Treatment Of HER2-overexpressing Breast Cancer Research Articles

Treatment of Her2-Positive Breast Cancer: What’s on the Horizon

Almost 30% of all breast cancers are noted to overexpress human epidermal growth factor receptor 2 (Her2), an epidermal growth factor receptor that is part of the HER family of tyrosine kinases. Her2 exerts its effect by forming heterodimers with other HER family members, resulting in the activation of a number of signaling pathways that are important for tumor progression and survival. Her2 overexpression has been linked with a more aggressive breast cancer phenotype and with decreased survival in patients with Her2-positive tumors. Trastuzumab and lapatinib are approved targeted agents for treatment of Her2-overexpressing breast cancer. The use of trastuzumab in this patient population resulted in phenomenal responses and paved the way for use of molecularly targeted therapies in the treatment of many other cancers. However, despite the tremendous progress attained, disease progression, even with trastuzumab and lapatinib treatment, is inevitable in metastatic breast cancer. Thus, research efforts have focused on finding alternative therapies to trastuzumab and lapatinib for the treatment of Her2-positive breast cancer. Efforts aimed at understanding the mechanism of action of trastuzumab and lapatinib and the causes of resistance have led to the identification of several promising agents for the treatment of patients with Her2-positive breast cancer.

Inhibitors of HSP90 block p95-HER2 signaling in Trastuzumab-resistant tumors and suppress their growth

The anti-HER2 antibody Trastuzumab (Herceptin) has been proven to be effective in the treatment of HER2 overexpressing breast cancer; resistance, however invariably emerges in metastatic tumors. The expression of p95-HER2, a form of HER2 with a truncated extracellular domain that lacks the Trastuzumab binding epitope, has been implicated as a mechanism of resistance to the antibody. We utilized an in vivo tumor model that overexpresses p95-HER2 and demonstrate it to be resistant to the signaling and antitumor effects of Trastuzumab. We find that both full length and p95-HER2 interact with the HSP90 chaperone protein and are degraded in tumor cells exposed to HSP90 inhibitors in tissue culture and in vivo. Loss of expression of p95-HER2 is accompanied by downregulation of the PI3K/AKT and ERK signaling pathways and inhibition of cell proliferation. Chronic administration of HSP90 inhibitors in vivo results in sustained loss of HER2 and p95-HER2 expression and inhibition of AKT activation together with induction of apoptosis and complete inhibition of tumor growth in Trastuzumab-resistant, p95-HER2-overexpressing models. Thus, p95-HER2 is an HSP90 client protein, the expression and function of which can be effectively suppressed in vivo by HSP90 inhibitors. HSP90 inhibition is therefore a potentially effective therapeutic strategy for p95-HER2-mediated Trastuzumab-resistant breast cancer.

Lapatinib for the treatment of HER2-overexpressing breast cancer

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of lapatinib for the treatment of advanced or metastatic HER2-overexpressing breast cancer based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The scope included women with advanced, metastatic or recurrent HER2-overexpressing breast cancer who have had previous therapy that includes trastuzumab. Outcomes were time to progression, progression-free survival, response rates, overall survival, health-related quality of life and adverse effects. The submission's evidence came from one randomised controlled trial (RCT) of reasonable methodological quality, although it was not powered to detect a statistically significant difference in mean overall survival. Median time to progression was longer in the lapatinib plus capecitabine arm than in the capecitabine monotherapy arm {27.1 [95% confidence interval (CI) 17.4 to 49.4] versus 18.6 [95% CI 9.1 to 36.9] weeks; hazard ratio 0.57 [95% CI 0.43 to 0.77; p = 0.00013]}. Median overall survival was very similar between the groups [67.7 (95% CI 58.9 to 91.6) versus 66.6 (95% CI 49.1 to 75.0) weeks; hazard ratio 0.78 (95% CI 0.55 to 1.12; p = 0.177)]. Median progression-free survival was statistically significantly longer in the lapatinib plus capecitabine group than in the capecitabine monotherapy group [27.1 (95% CI 24.1 to 36.9) versus 17.6 (95% CI 13.3 to 20.1) weeks; hazard ratio 0.55 (95% CI 0.41 to 0.74); p = 0.000033]. The manufacturer's economic model to estimate progression-free and overall survival for patients with HER2-positive advanced/metastatic breast cancer who had relapsed following treatment with an anthracycline, a taxane and trastuzumab was appropriate for the disease area. The base-case incremental cost-effectiveness ratios (ICERs) for lapatinib plus capecitabine compared with capecitabine monotherapy or vinorelbine monotherapy were higher than would conventionally be considered cost-effective. When compared with trastuzumab-containing regimes, lapatinib plus capecitabine dominated. In sensitivity analyses the ICER for lapatinib plus capecitabine compared with capecitabine monotherapy or vinorelbine monotherapy was robust to variation in assumptions. In all sensitivity analyses the ICERs remained higher than would conventionally be considered cost-effective. ICERs for trastuzumab-containing regimes were particularly sensitive to assumptions over the frequency of treatment, which had a large effect on the cost-effectiveness of lapatinib plus capecitabine. In conclusion, there was a general lack of evidence on the effectiveness of comparators included in the model and on key parameters such as dose adjustments and the model outputs need to be interpreted in the light of this uncertainty. At the time of writing, NICE were still considering the available evidence for this appraisal.

