Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5.

PURPOSE: Certain anthracycline-containing adjuvant chemotherapy regimens are associated with improved relapse-free survival (RFS) and overall survival (OS) compared with the classic regimen of cyclophosphamide, methotrexate, and fluorouracil in women with early-stage breast cancer. PATIENTS AND METHODS: Between 1989 and 1993, 710 pre- and perimenopausal women with axillary node-positive breast cancer were randomly assigned to either cyclophosphamide 75 mg/m(2) orally days 1 through 14, epirubicin 60 mg/m(2) intravenously days 1 and 8, and fluorouracil 500 mg/m(2) intravenously days 1 and 8 (CEF) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14, methotrexate 40 mg/m(2) intravenously days 1 and 8, and fluorouracil 600 mg/m(2) intravenously days 1 and 8). On the basis of follow-up to May 1997 (median follow-up time, 59 months), there was a statistically significant improvement in RFS and OS for CEF compared with CMF. RESULTS: The trial results are now updated, with a median follow-up of 10 years for live patients. The 10-year RFS is 52% for patients who received CEF compared with 45% for CMF patients (hazard ratio [HR] for CMF v CEF = 1.31; stratified log-rank, P = .007). The 10-year OS for patients who received CEF and CMF are 62% and 58%, respectively (HR for CMF v CEF = 1.18; stratified log-rank, P = .085). The rates of acute leukemia have not changed since the original report, whereas the rates of congestive heart failure are slightly higher but acceptable (four patients [1.1%] in the CEF group v one patient [0.3%] in the CMF group). CONCLUSION: The previously demonstrated benefit of CEF compared with CMF adjuvant chemotherapy is maintained with longer follow-up in the MA5 trial.     

Adjuvant treatment for early breast cancer: the Ludwig breast cancer studies

The Ludwig Breast Cancer Study Group conducted four concomitant trials involving adjuvant chemotherapy and endocrine therapy. In Ludwig I, adjuvant combination chemotherapy was used with or without prednisone to treat premenopausal and perimenopausal women with metastases in 1-3 axillary lymph nodes. The impact of adding low-dose, continuous prednisone (7.5 mg/day) to an adjuvant, chemotherapy regimen of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) was investigated in a randomized trial of 491 premenopausal and perimenopausal patients with operable breast cancer and metastases in 1-3 axillary lymph nodes. As a consequence of lower hematologic toxicity, a significantly higher dose of CMF could be administered with added prednisone (P less than 0.0001). However, at the 4-year median follow-up, no significant improvement was observed in disease-free survival (DFS) (73% vs. 77%; P = 0.35) or overall survival (OS) (both 86%; P = 0.73). Induced amenorrhea was associated with a longer DFS for younger patients, those who received lower CMF doses, and those with tumors that were estrogen receptor (ER) positive. In Ludwig III, adjuvant therapy was administered to younger postmenopausal women in a study of chemotherapy plus endocrine therapy versus endocrine therapy alone versus mastectomy alone. In this randomized trial of 463 postmenopausal women 65 years of age or younger with axillary node metastases, treatment with the combination of CMF plus low-dose prednisone and tamoxifen (CMFp + T), was compared to endocrine therapy alone (p + T) or to no further treatment after total mastectomy and axillary clearance. At a median follow-up of 4 years, the DFS was 61% for the CMFp + T group, compared with 48% for the p + T group (P = 0.01) and 31% for the observation group (P less than 0.0001). The 4-year OS rates were not statistically different (76%, 67%, and 68%, respectively; P = 0.30). Treatment with CMFp + T reduced local, regional, and distant metastases and was equally effective in improving DFS in patients with ER-positive or ER-negative tumors. In Ludwig II, chemotherapy was given with or without oophorectomy in premenopausal and perimenopausal patients with metastases in 4 or more axillary nodes.(ABSTRACT TRUNCATED AT 400 WORDS)     

Evidence of a castration-mediated effect of adjuvant cytotoxic chemotherapy in premenopausal breast cancer

