Over the past 20 years we have witnessed the emergence of a new generation of aromatase inhibitors as valuable antiestrogens in the management of both advanced and early-stage breast cancer. In addition, the list of cytotoxic chemotherapeutic agents useful in the control of breast cancer has grown considerably. The emergence of anthracyclines was a major chemotherapeutic step forward in the 1980s, and the taxanes have clearly been the agents with the greatest impact on breast cancer treatment over the past decade. The end of the past 2 decades has been characterized by a greater understanding of the molecular biology of breast cancer, rational drug design, and the development of agents that disrupt specific cellular targets and pathways. The development of better prognostic and predictive assays that employ a panel of genes involved in the malignant and metastatic phenotype promises to allow clinicians to better select patients who could forgo adjuvant chemotherapy. Finally, adjunctive and supportive therapy of breast cancer has evolved substantially over the past 20 years. This review will highlight some of the landmark accomplishments during this time, and offer a glimpse at where we might be 20 years from now.
In this issue of ONCOLOGY, Dr. Seidman gives a concise review of where we were and where we have reached in our endeavors to improve systemic treatment of breast cancer both in the adjuvant and metastatic setting, with the ultimate goal of improving survival. He takes us on a journey of decades of research, highlights key advances that have made a huge impact on the breast cancer community, and emphasizes the importance of accurately and ethically presenting data. He does not, however, address the health cost implications and the price of toxicity that comes with advances in research and development.
Metastatic Breast Cancer
Systemic treatment of metastatic breast cancer has not only served to palliate symptoms, but emerging data also suggest that it may have an impact on improving the overall survival in this incurable setting. With the proper use of taxanes and the development of targeted agents such as trastuzumab (Herceptin) we are seeing better response rates and time to disease progression. However, several important unanswered questions remain. Is sequential use of single agents as effective as combination therapy? How long do we continue to use trastuzumab once a patient has developed resistance to a particular chemotherapy/trastuzumab combination? Answers to both would not only have a huge impact on cost issues but would also serve to better patient quality of life by reducing unnecessary toxicities.
Not all patients with metastatic breast cancer do badly. Several groups have been identified that appear to do well with systemic treatment. In general most patients with metastatic breast cancer attain an objective response to systemic treatment but will eventually develop resistance to currently used therapeutic agents. There is, however, a subgroup of patients that upon attaining a complete response are able to maintain prolonged disease-free survival. In addition there are groups of patients with stage IV breast cancer that present with isolated metastatic lesions that when treated with a combined-modality approach involving surgery, chemotherapy, radiation therapy, and hormonal manipulation, remain disease-free for prolonged periods of time.
Adjuvant Therapy: Which Agent and How to Administer It?
A meta-analysis published by the Early Breast Cancer Trialists' Collaborative Group (EBCTG) clearly demonstrates that polychemotherapy is superior to single-agent therapy in the adjuvant setting. In addition, the recent 15-year update shows that 6 months of adjuvant anthracycline-based combination therapy reduces the annual breast cancer death rate by approximately 38% for women younger than 50 years and by 20% for those aged 50 to 69 years. A number of trials have also evaluated the role of taxanes[5-8] and biologic agents such as trastuzumab[9,10] (in patients with HER2/neupositive disease) in the adjuvant setting, demonstrating that its addition to combination chemotherapy improves disease-free and overall survival significantly.
Although the active agents have been identified, certain questions remain as to the most appropriate dose and schedule of administration. We know that escalating doses of anthracyclines and alkylating agents beyond standard doses does not further enhance the efficacy of combination therapy.[11,12] We also know that continuing adjuvant chemotherapy beyond the standard number of cycles is not associated with additional benefit. In addition we have in recent times been able to better define the best method of taxane administration; the development of the more efficacious weekly paclitaxel over the standard 3-weekly schedule is a prime example. To date the therapeutic efficacy of docetaxel (Taxotere) has not been enhanced by more frequent schedules of administrations.
