Breast Cancer - First-Line Treatment Options for Patients with HER-2–Negative Metastatic Article Abstract

The Impact of Modern Adjuvant Chemotherapy.
The management of early breast cancer has evolved rapidly in recent years. The paradox is that for those patients who subsequently develop metastatic breast cancer (MBC), treatment options are becoming increasingly complicated and the choice of first-line treatment depends on a complex interaction of tumor, patient, and physician variables.
The main options for MBC are hormonal therapy, chemotherapy, or chemotherapy in combination with trastuzumab. More recently, the addition of bevacizumab to chemotherapy has become an option. Unfortunately, despite the range of exciting therapies available, the outlook for patients with distant metastases remains quite dismal, with a 5-year survival rate of only 26%. One of the most important factors determining the choice of first-line chemotherapy is the type of treatment given in the adjuvant setting.
In the U.S., the standard of care adjuvant therapy for high-risk disease is doxorubicin plus cyclophosphamide (AC) followed by or in combination with a taxane, while in Europe the most commonly used regimens are 5-fluorouracil, cyclophosphamide, and either doxorubicin or epirubicin (FAC/FEC) with or without sequential docetaxel or docetaxel, doxorubicin, and cyclophosphamide (TAC). Inclusion of an anthracycline is considered standard of care, based on superior efficacy of sequential epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) versus CMF alone.
In patients treated with anthracyclines and/or taxanes in the adjuvant setting, first-line treatment options include re-exposure to the same agent or introduction of a different treatment. Studies evaluating retreatment with anthracyclines and taxanes after exposure in the adjuvant setting have yielded conflicting results. In the past 5 years, data for other agents evaluated in the growing population of anthracycline- and/or taxane-pretreated patients have become available.
About questions:
- WHAT IS THE OPTIMAL FIRST-LINE OPTION FOR PATIENTS TREATED WITH ADJUVANT ANTHRACYCLINES?
- WHAT IS THE OPTIMAL FIRST-LINE OPTION FOR PATIENTS TREATED WITH ADJUVANT TAXANES AND ANTHRACYCLINES?
- WHAT IS THE OPTIMAL FIRST-LINE OPTION FOR ANTHRACYCLINE- AND TAXANE-NAÏVE PATIENTS?
THE CONCLUSION: Rapid developments in adjuvant chemotherapy for breast cancer, and in particular the earlier use of anthracyclines and taxanes, are likely to drive changes in the first-line treatment of MBC.
The rapid progress in newer adjuvant regimens with lower doses of both anthracyclines and taxanes will mean that the choices for patients with MBC will continue to expand. Treatment options will range from re-exposure to either anthracyclines or taxanes after adjuvant administration to the use of newer chemotherapeutic and/or biologic agents.
Results of small studies in anthracycline-pretreated breast cancer suggest that retreatment may be an option in some patients, providing the cumulative anthracycline dose does not put patients at a higher risk for cardiotoxicity. However, strong data support the use of several other regimens in this setting. Taxanes are a well-established and highly effective treatment option in anthracycline-pretreated patients and data indicate that survival can be further improved by combining taxanes with capecitabine. The response rate is improved with the addition of gemcitabine to taxane therapy, although survival data are not conclusive.The addition of bevacizumab to chemotherapy appears to further improve outcomes, and numerous trials are evaluating chemotherapy plus bevacizumab as first-line therapy.
It is difficult to comment on the impact of the interval between adjuvant anthracycline treatment and re-exposure in the metastatic setting because some of the trials excluded patients with an anthracycline-free interval <12 months. In the study that included patients regardless of anthracycline-freeinterval, retrospective analysis suggested no influence of this factor on the efficacy of PLD. Without data from randomized trials, the benefit of re-exposure to anthracyclines versus other treatment options cannot be determined. Because the single study designed to prospectively evaluate anthracycline retreatment had to be terminated because of recruitment difficulties, it seems unlikely that we will have a definitive answer to this issue. In patients who have received neither anthracyclines nor taxanes in the adjuvant setting, anthracyclines are frequently used. However, data are emerging to suggest that non–anthracycline-based regimens, such as capecitabine plus a taxane, may provide valid, equally effective and well-tolerated alternatives to anthracycline–taxane combinations. At the opposite end of the spectrum, the only approved agent for patients with anthracycline- and taxane-pretreated disease is capecitabine, and therefore this can be considered a valid first-line treatment option in patients who have received adjuvant anthracyclines and taxanes.
By extrapolating data from the metastatic setting, it is suggest that the options may be appropriate. Above all, treatment should be tailored to each individual patient based not only on prior adjuvant chemotherapy, but also on tumor characteristics, robust efficacy and safety data, important considerations such as convenience and potential impact on quality of life. Of these, tolerability will probably become one of the most important factors in the future, with increasing emphasis on the quality as well as the duration of survival after development of metastatic disease.
Oncologists will have to accept that there will be many effective treatment options for patients in this setting and that none is likely to become the gold standard first-line treatment for MBC. Lastly, as the use of newer agents moves into the (neo)adjuvant setting and patients are exposed to a greater range of treatments in the early breast cancer setting, first-line treatment practice for MBC will continue to evolve.
Clinical trials in the first-line metastatic setting will become increasingly difficult to interpret because of the wider range of previous treatments and differences in patient populations.