This prospective randomized trial, conducted by the Danish Breast Cancer Cooperative Group, is the largest study, so far, of adjuvant chemotherapy in premenopausal breast cancer. The trial is unique in that it is nationwide and based on a nonselected population of patients, and is the only adjuvant trial studying the effect of cyclophosphamide monotherapy. After total mastectomy with axillary node sampling, followed by local radiotherapy, 1,032 pre- and perimenopausal women with operable breast cancer were randomized to observation alone, or to adjuvant chemotherapy for 1 year with either cyclophosphamide monotherapy or with a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). As of January 1987, median follow-up was 68 months. From early on both cyclophosphamide alone and CMF were found to improve recurrence-free survival (RFS) significantly and to a similar degree (P = .0001). However, an overall survival advantage did not become evident until 5 years after the start of treatment. So far, this advantage appears to be more pronounced in CMF (P = .0065) than in cyclophosphamide-only patients (P = .08). Thus, the study confirms the findings of the National Surgical Adjuvant Breast Project (NSABP) and Milan trials that adjuvant chemotherapy prolongs the survival of premenopausal women with early breast cancer. A retrospective analysis revealed that, in contrast with CMF, cyclophosphamide alone did not improve RFS significantly in subsets of patients without amenorrhea, with estrogen-receptor (ER) negative tumors, and with tumors of low histological differentiation. Assuming that cyclophosphamide alone is a less tumoricidal treatment than CMF, these findings suggest that the effect of adjuvant cytotoxic chemotherapy is mediated partly through chemical castration, and partly through a purely cytotoxic effect.     

Adjuvant hormone treatment and chemotherapy in postmenopausal women with operable breast cancer: a retrospective analysis.

Two hundred consecutive postmenopausal women with operable breast cancer and metastatic axillary nodes were treated during the period January - December 1981 with adjuvant chemotherapy (CMF) or hormonal treatment (tamoxifen). The distribution of receptor status (estrogen or progesterone), number of axillary metastatic nodes (less than = 3 or greater than 3), surgical treatment and size of the primary tumor were homogeneous in both groups. Receptor status and number of axillary lymph nodes were correlated with adjuvant treatment efficacy. Ten-year disease-free survival (DFS) was higher in the TAM-treated (72%) than in the CMF-treated group (52%) (p less than 0.01). In patients with less than = 3 axillary metastatic nodes, those treated with TAM had a higher DFS rate than those treated with CMF (75% vs 59%, p less than 0.01). There was no difference in DFS between CMF-and TAM-treated groups within the greater than 3 metastatic lymph node patients. In ER + primary tumors, DFS was higher in the subset treated with TAM (62%) than with CMF (51%) (p less than 0.05), whereas no difference in DFS was observed in ER- patients between the two treatment groups. Considering the TAM group, DFS was better (p less than 0.01) for ER+ cases than for ER- cases only at 5 years of observation. In the CMF group, DFS was not influenced by ER status. PgR content did not affect DFS in either adjuvant treatment group.     

Survival analyses from the ZEBRA study. goserelin (Zoladex) versus CMF in premenopausal women with node-positive breast cancer

The Zoladex Early Breast Cancer Research Association (ZEBRA) trial compared the efficacy and tolerability of goserelin (Zoladex) with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy in pre-/perimenopausal women with node-positive early breast cancer. The results of disease-free survival (DFS) analyses have already been published. Here we present an update including data on overall survival (OS) from the ZEBRA trial at a median follow-up of 7.3 years. In patients with oestrogen receptor (ER)-positive tumours, non-inferiority of goserelin versus CMF for OS was shown; goserelin was again shown to be equivalent to CMF for DFS. This updated analysis has demonstrated that the two treatments are also equivalent for distant disease-free survival (DDFS). In patients with ER-negative disease, goserelin was inferior to CMF for DFS, DDFS and OS. This follow-up analysis confirms the previously reported outcomes from the ZEBRA trial and demonstrates that goserelin offers an effective alternative to CMF chemotherapy for adjuvant therapy of premenopausal patients with ER-positive, node-positive early breast cancer.     