Although there is a debate over the therapeutic superiority between the two commonly used taxanes, to date paclitaxel has not been shown to be superior to docetaxel. We have yet to determine the equivalence of administering sequential vs up-front combination (although associated with increased morbidity) of various therapeutic agents. Controversy also exists within the oncology community regarding the superior efficacy of dose-dense chemotherapy over standard dose regimens, a concept not fully accepted by all.
Omitting anthracyclines from combination regimens has been another focus of research interest in recent times. Preclinical studies demonstrated the synergism of a paclitaxel/carboplatin/trastuzumab regimen which has shown mixed results in phase III trials of metastatic breast cancer. The Breast Cancer International Research Group trial BCIRG 006 is currently studying the efficacy equivalence of a docetaxel/carboplatin/trastuzumab adjuvant regimen to that of an anthracycline combination. Although results are immature at this time preliminary safety data give us the option to consider the combination in patients unable to receive anthracyclines. The role of assessing tumor topoisomerase II amplification in an attempt to select patients that will most benefit from anthracycline therapy will require prospective validation before defining its role in routine clinical practice.
Despite these burning questions we cannot deny the progress that we have made, not only in patients with early-stage breast cancer but also in those who suffer from locally advanced disease who can now achieve long-term disease control. In addition, a significant number of patients with inflammatory carcinoma of the breast considered to have a truly grim prognosis can expect to remain alive without disease when treated with the optimal combined-modality approach-a phenomenon almost unheard of a few decades ago.
With the administration of more complex combination regimens and the development of a wide variety of biologic agents that target specific cellular pathways comes a whole set of side effects that we must recognize, understand, and appropriately treat. Growth factors and erythropoetic agents are often used routinely to support chemotherapy-associated neutropenia and anemia, respectively. Provocative data from at least two prospective trials have demonstrated the adverse effect of erythropoietin on the survival of patients with malignancy.[16,17] As such one must be cautious in using such agents, particularly in the adjuvant setting where the primary aim is cure.
The last year has shown very promising data with the use of anti-vascular endothelial growth factor agents such as bevacizumab (Avastin) in the treatment of metastatic breast cancer. Although this is an exceptionally promising agent, there are very real concerns regarding its toxicities in terms of hypertension, proteinuria, and bleeding effects. Patients need to be selected carefully and one must exert caution and refer to the evidence when combining bevacizumab with other chemotherapeutic agents. Ongoing trials (Ribbon 1 and 2) will give us the data that we need in assessing the various combinations with bevacizumab.
The Era of Personalized Medicine
With a greater understanding of tumor biology and the discovery of pharmacoepidemiology/pharmacogenetics that describes the heterogeneity underlying varying individual responses and toxicity to chemotherapeutic agents, we are gradually moving into an era where will be able to individualize treatment programs geared to attain maximum efficacy with minimal toxicity.
The discovery of the association of the activity of tamoxifen to CYP2D6 activity may better select patients with estrogen receptor-positive disease. The development of the 21-gene reverse transcriptase-polymerase chain reaction assay (Oncotype DX) in North America and a similar 70-gene set in Europe that can stratify patients with node-negative estrogen receptor-positive disease into low- and high-risk groups by predicting for distant metastasis may obviate the need for chemotherapy in low-risk groups, thereby reducing associated morbidity. However, the data attained so far have been solely retrospective in nature, one must wait for currently ongoing validating prospective studies before applying it to routine clinical practice.
The treatment of breast cancer has certainly evolved over the years, a phenomenon exemplified by the 2.3% annual reduction in death rate and the improved 5-year survival rates of 98%, 81%, and 26% in patients with node-negative, node-positive, and metastatic disease, respectively. New biologic agents are continuously being developed, and incorporation of some of these effective targeted agents into the treatment may further favorably modify the natural history of this disease.
-Shaheenah Dawood, MBBCH, MRCP (UK)
-Aman U. Buzdar, MD
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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