New Strategies for Managing Metastatic Breast Cancer
New Strategies for Managing Metastatic Breast Cancer
Drs. Olin and Muss provide an excellent review of current state-of-the-art treatments and treatment strategies for patients with metastatic breast cancer. They explore a number of the existing questions in the treatment of metastatic breast cancer and emphasize the need for ongoing clinical trials.
Given the palliative nature of all currently available therapies, the authors recommend beginning with endocrine approaches for most patients with hormone receptor-positive metastatic breast cancer. They review the data that support this approach and describe the available endocrine options, including the selective estrogen receptor modulators (SERMs), pure antiestrogens, luteinizing hormonereleasing hormone (LHRH) agonists, and aromatase inhibitors.
For patients who are not candidates for or who become refractory to hormonal therapy, Drs. Olin and Muss recommend sequential single-agent chemotherapy. An important exception is the use of trastuzumab (Herceptin) plus chemotherapy in HER2-positive patients undergoing initial treatment for metastatic breast cancer.[Olin/Muss reference 68]
The authors cite the growing list of available chemotherapeutic agents for metastatic breast cancer, including the anthracyclines (particularly liposomally encapsulated doxorubicin [Doxil]), paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), gemcitabine (Gemzar), and capecitabine (Xeloda). They also mention several new combinations and discuss trastuzumab and several novel antiangiogenic agents. Several other promising combinations and novel therapies, such as vaccines, are worthy of comment as a supplement to this article.
As Drs. Olin and Muss discuss, several prior studies have shown no survival benefit afforded by combination chemotherapy, as compared with sequential single-agent therapy, in patients with metastatic breast cancer. However, several promising new combinations are currently undergoing evaluation.
For example, results of a phase II study of the combination of weekly trastuzumab and vinorelbine as second- or third-line therapy for women with metastatic breast cancer has recently been reported in abstract form. This combination produced an overall response rate of 71% in 34 evaluable patients, with little increase in toxicity for the doublet compared to single-agent vinorelbine. A confirmatory trial in the first-line setting is planned.
Another intriguing doublet is the combination of capecitabine and paclitaxel, which has shown synergy in preclinical models. A phase I study of capecitabine (days 1 through 14) and paclitaxel (day 1) administered every 3 weeks to women with previously treated, taxane-naïve metastatic breast cancer has been completed. Partial responses were seen in 5 of 10 evaluable patients. A phase I study of capecitabine and weekly paclitaxel is ongoing. The combination of capecitabine, paclitaxel, and trastuzumab is currently being evaluated as first-line therapy for metastatic breast cancer in a clinical trial at our center.
Combination therapy may have added toxicity. For example, the combination of doxorubicin and paclitaxel, one of the doublets mentioned in this review, has been associated with increased cardiotoxicity, which may be due to a 30% decrease in the clearance of doxorubicin when it is administered after paclitaxel. The taxane or its vehicle may cause nonlinear disposition of the anthracycline by competing for biliary excretion mechanisms.
More recent data suggest that sequencing paclitaxel after doxorubicin and limiting treatment to six or fewer cycles of the combination (total doxorubicin dose < 380 mg/m²) will result in an incidence of congestive heart failure no greater than that seen with other anthracycline-containing regimens. Similarly, efforts to define and minimize the cardiotoxicity of doxorubicin and trastuzumab are underway.
As new doublets combining cytotoxic agents or combining cytotoxics with biological or other novel therapies are explored, careful attention must be paid to potential and perhaps unanticipated toxicity, to the pharmacologic bases for any such interactions, and to the comparison of these new combinations with standard sequential single-agent therapy. These issues underscore the importance of clinical trials and the need to encourage patient enrollment in such trials.
In addition to the recombinant humanized monoclonal antibody trastuzumab and the antiangiogenesis agents discussed by Drs. Olin and Muss, breast cancer vaccines are another novel therapeutic strategy in active clinical development. This approach uses part of the tumor cell (peptide) as an immunogen to stimulate an immune response to treat breast cancer.
HER2 has emerged as a promising candidate for vaccine development because it is expressed at low levels in normal cells but is overexpressed in some breast cancers and is associated with a more aggressive phenotype. Furthermore, there is evidence of an endogenous immune response to HER2 in patients with HER2-overexpressing breast cancer.
Disis and colleagues recently reported the interim results of a phase I study of HER2 peptidebased vaccines in patients with advanced breast or ovarian cancer. In this trial, eight patients were immunized monthly with intradermal injections of HER2 peptides (derived from either the extracellular domain or the intracellular domain) mixed with granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine, Prokine]). All eight patients developed HER2 peptidespecific T-cell responses, and six developed HER2 proteinspecific responses. Except for one episode of transient urticaria, no toxicity was seen.
