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Liposomal Anthracyclines and New Treatment Approaches for Breast Cancer

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University, Baltimore, Maryland, USA

Correspondence: Antonio C. Wolff, M.D., The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Room 189, Baltimore, Maryland 21231-1000, USA. Telephone: 410-614-4192; Fax: 410-955-0125; e-mail: awolff{at}jhmi.edu

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Combination Therapy with... New Directions in Breast... Conclusions References

 
After completing this course, the reader will be able to:

1. Describe the rationale for combining growth factor pathway modulators and cytotoxic agents in the treatment of breast cancer.
   
2. Discuss clinical trials examining the efficacy and safety of trastuzumab in combination with other agents, including liposomal anthracyclines, in the treatment of breast cancer.
   
3. Discuss new directions in breast cancer research.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Combination Therapy with... New Directions in Breast... Conclusions References

 
Breast cancer research is entering a new and promising phase, with greater focus on patient quality of life and therapy selection based on specific targets of interest. Growth factor pathway modulators represent an area of increasing interest for clinicians treating various cancer types, including breast cancer. Therapeutic strategies combining cytotoxic drugs with specific targets using small molecules and targeted antibody therapy may help circumvent potential growth factor survival mechanisms in solid tumors. One of the challenges when combining these agents, however, is the potential for pharmacodynamic and pharmacokinetic interactions, making safety an important consideration. An example of a growth factor pathway modulator with clinical application in breast cancer is trastuzumab. Based on its efficacy in metastatic disease, ongoing clinical trials are examining trastuzumab in combination with chemotherapy in the adjuvant setting. Concerns about the cardiac safety of trastuzumab given concomitantly with conventional anthracyclines support ongoing investigations of regimens combining it with liposomal anthracyclines, based on available data indicating a more favorable cardiac safety profile with liposomal formulations.

Key Words. Anthracyclines • Liposome • Adjuvant chemotherapy • Breast neoplasms • Monoclonal antibodies

	INTRODUCTION

Top Learning Objectives Abstract Introduction Combination Therapy with... New Directions in Breast... Conclusions References

 
Breast cancer research is increasingly focused on mechanistically based therapies and the preservation and improvement of the quality of life of those affected by this disease. Growth factor pathway modulators alone and in combination with various cytotoxic agents have generated significant interest regarding the potential activity of target-specific therapy. Trastuzumab (Herceptin^®; Genentech, Inc.; South San Francisco, CA; http://www.gene.com) is one of the most promising growth factor pathway modulators based on its activity in metastatic breast cancer (MBC). Several ongoing trials are examining the addition of trastuzumab to conventional chemotherapy regimens in the adjuvant treatment of breast cancer. As anthracyclines remain a mainstay of treatment for early-stage and metastatic disease, liposomal formulations were developed in an effort to increase the therapeutic index of conventional anthracyclines. This paper discusses some of these future directions and new treatment options relating to the research and treatment of breast cancer, with emphasis on the combination of growth factor pathway modulators and cytotoxic agents.

	COMBINATION THERAPY WITH CYTOTOXIC AGENTS AND GROWTH FACTOR PATHWAY MODULATORS

Top Learning Objectives Abstract Introduction Combination Therapy with... New Directions in Breast... Conclusions References

 
Modulators of Signaling Pathways
Several intracellular growth factor signal transduction pathways may become dysregulated during the development and progression of breast cancer, offering potential targets for a number of target-specific modulators, such as tyrosine kinase inhibitors and monoclonal antibodies directed against growth factor receptors [1–3]. One important example is trastuzumab, a monoclonal antibody against the human epidermal growth factor receptor 2 (HER-2), which has demonstrated clinical utility in patients with MBC that overexpress HER-2 [4]. However, several of the known signal transduction pathways share common downstream steps, and the net effects of activation or inhibition of a specific pathway will result from the interactions of a complementary cascade of signals. This may explain why only a fraction of patients whose tumors overexpress HER-2 benefit from trastuzumab and justifies the interest in combining different drugs affecting more than one target. It also suggests that the inhibition of a single specific target is not likely to translate into clinical benefit in most common malignancies, such as tumors of epithelial origin. This challenge is compounded by the shortage of clinically useful predictive markers of response to specific therapies, such as the expression of the estrogen receptor and antiestrogen therapy and HER-2 gene amplification and trastuzumab. This is complicated further by the lack of predictive markers to identify those who will respond to commonly used cytotoxic chemotherapeutic agents. It is also important to determine whether the inhibition of the apparent target in surrogate tissues like blood and skin will translate into an actual antitumor effect. With these considerations in mind, there has been much interest in combination strategies of cytotoxic drugs with target-specific signaling pathway modulators that may help circumvent growth factor survival mechanisms responsible for the resistance to standard therapies observed in many patients with metastatic disease.

