical circumstances (brain metastases, pregnancy) are also reviewed.

PMID: 20176546 [PubMed - as supplied by publisher]




Clinical Study

British Journal of Cancer (2010) 102, 815–826. doi:10.1038/sj.bjc.6605553 www.bjcancer.com
Published online 9 February 2010
Side-population cells in luminal-type breast cancer have tumour-initiating cell properties, and are regulated by HER2 expression and signalling

T Nakanishi^1,5, S Chumsri¹, N Khakpour¹, A H Brodie¹, B Leyland-Jones², A W Hamburger¹, D D Ross^1,3 and A M Burger⁴

1. ¹Departments of Medicine, Pathology, Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Marlene and Stewart Greenebaum Cancer Center (UMGCC), Baltimore, MD, USA
2. ²Department of Hematology and Medical Oncology, Winship Cancer Center, Emory University, Atlanta, GA, USA
3. ³Baltimore VA Medical Center, Baltimore, MD, USA
4. ⁴Barbara Ann Karmanos Cancer Institute and Department of Pharmacology, Wayne State University, Detroit, MI, USA

Correspondence: Dr AM Burger, Department of Pharmacology, Wayne State University, Hudson-Webber Cancer Research Center, Barbara Ann Karmanos Cancer Institute, Rm 640.2, 4100 John R. Street, Detroit, MI 48201, USA; E-mail: amburger@wayne.edu
⁵Current address: Kanazawa University School of Pharmaceutical Sciences, Kanazawa, Japan.
Received 18 August 2009; Revised 21 December 2009; Accepted 22 December 2009; Published online 9 February 2010.

Top of pageAbstract

Background:

The expression of side-population (SP) cells and their relation to tumour-initiating cells (T-ICs) have been insufficiently studied in breast cancer (BC). We therefore evaluated primary cell cultures derived from patients and a panel of human BC cell lines with luminal- or basal-molecular signatures for the presence of SP and BC stem cell markers.

Methods:

The SPs from luminal-type BC were analysed for BC T-IC characteristics, including human epidermal growth factor receptor 2 (HER2), ERα, IGFBP7 expression and their ability to initiate tumours in non-obese diabetic severe combined immunodeficiency (NOD/SCID) mice. Pharmacological modulators were used to assess the effects of HER2 signalling and breast cancer-resistance protein (BCRP) expression on SPs.

Results:

The SP was more prevalent in the luminal subtype of BC compared with the basal subtype. HER2 expression was significantly correlated with the occurrence of an SP (r²=0.75, P=0.0003). Disappearance of SP in the presence of Ko143, a specific inhibitor of the ATP-binding cassette transporter BCRP, suggests that BCRP is the predominant transporter expressed in this population. The SP also decreased in the presence of HER2 signalling inhibitors AG825 or trastuzumab, strengthening the notion that HER2 contributed to the SP phenotype, likely through downstream AKT signalling. The SP cells from luminal-type MCF-7 cells with enforced expression of HER2, and primary cells with luminal-like properties from a BC patient, displayed enrichment in cells capable of repopulating tumours in NOD/SCID mice. Engraftment of SP cells was inhibited by pretreatment with AG825 or by in vivo treatment with trastuzumab.

Interpretation:

Our findings indicate an important role of HER2 in regulating SP and hence T-ICs in BC, which may account for the poor responsiveness of HER2-positive BCs to chemotherapy, as well as their aggressiveness.

Keywords:

SP, BC, luminal, HER2, T-ICs

[Rich66]

An interesting counterpoint to the targeted approach:

1: Curr Med Chem. 2008;15(5):422-32.Links

From single- to multi-target drugs in cancer therapy: when aspecificity becomes an advantage.

