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Endocrine responsiveness and tailoring adjuvant therapy for postmenopausal lymph node-negative breast cancer: a randomized trial.



The role of adjuvant chemotherapy in postmenopausal 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.


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/m(2) on days 1-14, orally; methotrexate at 40 mg/m(2) on days 1 and 8, intravenously; and 5-fluorouracil at 600 mg/m(2) 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.


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).


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.


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    Journal of the National Cancer Institute 94:14 2002 Jul 17 pg 1054-65


    Aged, 80 and over
    Antineoplastic Agents, Hormonal
    Antineoplastic Combined Chemotherapy Protocols
    Breast Neoplasms
    Chemotherapy, Adjuvant
    Endocrine System
    Lymphatic Metastasis
    Middle Aged
    Quality of Life
    Time Factors
    Treatment Outcome

    Pub Type(s)

    Clinical Trial
    Journal Article
    Randomized Controlled Trial
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, P.H.S.



    PubMed ID