Potential for Deleterious Interactions
Preclinical and animal models often fail to predict toxicities of concern among humans and potential interactions with commonly used drugs (e.g., trastuzumab, particularly when combined with free doxorubicin, and myocardial dysfunction) [4]. Another challenge in combining cytotoxic drugs with growth factor pathway modulators is the potential for drug interactions involving phase I and II metabolic enzymes. For instance, imatinib mesylate (STI-571, Gleevec^TM; Novartis Pharmaceutical Corporation; East Hanover, NJ; http://www.novartis.com.) is both a substrate and an inhibitor of the cytochrome P450 3A4 enzyme, which raises concerns about potentially meaningful pharmacokinetic interactions if this tyrosine kinase inhibitor were combined with drugs primarily metabolized via this specific pathway, such as docetaxel (Taxotere^®; Aventis Pharmaceuticals Products Inc.; Bridgewater, NJ; http://www.aventis.com) [5,6].

Trastuzumab and Its Role in the Adjuvant Breast Cancer Setting
Trastuzumab and antiestrogen therapy are important examples of targeted therapy in breast cancer. The addition of trastuzumab to chemotherapy was shown to result in longer survival times in patients with HER-2-positive MBC compared with chemotherapy alone [4]. This survival benefit supported its testing in the adjuvant setting. However, the cardiac toxicity observed with the combination of conventional doxorubicin and trastuzumab [4] has raised concerns about its safety if administered to patients with potentially curable early-stage disease. Ongoing adjuvant studies are exploring alternative administration sequences and regimens to minimize this risk. Some of these studies are briefly discussed in the following sections, and study schemas are outlined in Table 1.

The NSABP B-31 Trial
The National Surgical Adjuvant Breast and Bowel Project (NSABP) is conducting a randomized trial (B-31) evaluating the safety and efficacy of combining trastuzumab with chemotherapy in 2,700 patients with node-positive breast cancers that overexpress the HER-2 protein. The primary objective of the study is to determine whether trastuzumab can provide a significant improvement when added to standard adjuvant therapy with surgery, chemotherapy, and radiation. An interim cardiac safety analysis will occur after the first 1,000 patients are enrolled [7].

The NCCTG 9831 Trial
Similar to the NSABP B-31 trial, the North Central Cancer Treatment Group (NCCTG) 9831 intergroup randomized trial is evaluating whether the addition of trastuzumab to chemotherapy adds benefit to patients with node-positive disease in the adjuvant setting. In the trial protocol, trastuzumab therapy begins immediately following (with weekly paclitaxel) or 3 months after (following 12 weekly doses of paclitaxel) the completion of four cycles of conventional doxorubicin and cyclophosphamide (AC) and these are compared with a control arm without trastuzumab. The projected accrual to these three arms is 3,000 patients with node-positive disease. In January 2002, patient enrollment to the arm combining paclitaxel with trastuzumab immediately after AC was temporarily suspended following an interim safety analysis due to concerns of an apparently greater risk of congestive heart failure. This was not subsequently confirmed, and that study arm has since been reopened to patient enrollment.