Petrelli A, Giordano S.
Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Str. Provinciale 142, 10060, Candiolo (Torino), Italy. annalisa.petrelli@ircc.it
Targeted therapies by means of compounds that inhibit a specific target molecule represent a new perspective in the treatment of cancer. In contrast to conventional chemotherapy which acts on all dividing cells generating toxic effects and damage of normal tissues, targeted drugs allow to hit, in a more specific manner, subpopulations of cells directly involved in tumor progression. Molecules controlling cell proliferation and death, such as Tyrosine Kinase Receptors (RTKs) for growth factors, are among the best targets for this type of therapeutic approach. Two classes of compounds targeting RTKs are currently used in clinical practice: monoclonal antibodies and tyrosine kinase inhibitors. The era of targeted therapy began with the approval of Trastuzumab, a monoclonal antibody against HER2, for treatment of metastatic breast cancer, and Imatinib, a small tyrosine kinase inhibitor targeting BCR-Abl, in Chronic Myeloid Leukemia. Despite the initial enthusiasm for the efficacy of these treatments, clinicians had to face soon the problem of relapse, as almost invariably cancer patients developed drug resistance, often due to the activation of alternative RTKs pathways. In this view, the rationale at the basis of targeting drugs is radically shifting. In the past, the main effort was aimed at developing highly specific inhibitors acting on single RTKs. Now, there is a general agreement that molecules interfering simultaneously with multiple RTKs might be more effective than single target agents. With the recent approval by FDA of Sorafenib and Sunitinib--targeting VEGFR, PDGFR, FLT-3 and c-Kit--a different scenario has been emerging, where a new generation of anti-cancer drugs, able to inhibit more than one pathway, would probably play a major role.
PMID: 18288997 [PubMed - indexed for MEDLINE]

BMC Cancer. 2010 Mar 8;10(1):84. [Epub ahead of print]
Enhanced antiproliferative and apoptotic response to combined treatment of gamma-tocotrienol with erlotinib or gefitinib in mammary tumor cells.

Bachawal SV, Wali VB, Sylvester PW.
ABSTRACT: BACKGROUND: Aberrant ErbB receptor signaling is associated with various types of malignancies. gamma-Tocotrienol is a member of the vitamin E family of compounds that displays potent anticancer activity that is associated with suppression in ErbB receptor phosphorylation and mitogenic signaling. Erlotinib and gefitinib are tyrosine kinase inhibitors that block ErbB1 receptor activation, whereas trastuzumab is a monoclonal antibody that has been designed to specifically inhibit ErbB2 receptor activation. However, the clinical effectiveness of these agents have been disappointing because of cooperation between different ErbB family members that can rescue cancer cells from agents directed against a single ErbB receptor subtype. It was hypothesized that targeting multiple ErbB receptor subtypes with combined treatment of gamma-tocotrienol and ErbB receptor inhibitors would provide greater anticancer effects than monotherapy targeting only a single ErbB receptor subtype. METHODS: Highly malignant mouse +SA mammary epithelial cells were maintained in culture on serum-free defined media containing 10ng/ml EGF as a mitogen. Cell viability wase determined by MTT assay, whereas Western blot and immunofluorescent staining was used to determine treatment effects on ErbB receptor subtype level and activation. Treatment-induced apoptosis was determined using annexin V staining and Western blot analysis of cleaved caspase-3 and PARP levels. RESULTS: Treatment with 3.5 uM gamma-tocotrienol, 0.5 uM erlotinib or 1.0 uM gefitinib alone, significantly inhibited +SA tumor cell growth. Combined treatment with subeffective doses of erlotinib (0.25 uM) or gefitinib (0.5 uM) with subeffective doses of gamma-tocotrienol (0.5-3.0 uM) significantly inhibited the growth and induced apoptosis in a dose-responsive manner. Trastuzumab treatment alone or in combination had no effect on +SA cell growth and viability. Combined treatment of gamma-tocotrienol with erlotinib or gefitinib also cause a large decrease in ErbB3, ErbB4, and to a lesser extent ErbB2 receptor levels, and EGF-dependent ErbB2-4 tyrosine phosphorylation (activation), but had no effect on ErbB1 receptor levels or activation. CONCLUSION: Combination treatment of gamma-tocotrienol with specific ErbB receptor inhibitors is more effective in reducing mammary tumor cell growth and viability than high dose monotherapy, suggesting that targeting multiple ErbB receptors with combination therapy may significantly improve the therapeutic response in breast cancer patients.