Other investigators have pursued vaccination therapies using peptide-pulsed dendritic cells, seeking to capitalize on the ability of these cells to stimulate CD8-positive cytotoxic T-lymphocyte responses (CTL). In a recent phase I trial, 10 patients with metastatic breast or ovarian cancer were treated with dendritic cells pulsed with human lymphocyte antigen A2 (HLA-A2)restricted HER2 or mucin core protein (MUC1) peptides. The subcutaneous injections were well tolerated. Half of the patients developed antigen-specific CTL. One patient with breast cancer demonstrated a complete response of subcutaneous lesions.
Another approach involves modifying the peptide (immunogen) in an attempt to increase major histocompatibility complex (MHC) binding. A recent trial in melanoma showed that modification of amino acids in the peptide made the peptide-based vaccine more effective. To test this concept, investigators at our institution are conducting a phase I trial in which patients with stable metastatic breast cancer are being randomized to treatment with dendritic cells pulsed with either an altered HER2 epitope or wild-type peptide.
Vaccines targeted against other antigens, such as carcinoembryonic antigen (CEA), p53, MUC-1, or tumor-associated sialated carbohydrate antigens, are also currently being evaluated in early clinical trials. A variety of other novel therapeutics with potential applications in breast cancer treatment are also in preclinical and phase I testing, including agents that target signal transduction (eg, receptor tyrosine kinase inhibitors, farnesyl transferase inhibitors, proteinkinase-C inhibitors) or cell-cycle modulation (eg, UCN-01 [7-hydroxystaurosporine], flavopiridol). Further development and evaluation of these targeted therapies are eagerly awaited.
Novel Trial Design
The most effective setting in which to evaluate novel compounds may be during a window period of stable disease following initial response to one of the available cytotoxic regimens. This strategy allows for testing of new agents in patients before they have refractory disease, without compromising time to palliation, as all patients receive standard first-line therapy.
The Cancer and Leukemia Group B (CALGB) has launched an evaluation of novel therapeutics for metastatic breast cancer using an innovative, randomized, phase II trial design. In this trial design, patients who achieve palliation after four to six cycles of standard chemotherapy are eligible for randomization to observation for 3 to 6 months or treatment with a novel therapeutic agent. The end point is the percentage of patients who are progression free at 6 months. Patients randomized to observation may receive the novel agent at the time of progression. Measurable disease is not required. This increases the number of eligible patients (eg, to include those with bone-only disease or pleural effusion) and permits greater generalizability of results.
Despite the wide variety of agents currently available to treat metastatic breast cancer, long-term survival rates remain disappointing. Both new therapies and new study designs are needed, and enrollment in clinical trials of new compounds should be encouraged.
1. Burstein HJ, Kuter I, Richardson PG, et al: Herceptin (H) and vinorelbine (V) as second-line therapy for HER2-positive (HER2+) MBC (metastatic breast cancer): A phase II study. Breast Cancer Res Treat 57(1):29, 1999.
2. Khoury P, Villalona-Calera M, Blum J, et al: Phase I study of capecitabine in combination with paclitaxel in patients with previously treated metastatic breast cancer (abstract). Proc Am Soc Clin Oncol 17:206a, 1998.
3. Elza-Brown K, Dees EC, Wolff AC, et al: A phase I study of capecitabine and weekly paclitaxel in advanced solid tumors (abstract). Proc Am Soc Clin Oncol, 2000 (in press).
4. Holmes FA, Madden T, Newman RA, et al: Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer. J Clin Oncol 14:2713-2721, 1996.
5. Gianni L, Vigano L, Locatelli A, et al: Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer. J Clin Oncol 15:1906-1915, 1997.
6. Gianni L, Dombernowsky P, Sledge G, et al: Cardiac function following combination therapy with Taxolâ (T) and doxorubicin (A) for advanced breast cancer (ABC) (abstract). Proc Am Soc Clin Oncol 17:115a, 1998.
7. Borden EC, Esserman L, Linder DJ, et al: Biological therapies for breast carcinoma: Concepts for improvement in survival. Semin Oncol 26(suppl 12):28-40, 1999.
8. Disis ML, Grabstein KH, Sleath PR, et al: Generation of immunity to the HER-2/neu oncogenic protein in patients with breast and ovarian cancer using a peptide-based vaccine. Clin Cancer Res 5:1289-1297, 1999.
9. Brossart P, Stuhler G, Reichardt VL, et al: Vaccination therapy of patients with metastatic breast and ovarian carcinoma using peptide pulsed dendritic cells (abstract). Blood 94(10):216a, 1999.
10. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al: Immunologic and therapeutic evaluation of synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4(3):321-327, 1998.