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.[1] With the proper use of taxanes and the development of targeted agents such as trastuzumab(Drug information on 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.[2] 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.[3]

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.[4] 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(Drug information on paclitaxel) over the standard 3-weekly schedule is a prime example. To date the therapeutic efficacy of docetaxel(Drug information on docetaxel) (Taxotere) has not been enhanced by more frequent schedules of administrations.[13]

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[14] 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.[15] 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.