Lapatinib for the treatment of HER2-overexpressing breast cancer

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of lapatinib for the treatment of advanced or metastatic HER2overexpressing breast cancer based upon a review of the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The scope included women with advanced, metastatic or recurrent HER2-overexpressing breast cancer who have had previous therapy that includes trastuzumab. Outcomes were time to progression, progression-free survival, response rates, overall survival, health-related quality of life and adverse effects. The submission’s evidence came from one randomised controlled trial (RCT) of reasonable methodological quality, although it was not powered to detect a statistically significant difference in mean overall survival. Median time to progression was longer in the lapatinib plus capecitabine arm than in the capecitabine monotherapy arm {27.1 [95% confidence interval (CI) 17.4 to 49.4] versus 18.6 [95% CI 9.1 to 36.9] weeks; hazard ratio 0.57 [95% CI 0.43 to 0.77; p = 0.00013]}. Median overall survival was very similar between the groups [67.7 (95% CI 58.9 to 91.6) versus 66.6 (95% CI 49.1 to 75.0) weeks; hazard ratio 0.78 (95% CI 0.55 to 1.12; p = 0.177)]. Median progression-free survival was statistically significantly longer in the lapatinib plus capecitabine group than in the capecitabine monotherapy group [27.1 (95% CI 24.1 to 36.9) versus 17.6 (95% CI 13.3 to 20.1) weeks; hazard ratio 0.55 (95% CI 0.41 to 0.74); p = 0.000033]. The manufacturer’s economic model to estimate progression-free and overall survival for patients with HER2-positive advanced/metastatic breast cancer who had relapsed following treatment with an anthracycline, a taxane and trastuzumab was appropriate for the disease area. The base-case incremental cost-effectiveness ratios (ICERs) for lapatinib plus capecitabine compared with capecitabine monotherapy or vinorelbine monotherapy were higher than would conventionally be considered cost-effective. When compared with trastuzumab-containing regimes, lapatinib plus capecitabine dominated. In sensitivity analyses the ICER for lapatinib plus capecitabine compared with capecitabine monotherapy or vinorelbine monotherapy was robust to variation in assumptions. In all sensitivity analyses the ICERs remained higher than would conventionally be considered cost-effective. ICERs for trastuzumab-containing regimes were particularly sensitive to assumptions over the frequency of treatment, which had a large effect on the cost-effectiveness of lapatinib plus capecitabine. In conclusion, there was a general lack of evidence on the effectiveness of comparators included in the model and on key parameters such as dose adjustments and the model outputs need to be interpreted in the light of this uncertainty. At the time of writing, NICE were still considering the available evidence for this appraisal.

5022 A retrospective study on the efficacy of elliptinium acetate in metastatic breast cancer patients

Human epidermal growth factor receptor 2 (HER2), a member of the ErbB family of transmembrane receptor tyrosine kinases, is amplified in 20–30% of invasive breast cancers. HER2 amplification is associated with metastasis and reduced survival. Two HER2-directed therapies have been approved by the United States Food and Drug Administration for the treatment of HER2-overexpressing breast cancer: trastuzumab, a humanized monoclonal antibody against the extracellular portion of HER2; and lapatinib, a dual HER2- and epidermal growth factor receptor-specific tyrosine kinase inhibitor. Despite the improvement in overall survival with the addition of HER2-targeted agents to chemotherapy, many patients do not benefit from these agents because of inherent resistance. In addition, many patients who achieve an initial response eventually acquire drug resistance. Currently, several mechanisms of resistance have been described, including mutations in other signaling pathways, expression of a truncated form of HER2, receptor crosstalk, and autophagy. There are several approaches under study to target these pathways of resistance, including blocking PI3 kinase and mammalian target of rapamycin signaling, blocking neoangiogenesis and the vascular endothelial growth factor axis, using monoclonal antibody targeting of the HER2 dimerization site, and using HER2 monoclonal antibody-drug conjugates. Here we will review the current scientific rationale for these agents and how combinations of these agents may yield additive or synergistic effects and lead to improved outcomes for patients with HER2-amplified breast cancer.

