Options for patients with estrogen receptor/progesterone receptor/HER2–negative (triple-negative) metastatic breast cancer are limited. These “basal-like” tumors are seen more commonly in BRCA1-mutation carriers and appear sensitive to platinum-based therapies. Recent preliminary data from the Translational Breast Cancer Research Consortium (TBCRC) trial 001 showed no meaningful activity when using the anti-EGFR monoclonal antibody cetuximab(Drug information on cetuximab) (Erbitux) as a single agent in triple-negative disease, and data on the combination with carboplatin(Drug information on carboplatin) will be presented at the 2008 annual meeting of the American Society of Clinical Oncology (ASCO).
Others found response rates of 49% among the subset of triple-negative tumors treated with weekly irinotecan(Drug information on irinotecan) (Camptosar), carboplatin, and cetuximab in a phase II trial, but this regimen was associated with higher rates of thrombocytopenia, diarrhea, and grade 3/4 neutropenia. Inhibitors of peroxisome proliferator-activated receptor gamma are now being tested in this setting.
The use of multitargeted TKIs of VEGF in metastatic breast cancer is an area of ongoing growth. Agents including axitinib, sunitinib (Sutent), sorafenib(Drug information on sorafenib) (Nexavar), and pazopanib are being examined in this setting. TKIs of EGFR such as erlotinib (Tarceva) and gefitinib(Drug information on gefitinib) (Iressa) have negligible activity as single agents in metastatic breast cancer and are being tested in combination with other targeted drugs. Sunitinib has activity as a single agent in heavily pretreated patients with metastatic breast cancer and is now being tested in combination regimens with taxanes and other drugs.
Enrolling Metastatic Breast Cancer Patients in Investigational Studies as First-Line Therapy
The topic of enrolling metastatic breast cancer patients in clinical trials before using standard chemotherapy is an emotive one. However, academic endeavours must be encouraged if progress is to continue and new agents developed.
A prospective, randomized phase III trial to evaluate the safety and efficacy of using a phase II agent before initiating therapy with standard combination chemotherapy in metastatic breast cancer patients was performed by the Cancer and Leukemia Group B during the 1990s. Women with measurable metastatic breast cancer, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either immediate chemotherapy with CAF, which was standard of care at that time, or up to four cycles of one of five sequential regimens of single-agent drugs followed by CAF.
The toxicity of each single agent followed by CAF was comparable to that of CAF alone. The cumulative response rates and overall survival for the single agent followed by CAF were not statistically different from those of CAF alone, but in the multivariate analysis, patients with visceral disease had a trend toward lower response rates on the arm where a phase II agent was followed by CAF at progression. Therefore, upfront use of investigational agents in patients with metastatic breast cancer followed by standard chemotherapy options at the time of progression is a valid and safe option to be discussed with patients.
Transitioning to Palliative Care
A good performance status and wide choice of therapeutic agents, even in the face of progressive disease, will allow most patients with breast cancer to pursue several lines of treatment. In the absence of progressive symptoms or overt disease progression, patients should be restaged radiologically after 3 or 4 months of therapy to assess response. Patients with a more indolent process are restaged less frequently.
The decision to stop active disease-directed treatments is rarely simple. Quality of life, adverse effects of treatment, performance status, and end-of-life wishes must be considered and discussed with patients, their caregivers, and their health-care providers. The early introduction of palliative care while patients are still on active chemotherapy may help the transition to palliative care alone in later disease stages.
Systemic anticancer therapies are only one part of the multilayered management of patients with metastatic breast cancer. These patients should have a wide range of multidisciplinary support including representatives of other medical specialties as well as nutrition, psychology, nursing, and palliative services.
Bone is the most common site of breast cancer recurrence. Bisphosphonates have been shown to reduce the incidence of skeletal-related events and may be a useful adjunct to conventional measures for control of bone pain. An effect on skeletal morbidity outcomes is not seen before 6 months of therapy, and a reduction in the need for orthopedic surgery becomes significant only after 12 months. It is reasonable, therefore, to offer bisphosphonates to all breast cancer patients with bone metastases, with the exception of patients who have an expected survival of less than 6 months and well-controlled bone pain.
No evidence from clinical trials addresses the optimal duration of bisphosphonate therapy. Safety data beyond 2 years is sparse, and complications such as osteonecrosis of the jaw are increasingly being reported after longer durations of treatment with more potent IV bisphosphonates. ASCO guidelines suggest that treatment be continued until evidence of a substantial decline in the patient’s performance status appears.
The use of erythropoiesis-stimulating agents (ESAs) for chemotherapy-induced anemia is an area of ongoing study. While these agents can be considered in patients with chemotherapy-induced anemia, data are not sufficient to exclude the possibility of shortened survival and tumor progression in various tumor settings including breast cancer. Potential restrictions on the use of ESAs were being considered by the FDA in early 2008.
The treatment of metastatic breast cancer remains challenging. New biologic and targeted agents are adding to the wide choices of standard chemotherapies already available. Increasingly, these new drugs will be considered for testing in patients with early-stage disease once safety data become available in metastatic breast cancer studies. Duration of therapy for the new, more expensive biologic drugs is becoming a critical issue for individuals and society, as recently exemplified by the monoclonal antibody bevacizumab(Drug information on bevacizumab).
It is also becoming increasingly clear that metastatic breast cancer is a heterogeneous disease, and there is no single optimal strategy for all patients. Many patients have an indolent course of progression, and those with limited stage IV disease are being considered for surgery and multimodality therapy with the goal of further improving their survival. Ultimately, physicians should be guided to rational and flexible treatment regimens for their patients by current best clinical guidelines and ongoing research.
Financial Disclosure: Dr. Wolff receives research funding from Roche. The authors have no other significant financial interest or relationship with the manufacturers of any products or providers of any service mentioned in this article.
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