Taxanes in Adjuvant and Neoadjuvant Therapies for Breast Cancer

ABSTRACT: Paclitaxel (Taxol) is a diterpene originally obtained from the bark of the Pacific Yew Tree, Taxus Brevifolia. Its mechanism of action is unique. it stabilizes microtubule polymerization, thus blocking cells in the G2/M phase of the cell cycle. In breast cancer, initial studies using paclitaxel demonstrated high activity. The first study was reported in 1991 by Holmes et al who gave paclitaxel as a 24-hour infusion at 250 mg/m² to 25 patients with metastatic breast cancer following only one prior chemotherapy regimen—they achieved a 56% response rate. Since then, numerous studies have confirmed the effectiveness of paclitaxel in patients with metastatic disease. a second taxane, docetaxel (Taxotere), has also demonstrated excellent activity. Clinical research is now focused on integrating the taxanes into combination drug regimens and into neoadjuvant and adjuvant schedules for patients with early stage breast cancer, as well as looking at the biologic determinants of response and resistance to taxanes. This article will review developments in the use of taxanes in the adjuvant and neoadjuvant settings and it will review the information on possible molecular markers that may be useful in predicting tumor responsiveness to taxanes.[ONCOLOGY 12(Suppl 1):23-27, 1998]

Two taxanes are currently available for the treatment of advanced breast cancer—paclitaxel (Taxol) and docetaxel (Taxotere). These agents have different and specific mechanisms of action, and this article will focus on the most extensively studied of them, paclitaxel. The observation that taxanes do not exhibit cross-resistance to doxorubicin (Adriamycin) underlies the international effort to bring them into the adjuvant and neoadjuvant setting. The role of taxanes, and specifically paclitaxel, in the adjuvant setting follows logically from their demonstrated activity against metastatic disease and from their lack of cross-resistance to doxorubicin. In the original series of 25 patients treated by Holmes et al, all but two had received prior doxorubicin and six were considered to be doxorubicin-resistant.[1] two partial responses were observed in the doxorubicin-resistant patients.

In a phase II trial of heavily pretreated patients (median number of prior chemotherapy regimens 3; range 2-6), investigators at Memorial Sloan-Kettering Cancer Center gave 51 patients paclitaxel 200 mg/m² by 24-hour infusion every three weeks and observed a response rate of 28%.[2] The same investigators subsequently studied patients who had received only one prior chemotherapy regimen for metastatic disease. After administering paclitaxel at 250 mg/m² to these patients, they observed a response rate of 48%.[2] In both of these studies, previous resistance to anthracycline did not predict resistance to paclitaxel. As expected, in patients with newly diagnosed metastatic disease, an even higher response rate of 62% was achieved and prior use of adjuvant anthracycline therapy did not decrease the likelihood of a response.[3]

Other studies limited to patients with anthracycline-resistant disease have confirmed the lack of cross-resistance between the two drugs. Wilson et al treated 36 metastatic breast cancer patients who had progressed after treatment with an anthracycline with paclitaxel given as a 96-hour infusion at 140 mg/m². They observed a response rate of 48%.[4] Response rates ranging from 29% to 46% have been achieved in trials of docetaxel in patients with anthracycline-resistant disease.[5-7]

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