High-dose chemotherapy: how resistant is breast cancer?

This report reviews clinical experience with high-dose chemotherapy with stem-cell support in breast cancer and attempts to integrate clinical and molecular biological observations into a model of drug resistance. Despite the remarkable initial chemosensitivity of breast cancer, the majority of patients with advanced breast cancer die of their disease. In trials to date, high-dose chemotherapy has not been able to overcome primary drug resistance and patients with disease progression during induction therapy benefit little from further high-dose therapy. On the other hand, high-dose chemotherapy produces improved objective response rates compared with standard-dose chemotherapy due to converting some partial responses achieved by standard-dose induction therapy to complete response. This suggests that high-dose chemotherapy may overcome partial clinical drug resistance and may result in a more complete elimination of chemosensitive cells. Whether increased complete response rates will translate into higher cure rates and increased overall survival remains to be unequivocally demonstrated. There are multiple clinical patterns of drug failure including continued growth during chemotherapy, partial response followed by a period of stable disease, initial complete response with subsequent recurrence within a few months or after several years. Different mechanisms of drug resistance may operate at different stages of the disease and predispose patients to different clinical patterns of failure. A model of clonal progression of cancer is proposed that could explain several intriguing features of clinical drug resistance. We hypothesize that drug-sensitivity is an acquired characteristic of neoplastic cells and that a 'physiological drug-resistant' state may precede drug sensitivity at early stages of neoplastic transformation. Some recurrences may, in this context, represent progression of physiologically drug-resistant clones to sensitivity and subsequently to 'pathologic resistance' to chemotherapy. Optimal therapy to delay or prevent recurrence may differ depending on the stage and biology of the tumor and may include combinations of cytotoxic drugs and chemopreventive agents to arrest progression of early physiologically drug-resistant neoplastic stem cells.