The ECOG 2198 Trial
The Eastern Cooperative Oncology Group (ECOG) tried a different approach to sequential therapy with a small feasibility study in which all patients received initial adjuvant therapy with paclitaxel and trastuzumab preceding four cycles of AC in patients with node-positive, HER-2-positive disease. The accrual target was 220 patients and, in one of the two arms, trastuzumab was restarted after AC and given for a total of 52 weeks. This study was not powered for efficacy comparisons.

The BCIRG 006 Trial
The Breast Cancer International Research Group (BCIRG) 006 trial has a design similar to those previously described, but with an additional nonanthracycline investigational arm. Based on both preclinical [8] and clinical [9] data suggesting a potential additive or synergistic effect with the combination of a platinum salt and trastuzumab, the third arm combines trastuzumab with a docetaxel and platinum salt regimen piloted in patients with MBC [10]. The projected accrual is 3,150 patients with node-positive or high-risk node-negative operable breast cancer.

The HERA Trial
The Breast International Group (BIG) is conducting the Herceptin^® Adjuvant (HERA) trial, which was designed to study the effects of 1- or 2-year therapy with trastuzumab following standard adjuvant chemotherapy in patients with HER-2-positive breast cancer. Several standard chemotherapy regimens are permitted, and the projected accrual is 3,192 participants. This study allows a 3-weekly dosing schedule of trastuzumab.

Combination Therapy with Trastuzumab and Liposomal Anthracyclines
The adjuvant trials described above explore the use of trastuzumab either sequentially with conventional doxorubicin or combined with a nonanthracycline-based regimen. Another potential strategy that might allow for exploring the observed clinical activity of anthracyclines and trastuzumab while potentially minimizing cardiac toxicity is a combination of trastuzumab with a liposomal anthracycline formulation. These formulations were developed with the intent of increasing the therapeutic index of conventional anthracyclines, and several studies are now examining their use in combination with trastuzumab in patients with advanced breast cancer.

Liposomal Doxorubicin (D-99)
A phase I/II study was conducted to determine the cardiac safety of liposomal doxorubicin (D-99, Myocet^TM; Elan Pharmaceuticals; Princeton, NJ; http://www.elan.com) in combination with trastuzumab in patients (n = 37) with locally advanced, inflammatory, or metastatic breast cancer (Table 2) [11]. Patients received liposomal doxorubicin, 60 mg/m², every 3 weeks and trastuzumab, 4 mg/kg, then 2 mg/kg weekly. That study is discussed in detail elsewhere in this supplement [12]; however, the results are relevant to the current discussion. There were two reports of cardiac toxicity in the small number of patients enrolled, and the overall response rate was 59% (one complete response, 18 partial responses).

Pegylated Liposomal Doxorubicin
The better cardiac safety profile of pegylated liposomal doxorubicin (Doxil^®; Ortho Biotech Products, L.P.; Bridgewater, NJ; http://www.orthobiotech.com or Caelyx^®; Schering-Plough Corporation; Kenilworth, NJ; http://www.schering-plough.com) has been documented in several trials [14–18]. A phase III trial comparing pegylated liposomal doxorubicin with conventional doxorubicin in patients with MBC showed a significantly lower risk of cardiotoxicity (p < 0.001), with no apparent loss in antitumor activity [17].

Our group also conducted a phase I/II trial, discussed in detail elsewhere in this supplement [19], to determine the maximum tolerated dose of pegylated liposomal doxorubicin that could be used safely in combination with docetaxel, as well as the efficacy of the combination in patients with locally advanced and metastatic breast cancers [20]. Patients received doses of pegylated liposomal doxorubicin ranging from 30-45 mg/m² and docetaxel 60 or 75 mg/m² every 3-4 weeks. These doses were selected based on previous studies combining docetaxel with conventional doxorubicin; however, the dose of pegylated liposomal doxorubicin was reduced due to its altered pharmacokinetic profile compared with conventional doxorubicin. In an effort to develop a 21-day regimen similar to ongoing adjuvant trials, doses of pegylated liposomal doxorubicin, 30 mg/m², in combination with docetaxel, 60 mg/m², every 3 weeks without growth factor support, were recommended for subsequent studies. As no apparent cardiac toxicity was observed with this regimen, ECOG investigators decided to examine it in combination with trastuzumab in patients with MBC in an attempt to circumvent the excessive cardiac toxicity seen with trastuzumab and conventional doxorubicin.

