Reflections on the development of resistance during therapy for advanced breast cancer. Implications of high levels of activity of docetaxel in anthracycline-resistant breast cancer patients

Abstract

Anthracyclines play a central role in the treatment of breast cancer. They are perhaps the most active single agents available for the treatment of this disease. For patients with primary breast cancer for whom chemotherapy would be appropriate, anthracyclines are often incorporated in adjuvant regimens. For patients with endocrine-therapy-resistant metastatic disease, anthracyclines are nearly always included in the first or second-line therapeutic regimes. Unfortunately, despite the fact that anthracyclines and anthracycline-containing regimens can achieve impressive objective response rates, this impressive activity has not translated into a great improvement in disease-free survival for patients with early stage breast cancer or overall survival for patients with metastatic disease. The addition of anthracyclines to adjuvant therapy regimens in general only modestly improves their efficacy and the use of anthracyclines in metastatic disease does not cure these patients. The clinical utility of anthracyclines would be greatly improved if we could predict which patients would be anthracycline resistant, interfere with the development or expression of anthracycline resistance and predict which anticancer agents would be non-cross-resistant with anthracyclines. Some progress is being made in all these areas. Preclinical studies have identified several intracellular processes that are perturbed by anthracyclines, or that may modulate anthracycline sensitivity of cells. These processes include topoisomerase II activity, drug and toxin transmembrane pumps, intracellular detoxification systems (such as that related to glutathione), stress-related proteins and apoptotic mechanisms. Although measurement of the components of these systems has not yet shown clinical utility in breast cancer, some preclinical work and exploratory studies with small numbers of patients suggest that we may in the future be able to predict which patients will respond or be resistant to anthracyclines. An important avenue of work is the identification of anticancer agents that are noncross-resistant with anthracyclines in breast cancer patients. These agents would be particularly valuable in patients with metastatic disease who had progressed while on anthracyclines. In general, such patients have a very poor prognosis with a median survival of less than 1 year. Also of importance in non-cross-resistant agents is that they might be used in combination with anthracyclines in regimens with very high response rates. Recently completed work suggests that taxoids might be such agents. This finding opens up exciting possibilities in the treatment of metastatic disease and, even more importantly, in the adjuvant arena. The identification of agents that clinically are noncross-resistant with anthracyclines depends on the careful interpretation of clinical trial data. Unfortunately, a number of definitions of anthracycline resistance have been used in the medical literature. These range from very weak definitions, which include many patients with only prior anthracycline exposure (for example, in an adjuvant regimen), to more biologically and clinically appropriate definitions, such as documented progression while receiving an anthracycline. This distinction is very important because it is clear that many patients who have relapsed after an anthracycline-based adjuvant therapy will respond to anthracyclines for metastatic disease and are, therefore, not truly anthracycline resistant. In this regard, the recently completed trials with docetaxel in patients with rigorously defined anthracycline resistance are particularly provocative. These trials show that docetaxel maintains much of its excellent first-line levels of efficacy in patients with anthracycline-resistant breast cancer. Agents with this type of maintenance of efficacy in anthracycline-resistant tumours may find immediate utility in this clinical scenario as single agents but, more importantly, have great potential in future combination regimens including anthracyclines.