A phase I dose-escalation study of 5-day intermittent oral lapatinib therapy with biomarker analysis in patients with HER-2–overexpressing breast cancer

e14530 Background: Although current HER2 targeting agents have made measurable impact on the treatment of HER2overexpressing breast cancer, their effects have been modest. Recent evidence has redefined the target of interest as the HER2-HER3 signaling dimer and identified inherent signal buffering capacity that protects it against partial inhibitors of HER2 function. In preclinical studies, HER2 catalytic function and HER2-HER3 signaling can be suppressed, but this requires higher fully inactivating doses of HER- family tyrosine kinase inhibitors (TKIs) leading to apoptotic tumor cell death. We hypothesize that TKIs may be much more clinically effective if used at much higher and fully inactivating doses. Such high dosing may only be tolerable if given intermittently rather than continuously. Methods: To test this hypothesis clinically, we conducted a phase 1 dose-escalation study of a 5-day course of lapatinib (Lp) in women with advanced HER2-overexpressing breast cancer. Lp was administered on days 1–5 of a 14 day cycle. Starting Lp dose was 1750 mg/day and was escalated in cohorts of 3 until the maximum tolerated dose (MTD) was defined. The first cycle of Lp therapy was bracketed by tumor fine needle aspirations and serologic studies, performed at baseline and on day 5. Functional signaling pathway biomarker analysis was performed on tumor lysates using Reverse Phase Protein Microarrays to assay the inactivation of HER2-HER3 signaling. Plasma Lp concentration was assayed at all dose levels and cardiac function was rigorously monitored. Tumor core biopsies were performed on a subset of patients at the MTD to determine tissue Lp levels. Results: 17 patients have been treated to date. No grade 4 or serious adverse events (AEs) attributable to Lp have been noted. 1 patient experienced dose-limiting toxicity at dose level 6 (7000 mg/day) consisting of grade 3 diarrhea despite maximal anti-diarrheal support. There have been no cardiac AEs. The most common AEs include grade 2 diarrhea, nausea, vomiting, acne. Conclusions: The MTD and systemic exposure of Lp can be considerably increased throsugh intermittent dosing. [Table: see text]

Tumor-targeted PE38KDEL delivery via PEGylated anti-HER2 immunoliposomes

We previously reported the development of PE38KDEL-loaded anti-HER2 poly(lactic-co-glycolic acid) (PLGA) nanoparticles that bind and internalize in HER2-overexpressing breast cancer cells, enabling potent anti-tumor activity. To overcome the problems associated with the short half-lives of this drug delivery system, we have constructed PE38KDEL-loaded anti-HER2 PEGylated liposomes (PE-HER-liposomes). PE-HER-liposomes were constructed with Fab′ of recombinant humanized anti-HER2 monoclonal antibody (anti-HER2 Fab′) covalently linked to PEGylated liposomes containing PE38KDEL (PE-liposomes). We attached anti-HER2 Fab′ to the terminus of PEG (polyethylene glycol) on PEGylated liposomes. Incorporation of pyridylthiopropionoylamino-PEG-distearoylphosphatidylethanolamine (PDP-PEG-DSPE) into PEGylated liposomes followed by mild thiolysis of the PDP groups resulted in the formation of reactive thiol groups at the periphery of the liposomes. Efficient attachment of maleimide-derivatized anti-HER2 Fab′ took place under mild conditions. The characterization of PE-HER-liposomes, such as particle size, was evaluated by dynamic light-scattering detector. The Micro BCA method was used to determine the encapsulation efficiency of PE38KDEL and the quantity of conjugated Fab′. Flow cytometry and confocal microscopy showed that PE-HER-liposomes possessed receptor-specific binding and internalization for HER2-overexpressing SK-BR3 cells. Remarkably, PE-HER-liposomes were more cytotoxic than non-targeted PE-liposomes in HER2-overexpressing breast cancer cells. In conclusion, PE-HER-liposomes could serve as a promising therapeutic candidate for the treatment of HER2-overexpressing breast cancers.

