TY - JOUR
T1 - Endocrine responsiveness and tailoring adjuvant therapy for postmenopausal lymph node-negative breast cancer
T2 - A randomized trial
AU - International Breast Cancer Study Group (IBCSG)
AU - Castiglione-Gertsch, Monica
AU - Price, Karen N.
AU - Goldhirsch, Aron
AU - Coates, Alan S.
AU - Colleoni, Marco
AU - Nasi, M. Laura
AU - Bernhard, Jürg
AU - Zahrieh, David
AU - Bonetti, Marco
AU - Gelber, Richard D.
AU - Egli, G.
AU - Rabaglio, M.
AU - Maibach, R.
AU - Gerber, M. Iannino
AU - Hiltbrunner, A.
AU - Peterson, H.
AU - Zelen, M.
AU - Gelber, S.
AU - O'Neill, A.
AU - Litman, H.
AU - Hinkle, R.
AU - Isley, M.
AU - Blacher, L.
AU - Lippert, S.
AU - Celano, J.
AU - Guster-Son, B.
AU - Bettelheim, R.
AU - Reed, R.
AU - Mallon, E.
AU - Hürny, Ch
AU - Gusset, H.
AU - Mathys, N.
AU - Cliffe, B.
AU - Crivellari, D.
AU - Mon-Fardini, S.
AU - Galligioni, E.
AU - Magri, M. D.
AU - Veronesi, A.
AU - Buonadonna, A.
AU - Massarut, S.
AU - Rossi, C.
AU - Candiani, E.
AU - Carbone, A.
AU - Volpe, R.
AU - Roncadin, M.
AU - Arcicasa, M.
AU - Coran, F.
AU - Morassut, S.
AU - Simoncini, E.
AU - Forbes, J. F.
PY - 2002/7/17
Y1 - 2002/7/17
N2 - Background: The role of adjuvant chemotherapy in post-menopausal patients with lymph node-negative breast cancer is controversial. After demonstrating the efficacy of chemotherapy combined with tamoxifen for postmenopausal patients with lymph node-positive disease, the International Breast Cancer Study Group launched a randomized trial (Trial IX) to evaluate the role of adjuvant chemotherapy preceding treatment with tamoxifen for patients with lymph node-negative disease. Methods: After stratification by estrogen receptor (ER) status, patients were randomly assigned to receive three 28-day courses of "classical" adjuvant CMF chemotherapy (cyclophosphamide at 100 mg/m2 on days 1-14, orally; methotrexate at 40 mg/m2 on days 1 and 8, intravenously; and 5-fluorouracil at 600 mg/m2 on days 1 and 8, intravenously) followed by tamoxifen (20 mg/day, orally for 57 months) (CMF→tamoxifen) or to receive tamoxifen alone (20 mg/day, orally for 60 months). We enrolled 1669 eligible patients, 382 (23%) with ER-negative tumors, 1217 (73%) with ER-positive tumors, and 70 (4%) with unknown ER status. The median follow-up was 71 months. All statistical tests were two-sided. Results: The added benefit of CMF followed by tamoxifen over tamoxifen alone was statistically significantly dependent on ER status (tests for interaction: P = .01 for disease-free survival [DFS] and P = .07 for overall survival [OS]). For patients with ER-negative tumors, the addition of CMF statistically significantly improved DFS (5-year DFS = 84% for CMF→tamoxifen versus 69% for tamoxifen alone; difference = 15%; 95% confidence interval [CI] = 6% to 24%; risk ratio [RR] = 0.52; 95% CI = 0.34 to 0.79; P = .003) and OS (5-year OS = 89% for CMF→tamoxifen versus 81% for tamoxifen alone; difference = 8%; 95% CI = 0% to 16%; RR = 0.51; 95% CI = 0.30 to 0.87; P = .01). By contrast, for patients with ER-positive tumors, addition of CMF provided no benefit in terms of DFS (5-year DFS = 84% for CMF→tamoxifen versus 85% for tamoxifen alone; difference = -1; 95% CI = -6% to 4%; RR = 0.99; 95% CI = 0.75 to 1.30; P = .92) or OS (5-year OS = 95% for CMF→tamoxifen versus 93% for tamoxifen alone; difference = 2%; 95% CI = -1% to 5%; RR = 0.95; 95% CI = 0.64 to 1.40; P = .80). Conclusions: Postmenopausal patients with lymph node-negative breast cancer benefited substantially from adjuvant chemotherapy if their cancer was ER-negative (i.e., endocrine-nonresponsive). In contrast, if their cancer was ER-positive (i.e., endocrine-responsive), they obtained no benefit from the combination treatment compared with tamoxifen alone.