The ECOG 3198 Trial
The ECOG 3198 trial is evaluating the safety and efficacy of pegylated liposomal doxorubicin and docetaxel with or without trastuzumab in patients with advanced breast cancer. The study schema is illustrated in Figure 1. Patients are stratified on the basis of HER-2 disease status (central review required if local HER-2 test is positive). Cardiac safety (and not response) is the primary end point of that trial, and patients with HER-2-negative disease treated with pegylated liposomal doxorubicin and docetaxel alone serve as the internal control group. This is a trial for first-line therapy, and no prior anthracycline exposure is permitted to minimize the risk of cardiac injury—safety measures that reduce the pool of patients potentially eligible for the trial.

View larger version (28K): [in this window] [in a new window]   Figure 1. Study schema for the ECOG protocol 3198 trial: a safety and efficacy study of pegylated liposomal doxorubicin and docetaxel with and without trastuzumab in patients with MBC. Abbreviations: D = pegylated liposomal doxorubicin; T = docetaxel; H = trastuzumab; SD = stable disease; CR = complete response; PR = partial response; LVEF = left ventricular ejection fraction [21].

	NEW DIRECTIONS IN BREAST CANCER RESEARCH

Top Learning Objectives Abstract Introduction Combination Therapy with... New Directions in Breast... Conclusions References

 
Trials are being designed to identify potential intermediate markers and their relationships to conventional survival end points. Traditionally, studies have examined primary survival end points such as overall survival and disease-free survival, which require large sample sizes and years of long-term follow-up. There is much interest in identifying surrogate markers of response and survival potentially derived from a combination of biopsy and imaging studies for use in adjuvant trials. Protocol NSABP B-18 identified pathologic complete response as a potential early predictive marker of survival in patients treated with preoperative systemic therapy [22]. If these data are confirmed in ongoing studies, new concepts and/or targeted agents may be potentially tested in trials with much smaller patient populations (i.e., 100-200 patients). Promising strategies and compounds would then be taken to larger efficacy trials with survival end points. The identification of predictive markers of response may also allow for a better selection of patients who are likely to respond to an investigational therapy, an important step in the evaluation of new therapeutic interventions.

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Combination Therapy with... New Directions in Breast... Conclusions References

 
We have entered an important phase of breast cancer research and treatment. Many novel agents and combination regimens are currently being considered, including the potential combination of growth factor pathway modulators and chemotherapeutic agents. An important example is the monoclonal antibody trastuzumab. Although trastuzumab has demonstrated cardiotoxicity when combined with conventional doxorubicin in patients with MBC, new treatment regimens currently under investigation suggest the potential for cardiac safety with trastuzumab given in combination with liposomal anthracyclines. Ultimately, novel therapies are likely to offer greater therapeutic impacts in patients with early-stage disease. In addition, concerns about the long-term safety of regimens used in the adjuvant setting mandate a careful evaluation of these new promising targeted therapies. Due to their better cardiac safety profiles, liposomal anthracyclines may offer a viable therapeutic option in the adjuvant setting or in patients with a history of cardiac disease. Several clinical trials are currently under way examining the use of trastuzumab combined with various chemotherapy regimens in the adjuvant setting. Researchers are also discussing unique trial design concepts, such as preoperative chemotherapy, to study novel therapeutic approaches in a more effective and rapid fashion.

	ACKNOWLEDGMENT

Top Learning Objectives Abstract Introduction Combination Therapy with... New Directions in Breast... Conclusions References

 
The author acknowledges the editorial assistance of Lisa A. Shannon, Pharm.D., in the preparation of this manuscript.

	FOOTNOTES

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This material is protected by U.S. Copyright law. Unauthorized reproduction is prohibited. For reprints contact: Reprints{at}AlphamedPress.com

	REFERENCES

Top Learning Objectives Abstract Introduction Combination Therapy with... New Directions in Breast... Conclusions References

 

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