Her2-positive breast cancer: Herceptin and beyond

Breast cancer accounts for approximately 30% of all new cancer cases each year, with an annual incidence of approximately 200,000. Additionally, almost 25% of breast cancers are noted to overexpress Her2, which is an epidermal growth factor receptor. Overexpression of Her2 has been associated with a more aggressive phenotype with decreased survival. Trastuzumab, a recombinant monoclonal antibody against the Her2 receptor, is the only FDA-approved targeted agent for treatment of Her2-overexpressing breast cancer. However, despite the great success achieved with trastuzumab, many women will either not respond or eventually progress despite trastuzumab treatment. As a result, significant efforts have been applied to finding other therapies besides trastuzumab for the treatment of Her2-positive breast cancer. Work has been directed at trying to elucidate the exact mechanism of resistance to trastuzumab and identifying ways to overcome them, at increasing the efficacy of trastuzumab by combining it with other therapeutic agents and at investigating other novel agents.

Trastuzumab-Resistant HER2-Driven Breast Cancer Cells Are Sensitive to Epigallocatechin-3 Gallate

Overexpression of the epidermal growth factor receptor family member HER2 is found in approximately 30% of breast cancers and is a target for immunotherapy. Trastuzumab, a humanized monoclonal antibody against HER2, is cytostatic when added alone and highly successful in clinical settings when used in combination with other chemotherapeutic agents. Unfortunately, HER2 tumors in patients develop resistance to trastuzumab or metastasize to the brain, which is inaccessible to antibody therapy. Previously, we showed that the green tea polyphenol epigallocatechin-3 gallate (EGCG) inhibits growth and transformed phenotype of Her-2/neu-driven mouse mammary tumor cells. The different modes of action of EGCG and trastuzumab led us to hypothesize that EGCG will inhibit HER2-driven breast cancer cells resistant to trastuzumab. We studied trastuzumab-resistant BT474 human breast cancer cells, isolated by chronic trastuzumab exposure, and JIMT-1 breast cancer cells, derived from a pleural effusion in a patient who displayed clinical resistance to trastuzumab therapy. EGCG treatment caused a dose-dependent decrease in growth and cellular ATP production, and apoptosis at high concentrations. Akt activity was suppressed by EGCG leading to the induction of FOXO3a and target cyclin-dependent kinase inhibitor p27Kip1 levels. Thus, EGCG in combination with trastuzumab may provide a novel strategy for treatment of HER2-overexpressing breast cancers, given that EGCG can cross the blood-brain barrier.

Potential use of humanized antibodies in the treatment of breast cancer

With the growing knowledge of key cellular pathways in tumor induction and evolution, targeted therapies make up an increasing proportion of new drugs entering clinical testing. In the treatment of breast cancer, humanized antibodies have become a major option. The humanized monoclonal antibody trastuzumab (Herceptin®; Genentech, Inc., CA, USA) for HER2-overexpressing, metastatic breast cancer, represents a successful agent associated with impressive survival benefits when combined with chemotherapy. Based on impressive results, trastuzumab will become a standard in the adjuvant treatment of HER2-overexpressing breast cancer. The role of trastuzumab in the neoadjuvant setting is promising, but must be further evaluated in large prospective, randomized trials. However, there is still a large proportion of patients overexpressing HER2 that do not respond to trastuzumab. Regarding this patient cohort, the optimal combination of trastuzumab with other agents needs further evaluation. In breast cancer lacking HER2 amplification, the role of the new antibody pertuzumab remains to be defined. The role of antibodies interfering with angiogenesis, tumor stroma or glycoproteins is of a preliminary nature and warrants further investigation. Here, an overview of humanized antibodies in human breast cancer is provided, with emphasis on the recent advances and future prospects in treating malignant breast cancer.

Targeted therapies for solid tumors: is the dream becoming a reality?

