The Breast Cancer Program of the NCCTG is committed to clinically meaningful research which addresses management issues important to women with all stages of this disease. There has also been an increased emphasis on laboratory correlative science studies. Patient accrual to treatment protocols has increased from 314 patients per year for the previous five-year grant period to 484 patients per year during the current grant period. Sixteen manuscripts and ten abstracts have been published since January 1, 1996. The major accomplishments of the Breast Program fall into four areas: 1) new hormonal therapy approaches for metastatic breast cancer (MBC): We demonstrated the anti-tumor activity of two dose schedules of letrozole; the lack of pharmacokinetic interaction between tamoxifen and letrozole; co-sponsored a Breast Intergroup study demonstrating similar benefit for medical versus surgical castration in pre-menopausal patients; 2) New chemotherapy approaches for MBC. We demonstrated the significant anti-tumor activity of the combination of paclitaxel plus carboplatin; the activity of different sequential schedules of AC-docetaxel chemotherapy in a randomized phase II trial which also included translational analysis of soluble Her-1 and Her-2 receptors; co- sponsored the PBT-1 intergroup trial which demonstrated a lack of survival improvement for patients receiving high dose chemotherapy with stem cell support versus conventional chemotherapy; and co-sponsored the E1193 Intergroup trial which demonstrated improved response rate and time to progression with the concurrent use of paclitaxel and adriamycin instead of the sequential use of these agents; 3) New radiotherapy approaches: We demonstrated the feasibility of hyperfractionated radiotherapy with shortening of therapy to three weeks with and without doxorubicin for patients with early stage breast cancer; 4) Adjuvant therapy: We cos-sponsored three Intergroup trials, INT 0100 which demonstrated the improvement in disease-free survival and overall survival of adjuvant chemotherapy-tamoxifen versus tamoxifen alone for post-menopausal patients with node positive breast cancer, and studies S9313 and C9741 which evaluated chemotherapy sequence and dosing in node (+) or node (-) breast cancer. Future plans: 1) Hormonal therapy for MBC: Evaluation of the activity of tamoxifen plus tratuzumub in patients with ER (-) metastatic breast cancer (with translational evaluation of solubl4e Her-1 and Her-2 receptors) and of the pure anti-estrogen Faslodex as third-line hormonal therapy; 2) New chemotherapy approaches for MBC: We will coordinate the N9931 Intergroup trial to evaluate whether the monoclonal antibody trastuzumab enhances the efficacy of chemotherapy in patients with lower degrees (+1, +2) of Her-2 expression (including quality of life analysis and correlative science studies), the study of a combination of docetaxel and carboplatin as first-line therapy (along with translational evaluation of genetic polymorphisms that may be associated with response and toxicity); the evaluation of MTA plus gemcitabine; the valuation of topical ceramides and quality of life for patients with cutaneous metastasis from breast cancer; and completion of our ongoing trials of dolastatin-10, irinotecan, and the combination of oral etoposide with intravenous paclitaxel for advanced breast cancer, as well as the optimization of schedule for paclitaxel, carboplatin, and trastuzumab for patients with higher Her2-2 (+3) expression; 3) Adjuvant therapy: We will coordinate the new Breast Intergroup adjuvant. The development of other novel therapeutic approaches, including immunotherapy and other biological therapies with appropriate correlative translational studies, is ongoing. The accomplishments and future plans of the Breast Program address the major research themes of the NCCTG as a whole; i.e., novel therapeutics, phase II trials, translational research, participation and coordination of national intergroup studies, quality of life, and active involvement of community physicians in all aspects of trials.