PMID: 20211018 [PubMed - as supplied by publisher]


Cancer Res. 2009 Dec 15;69(24):9163-8.
Upregulation of neutrophil gelatinase-associated lipocalin by ErbB2 through nuclear factor-kappaB activation.

Li SH, Hawthorne VS, Neal CL, Sanghera S, Xu J, Yang J, Guo H, Steeg PS, Yu D.
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Abstract

ErbB2 (HER2, neu) is a receptor tyrosine kinase overexpressed in about 25% of invasive breast carcinomas. Neutrophil gelatinase-associated lipocalin (NGAL) is a secreted glycoprotein expressed in a variety of cancers, including breast carcinomas. NGAL can inhibit erythroid cell production, leading to anemia. Anemia usually occurs in cancer patients and negatively affects quality of life. However, current treatment for cancer-related anemia has potential complications. ErbB2, NGAL, and anemia have all been associated with increased metastasis and poor prognosis in breast cancer patients, although the relationship between ErbB2 and NGAL expression is not clear. Here, using breast cancer cell lines in vitro and transgenic mice carrying the activated c-neu oncogene driven by a mouse mammary tumor virus (MMTV-neu) in vivo, we show that ErbB2 overexpression leads to NGAL upregulation, which is dependent on nuclear factor-kappaB (NF-kappaB) activity. MMTV-neu transgenic mice developed anemia after tumor onset, and anemia progression could be partially arrested by a NF-kappaB inhibitor and ErbB2-targeted therapy. Taken together, upregulation of NGAL by ErbB2 through NF-kappaB activation is involved in cancer-related anemia, and the ErbB2, NF-kappaB, and NGAL pathways may serve as potential therapeutic targets for cancer-related anemia.

PMID: 19951994 [PubMed - indexed for MEDLINE]PMCID: PMC2794902 [Available on 2010/12/15]

[Rich66]

1: Cancer Res. 2009 May 15;69(10):4270-6. Epub 2009 May 12. Links

The trifunctional antibody ertumaxomab destroys tumor cells that express low levels of human epidermal growth factor receptor 2.

Jäger M, Schoberth A, Ruf P, Hess J, Lindhofer H.
TRION Research GmbH, Martinsried, Germany.
Human epidermal growth factor receptor 2 (HER2/neu) is an important target for the treatment of the breast cancers in which it is overexpressed. However, no approved anti-HER2/neu therapy is available for the majority of breast cancer patients, who express HER2/neu at low levels (with scores of 1+ or 2+/fluorescence in situ hybridization-negative). The trifunctional antibody ertumaxomab targets HER2/neu, CD3, and activating Fcgamma receptors. In presence of ertumaxomab, tri-cell complexes consisting of tumor cells, T cells, and accessory cells form to cause tumor cell lysis. In a phase I trial with metastatic breast cancer patients, ertumaxomab could be applied safely and resulted in radiographically confirmed clinical responses. In this study, we compare ertumaxomab- and trastuzumab-mediated killing of cancer cell lines that express HER2/neu at low and high levels. Under optimal conditions for trastuzumab-mediated destruction of HER2/neu-overexpressing cells, only ertumaxomab was able to mediate the elimination of tumor cell lines that express HER2/neu at low levels (1+). Ertumaxomab-mediated activity was accompanied by a Th1-based cytokine release, a unique mode of action of trifunctional antibodies. Competitive binding studies with trastuzumab and 520C9 mapped the binding site of ertumaxomab to the extracellular regions II and III of the HER2/neu ectodomain. This site is distinct from the binding site of trastuzumab, so that HER2/neu-expressing tumor cells can be eliminated by ertumaxomab in the presence of high amounts of trastuzumab. The ability of ertumaxomab to induce cytotoxicity against various tumor cell lines, including those with low HER2/neu antigen density, may provide a novel therapeutic option for breast cancer patients who are not eligible for trastuzumab treatment.
PMID: 19435924 [PubMed - in process

The HER2 testing conundrum 2010
FREE TEXT
Problems in interpreting diagnostic tests for HER2 may be compromising patient access to effective treatments. As new versions of therapies targeting HER2 work their way through clinical trials, will the situation get even murkier? Malorye Allison investigates.