[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