AB - Background: The role of adjuvant chemotherapy in post-menopausal patients with lymph node-negative breast cancer is controversial. After demonstrating the efficacy of chemotherapy combined with tamoxifen for postmenopausal patients with lymph node-positive disease, the International Breast Cancer Study Group launched a randomized trial (Trial IX) to evaluate the role of adjuvant chemotherapy preceding treatment with tamoxifen for patients with lymph node-negative disease. Methods: After stratification by estrogen receptor (ER) status, patients were randomly assigned to receive three 28-day courses of "classical" adjuvant CMF chemotherapy (cyclophosphamide at 100 mg/m2 on days 1-14, orally; methotrexate at 40 mg/m2 on days 1 and 8, intravenously; and 5-fluorouracil at 600 mg/m2 on days 1 and 8, intravenously) followed by tamoxifen (20 mg/day, orally for 57 months) (CMF→tamoxifen) or to receive tamoxifen alone (20 mg/day, orally for 60 months). We enrolled 1669 eligible patients, 382 (23%) with ER-negative tumors, 1217 (73%) with ER-positive tumors, and 70 (4%) with unknown ER status. The median follow-up was 71 months. All statistical tests were two-sided. Results: The added benefit of CMF followed by tamoxifen over tamoxifen alone was statistically significantly dependent on ER status (tests for interaction: P = .01 for disease-free survival [DFS] and P = .07 for overall survival [OS]). For patients with ER-negative tumors, the addition of CMF statistically significantly improved DFS (5-year DFS = 84% for CMF→tamoxifen versus 69% for tamoxifen alone; difference = 15%; 95% confidence interval [CI] = 6% to 24%; risk ratio [RR] = 0.52; 95% CI = 0.34 to 0.79; P = .003) and OS (5-year OS = 89% for CMF→tamoxifen versus 81% for tamoxifen alone; difference = 8%; 95% CI = 0% to 16%; RR = 0.51; 95% CI = 0.30 to 0.87; P = .01). By contrast, for patients with ER-positive tumors, addition of CMF provided no benefit in terms of DFS (5-year DFS = 84% for CMF→tamoxifen versus 85% for tamoxifen alone; difference = -1; 95% CI = -6% to 4%; RR = 0.99; 95% CI = 0.75 to 1.30; P = .92) or OS (5-year OS = 95% for CMF→tamoxifen versus 93% for tamoxifen alone; difference = 2%; 95% CI = -1% to 5%; RR = 0.95; 95% CI = 0.64 to 1.40; P = .80). Conclusions: Postmenopausal patients with lymph node-negative breast cancer benefited substantially from adjuvant chemotherapy if their cancer was ER-negative (i.e., endocrine-nonresponsive). In contrast, if their cancer was ER-positive (i.e., endocrine-responsive), they obtained no benefit from the combination treatment compared with tamoxifen alone.
UR - http://www.scopus.com/inward/record.url?scp=0037125429&partnerID=8YFLogxK
M3 - Article
C2 - 12122096
AN - SCOPUS:0037125429
SN - 0027-8874
VL - 94
SP - 1054
EP - 1065
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 14
ER -