The articles published in Targeted Oncology clearly demonstrate that there is a revolution underway in the care of cancer patients with solid tumors, a revolution linked to the successful development of new targeted drugs. These drugs, which are known to affect critical molecular pathways in tumors or their surrounding stroma, are improving outcomes for cancer patients when given alone or in combination with standard therapies. For certain highly treatment-resistant tumors, such as kidney cancer, there may now be a light at the end of the tunnel, with the recent discovery of at least four targeted drugs showing clear antitumor activity in advanced disease. And there is new hope of improving cure rates if the synergy between chemotherapy and the anti-VEGF drug bevacizumab, which was recently demonstrated in advanced lung, breast and colorectal cancers, can be successfully transferred to the adjuvant setting. The most advanced of the new targeted agents is the anti-HER2 monoclonal antibody trastuzumab; it has become a central component in the treatment of HER2overexpressing breast cancer, improving survival in advanced and early disease. The successful development of trastuzumab has taught us several important lessons. First, a single oncogene can play a crucial role in a complex disease. Secondly, “bench-to-bedside” translational research has opened the way to truly tailored oncology and allows clinicians to move away from the “one-size-fits-all” strategy. However, this approach requires a great deal of energy and perseverance: 21 years elapsed between the time the HER2 gene was cloned and the time the antiHER2 monoclonal antibody trastuzumab demonstrated any survival impact in early breast cancer. Thirdly, targeted drugs can lead to unexpected and potentially severe side effects. Congestive heart failure, which occurs in a small proportion of patients receiving trastuzumab, was first detected in the randomized trial of anthracycline-based chemotherapy with or without trastuzumab in the treatment of advanced breast cancer. This result gave rise to translational research that led to the discovery of the important role the HER signaling pathway plays in how cardiac cells respond to stress signals. Fourthly, the cost of these new targeted agents is high and represents a new burden for health-care systems. And finally, the target’s presence in a tumor does not guarantee benefits from the targeted drug: only one in two women with HER2-positive breast cancer has positive results with trastuzumab. The new challenge is to identify those patients who will actually benefit from the targeted drugs, in order to maximize disease outcomes while minimizing unnecessary treatment. The high-throughput capabilities of new technologies— such as gene expression profiling, tissue arrays or proteomic approaches—are likely to dramatically improve our ability to make clinical predictions. However, for this second and much needed revolution to occur, we need structured strategies regarding biomarker development in clinical trials. Translational research is currently under-funded, yet the investment is well worth making, as it offers potentially substantial savings in healthcare costs and may be the only way to turn the dream of truly targeted treatments into a reality. Targ Oncol (2006) 1:113 DOI 10.1007/s11523-006-0020-7

Advances in the Adjuvant Treatment of HER2-Overexpressing Breast Cancer with the Anti-HER2 Antibody Trastuzumab

Advances in the Adjuvant Treatment of HER2-Overexpressing Breast Cancer with the Anti-HER2 Antibody Trastuzumab

Trastuzumab/chemotherapy combinations in metastatic breast cancer.

The past decade has seen many advances in the treatment of advanced breast cancer, including the development of both new chemotherapy drugs and novel targeted agents. Trastuzumab, a humanized monoclonal antibody directed against the HER2/neu protein, has been shown to be an efficacious treatment for HER2-overexpressing metastatic breast cancer, both as a single agent and when used in combination with chemotherapy. The US Food and Drug Administration has approved the use of trastuzumab and paclitaxel as first-line treatment of HER2-overexpressing metastatic breast cancer, based on the results of a randomized phase III clinical trial showing that this combination produced higher response rates and longer survival duration than treatment with chemotherapy alone. Further trials are currently underway evaluating the use of trastuzumab in combination with other forms of chemotherapy, including vinorelbine, docetaxel, anthracyclines, and platinum agents. Hopefully, information from these trials will help resolve questions regarding the efficacy of various combinations and dosing schedules so that trastuzumab may be used most effectively in the treatment of HER2-overexpressing breast cancer in both the metastatic and the adjuvant settings.

Trastuzumab/chemotherapy combinations in metastatic breast cancer

The past decade has seen many advances in the treatment of advanced breast cancer, including the development of both new chemotherapy drugs and novel targeted agents. Trastuzumab, a humanized monoclonal antibody directed against the HER2/ neu protein, has been shown to be an efficacious treatment for HER2-overexpressing metastatic breast cancer, both as a single agent and when used in combination with chemotherapy. The US Food and Drug Administration has approved the use of trastuzumab and paclitaxel as first-line treatment of HER2-overexpressing metastatic breast cancer, based on the results of a randomized phase III clinical trial showing that this combination produced higher response rates and longer survival duration than treatment with chemotherapy alone. Further trials are currently underway evaluating the use of trastuzumab in combination with other forms of chemotherapy, including vinorelbine, docetaxel, anthracyclines, and platinum agents. Hopefully, information from these trials will help resolve questions regarding the efficacy of various combinations and dosing schedules so that trastuzumab may be used most effectively in the treatment of HER2-overexpressing breast cancer in both the metastatic and the adjuvant settings. Semin Oncol 29 (suppl 11):38-43. Copyright 2002, Elsevier Science (USA). All rights reserved.