Advanced Breast Cancer: A Widening Spectrum of Options

October 1, 2007

Disease-free and overall survival have improved significantly for women diagnosed with early-stage breast cancer. At the same time, systemic therapy has only slightly enhanced long-term outcomes in advanced breast cancer, a disease that remains largely incurable. Several single-agent and combination chemotherapy approaches are available to women with hormone-insensitive advanced disease that may improve overall survival and progression-free survival, minimize symptoms and complications related to the disease, and improve overall quality of life. In addition, new cytotoxic and targeted agents have been recently introduced into practice and have improved both survival outcomes and quality of life. In this review, we will provide an update on commonly used chemotherapy-based regimens for the treatment of metastatic breast cancer, with a focus on tailoring therapy to different subtypes of the disease.

In this article, Drs. Briest and Stearns have provided a comprehensive review of the chemotherapeutic options for the treatment of advanced breast cancer. They also have provided a brief but cogent overview of nonchemotherapeutic approaches such as endocrine and targeted/biologic therapies, as well issues relevant to the management of advanced disease such as goals of therapy and factors that help determine the most appropriate treatment. All these topics are germane to clinical practice. The review is well organized and the summary tables of regimens commonly used in metastatic breast cancer will likely be a handy and useful resource for the practicing clinician.

Over the past 2 decades, there has been an expansion of chemotherapeutic options for the treatment of advanced breast cancer. Many of these therapies have significantly impacted our ability to palliate symptoms, control disease and even, in some cases, prolong survival. Whether population-based or single-institution studies[1,2] improvement in outcomes of patients diagnosed with metastatic breast cancer in the recent versus remote past can be attributed in part to these therapeutic advances. There remain, however, many unanswered questions regarding how to best use these chemotherapies.

Unaddressed Questions

Somewhat lacking in the review was an in-depth exploration of these questions: When considering single-agent vs combination chemotherapy, which approach is better, and why? When chemotherapies are used singly, is there an optimal way to sequence them? When combining therapies, what is the most rational way to combine them? Ultimately, can we further improve patient outcomes by simply knowing how to use currently available therapies optimally?

For many patients, the "demise of chemotherapy" is a much anticipated phenomenon, but it is unlikely that we can completely do away with chemotherapy any time soon. Many of the currently available biologic/targeted therapies work best in combination with chemotherapy. Take, for instance, trastuzumab (Herceptin) for patients with HER2-positive breast tumors. As a single agent it produces modest response rates[3] but has impressive response rates in combination with chemotherapy[4]—a classic example of synergy. The recently reported TrAstuzumab in Dual HER2 ER-positive Metastatic breast cancer (TAnDEM) trial showed a doubling in progression-free survival and improvement in overall response rates and time to progression when trastuzumab was combined with the endocrine therapy anastrozole.[5] However, these numbers were somewhat disappointing, especially in light of the high numbers seen with trastuzumab plus chemotherapy.

Optimizing Chemotherapy

So, if chemotherapy is here to stay for the next several decades, how can it be optimally used? Clearly, one way is to use it in a more "targeted" fashion. That is, as we learn more about the various subtypes of breast cancer and how biology dictates prognosis and response to therapy,[6,7] practicing clinicians can better select which chemotherapies are most appropriate for specific biologic subtypes. Of course, this will require knowing what predicts for response or resistance to specific chemotherapies. This is currently an area of active research.

The authors did not elaborate on how we might further elucidate this information. At the very least, the authors' insight or candid view of what critical milestones must be achieved or what pitfalls to watch out for, in my opinion, would have added a very interesting dimension to this review.

Predicting Individual Outcomes

Several times in their article, the authors mention that metastatic breast cancer is largely incurable. While this is true, it is also important to note that patients with metastasis have a wide range of survival, with some patients living for many years. Each patient diagnosed with breast cancer, more often than not, wants to know whether she is potentially curable and, if not, how much time she's "got left." The reality is that we do quite well at estimating averages but not so well at predicting these numbers for any given individual. We need to bridge this disconnect, the question is how? Perhaps a good place to start predicting "how an individual might perform" is in a truly individualized arena, the patient's quality of life.

The fact is, few physicians are adept at systematically assessing quality of life. This is especially poignant when considering that improving quality of life is an important therapeutic goal and often determines choice of treatment in metastatic disease. The hope is that if we can get a better sense of how individual patients tolerate therapy, we might also get better at predicting the long-term outcome of any individual patient.

Novel Therapies

As a final point, the authors discuss novel therapies that are in development. Although a number of the agents are not yet "ready for prime time," they offer the hope for improved treatment of the patient with breast cancer. More importantly, these future therapies may hold the cure for some subsets of patients. On this optimistic note, Drs. Briest and Stearns conclude, and I share the sentiment.

—Melanie E. Royce, MD, PHD

Disclosures:

Dr. Royce is a member of the speakers bureau for Genentech.

References:

1. Chia SK, Speers CH, D'Yachkova Y, et al: The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer 110:973-979, 2007.

2. Giordano SH, Buzdar AU, Smith TL, et al: Is breast cancer survival improving? Cancer 100:44-52, 2004.

3. Vogel CL, Cobleigh MA, Tripathy D, et al: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719-726, 2002.

4. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001.

5. Mackey JR, Kaufman B, Clemens M, et al: Trastuzumab prolongs progression-free survival in hormone-dependent and HER2-positive metastatic breast cancer. Breast Cancer Res Treat 100:S5, 2006.

6. Perou CM, Sorlie T, Eisen MB, et al: Molecular portraits of human breast tumours. Nature 406:747-752, 2000.

7. Sorlie T, Wang Y, Xiao C, et al: Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: Gene expression analyses across three different platforms. BMC Genomics 7:1-15, 2006.