Update on the Management of Advanced Breast Cancer

Fornier et al present an excellent summary of current treatment options and strategies for patients with metastatic breast cancer. This review summarizes currently available data (through the May 1998 American Society of Clinical Oncology [ASCO] meeting) regarding several key issues in the management of this disease. The relative merits of combination chemotherapy vs single-agent therapy are discussed; taxanes are reviewed in detail, with a focus on the efficacy and toxicities of different doses and frequencies of treatment with paclitaxel (Taxol) and docetaxel (Taxotere); the impact of newly approved therapies capecitabine (Xeloda) and trastuzumab (Herceptin) is summarized, along with the still investigational role of high-dose chemotherapy and stem-cell rescue; and information about hormonal strategies, including new agents, is presented.

We are experiencing a paradigm shift in our thinking about metastatic breast cancer as a chronic disease. The goals for treating patients with metastatic disease are to maximize the duration and quality of our patients’ lives by controlling the disease, maintaining performance status, and minimizing toxicity and inconvenience.

In the past, for most patients with metastatic breast cancer, particularly those with hormone-unresponsive disease, survival was brief and quality of life was impaired due to morbidity from the disease and the side effects of therapy. Prior to the introduction of the taxanes, the median survival duration after second- or third-line chemotherapy in patients who had received anthracyclines was less than 6 months.[1] The median survival times obtained with paclitaxel and docetaxel in anthracycline-resistant metastatic breast cancer are 9.5 months[2] and 10 months,[3] respectively.

Capecitabine

Our studies with capecitabine highlight the ability of an active new agent to significantly influence the survival of patients with refractory metastatic breast cancer. Patients with metastatic breast cancer whose disease had progressed despite therapy with paclitaxel showed a surprisingly long median survival of 12.8 months with capecitabine. In this study, 91% of the patients had previously been treated with an anthracycline, and all of the responding patients had received prior anthracycline therapy.[4] Among the patients who responded to capecitabine (20%), median survival had not been reached at the time of the clinical cut-off, and among those with stable disease, median survival was 391 days.[4]

We studied an additional 75 patients with metastatic breast cancer whose disease had progressed despite therapy with either paclitaxel or docetaxel. Among these patients, 24% responded to capecitabine given at a dosage of 2,500 mg/m2/d orally, divided twice daily, taken for 2 weeks with a 1-week rest, in 3-week cycles.[5]

Trastuzumab

The studies with trastuzumab demonstrate the impact of a novel approach using a humanized monoclonal antibody against HER-2/neu, an oncogene involved in growth stimulation.[6,7] For the first time, we now have an effective therapy for metastatic breast cancer that is neither chemotherapy nor hormonal therapy. Trastuzumab is well tolerated, and improves response rates and survival among a group of patients with extremely short disease-free and overall survival.[6]

Quality-of-Life Issues

An important principle in the treatment of patients with metastatic breast cancer is to evaluate and measure the effect of any treatment on the quality of patients' lives. Since we cannot currently cure metastatic breast cancer, our focus has to be on duration of survival and quality of life.

Our study of capecitabine measured the impact of treatment on clinical benefit response, as assessed by pain intensity, analgesic consumption, and Karnofsky performance status. Overall clinical benefit response was positive in 20% of patients.[4]

For the patients in this trial, the added benefit of a lack of alopecia combined with the convenience of a home-based oral therapy had an important impact on quality of life. A goal of future research and new drug development for metastatic breast cancer patients should be to focus on these important quality-of-life issues.

Role of Pamidronate

A key area not covered in this review by Fornier et al concerns the role of pamidronate (Aredia), which has proven to be beneficial for women with metastatic breast cancer. Hortobagyi et al showed that monthly infusions of pamidronate protect women with osteolytic bone metastases against fractures.[8] In this study, pamidronate therapy significantly reduced the requirement for radiation therapy and also prevented the pain of fracture and the necessity for orthopedic surgery.[8]

In addition, Conte et al showed that pamidronate slowed the progression of bone metastases in patients who were also receiving chemotherapy.[9] This therapy provides substantial benefits for our patients in terms of quality of life.

Current Status, Future Outlook

This is an exciting time for research in metastatic breast cancer. Never before have we had so many new agents with significant activity in this disease. With the weekly dosing schedules of paclitaxel and docetaxel, we are learning new ways of administering previously approved therapies. Weekly treatment nearly eliminates myelotoxicity, which is common when these agents are given at higher doses every 3 weeks, and provides equal or superior efficacy.

New agents with activity in metastatic breast cancer have been rapidly approved for use by the FDA, and these agents have had an impact on both patients’ survival and quality of life. We have new, well-tolerated hormonal therapies that have extended survival in patients with hormonally responsive disease. We also have drugs that are effective without causing hair loss.

The future is likely to bring the development of new agents that will attack breast cancer cells by blocking growth, inducing apoptosis, and inhibiting angiogenesis. These agents may be tumor-specific, and perhaps may be free of the kinds of side effects that have plagued our patients in the past. This review by Fornier et al nicely summarizes where we are now in the treatment of metastatic breast cancer and alludes to where we hopefully will be heading over the next few years .

References:

1. Henderson IC: Principles in the management of metastatic disease: Chemotherapy for metastatic disease, in Harris JR, Hellman S, Henderson IC, et al (eds): Breast Diseases, pp 604-665. Philadelphia, Lippincott, 1991.

2. Abrams JS, Vena DA, Baltz J, et al: Paclitaxel activity in heavily pretreated breast cancer: A National Cancer Institute Treatment Referral Center trial. J Clin Oncol 13:2056-2065, 1995.

3. Valero V, Holmes FA, Walters RS, et al: Phase II trial of docetaxel: A new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. J Clin Oncol 13:2886-2894, 1995.

4. Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17:485-493, 1999.

5. Blum JL, Buzdar AM, Dieras V, et al: A multicenter phase II trial of XelodaTM (capecitabine) in taxane-refractory metastatic breast cancer (abstract). Proc Am Soc Clin Oncol, 1999 (in press).

6. Cobleigh MA, Vogel CL, Tripathy D, et al: Efficacy and safety of Herceptin (humanized anti-HER2 antibody) as a single agent in 222 women with HER2 overexpression who relapsed following chemotherapy for metastatic breast cancer (abstract). Proc Am Soc Clin Oncol 17:97a, 1998.

7. Slamon D, Leyland-Jones B, Shak S, et al: Addition of Herceptin (humanized anti-HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer markedly increases anticancer activity: A randomized, multinational controlled phase III trial (abstract). Proc Am Soc Clin Oncol 17:98a, 1998.

8. Hortobagyi GN, Theriault RL, Porter L, et al: Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. N Engl J Med 335:1785-1791, 1996.

9. Conte PF, Latreille J, Mauriac L, et al: Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: Results from a multinational randomized controlled trial. J Clin Oncol 14:2552-2559, 1996.