Epirubicin versus CMF as adjuvant therapy for stage I and II breast cancer: a prospective randomised study

We compared a relatively short regimen of monochemotherapy with epirubicin versus polychemotherapy with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) as adjuvant treatment for stage I and II breast cancer patients. 348 patients with oestrogen receptor negative (ER-) node negative and ER- or ER+ node-positive with <10 nodes were accrued. CMF was given intravenously (i.v.) on days 1 and 8, every 4 weeks, for six courses; epirubicin was given weekly for 4 months. Postmenopausal patients received tamoxifen for 3 years. The primary endpoints were overall survival (OS), relapse-free survival (RFS) and event-free survival (EFS). Outcome evaluation was performed both in eligible patients and in all randomised patients according to the intention-to-treat principle. 8 randomised patients were considered ineligible. At a median follow-up of 8 years, there was no difference in OS (Hazard Ratio (HR)=1.11, 95% Confidence Interval (CI): 0.77-1.61, P=0.58), EFS (HR=1.14, 95% CI: 0.78-1.64, P=0.48), and RFS (HR=1.14, 95% CI: 0.8-1.64, P=0.48) between the two arms for all of the patients. At 8 years, the RFS percentages (+/-Standard Error (S.E.)) were 65.4% (+/-4%) in the CMF arm and 62.7% (+/-4%) in the epirubicin arm; for EFS these were 64.2% (+/-4%) for CMF and 60.8% (+/-4%) for epirubicin, respectively. A significant difference in RFS (P=0.015) was observed in patients with 4-9 positive nodes in favour of the CMF arm. Toxicity in the two arms was superimposable except for more frequent grade 3 alopecia in the epirubicin-treated patients (P=0.001). Overall, at a median follow-up of 8 years, there were no differences between the two arms in terms of OS, EFS and RFS.     

Identifying good prognosis group of breast cancer patients with 1-3 positive axillary nodes for adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy

OBJECTIVE: We conducted a retrospective analysis of prognosis factors for survival in breast cancer patients with 1-3 axillary lymph node metastases and tried to identify a subset of patients with good prognosis suitable for cyclophosphamide, methotrexate and 5-fluorouracil (CMF) adjuvant chemotherapy. METHODS: A cohort of 446 breast cancer patients received definite surgery and adjuvant chemotherapy with CMF at Chang Gung Memorial Hospital from 1990 to 1998. They were enrolled in the study. The median follow-up time was 69 months. Prognostic factors including age, tumor size, number of involved nodes, steroid receptor status, tumor ploidy, synthetic-phase fraction, histologic grade and administration of tamoxifen were analysed for disease-free survival (DFS) and overall survival (OS) by Cox regression model. RESULTS: The estimated 5 year OS and DFS for all patients were 85.4 and 71.5%, respectively. Multivariate analysis revealed that tumor size, age and estrogen receptor (ER) status were independent prognostic factors for OS, and tumor size, age, ER status and number of involved nodes were independent prognostic factors for DFS. The 5 year OS rates of the low-risk group (age >40, tumor < or =3 cm and positive ER) and average-risk group (either age < or =40, tumor >3 cm or negative ER) were 98.8 and 82.4%, respectively (P = 0.0001). The 5 year DFS of the low-risk and high-risk group were 88.2 and 67.7%, respectively (P = 0.0001). CONCLUSION: Among breast cancer patients with 1-3 positive lymph nodes excellent survival rate was found in those who had favorable prognostic factors, including age >40, tumor size < or =3 cm and positive ER. Adjuvant chemotherapy with CMF regimen is optimal for these low-risk patients.     

Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102.

PURPOSE: We evaluated the efficacy of cyclophosphamide, methotrexate, and fluorouracil (CMF) versus cyclophosphamide, doxorubicin, and fluorouracil (CAF) in node-negative breast cancer patients with and without tamoxifen (TAM), overall and by hormone receptor (HR) status. PATIENTS AND METHODS: Node-negative patients identified by tumor size (> 2 cm), negative HR, or high S-phase fraction (n = 2,690) were randomly assigned to CMF, CAF, CMF + TAM (CMFT), or CAF + TAM (CAFT). Cox regression evaluated overall survival (OS) and disease-free survival (DFS) for CAF versus CMF and TAM versus no TAM separately. Two-sided CIs and one-sided P values for planned comparisons were calculated. RESULTS: Ten-year estimates indicated that CAF was not significantly better than CMF (P = .13) for the primary outcome of DFS (77% v 75%; HR = 1.09; 95% CI, 0.94 to 1.27). CAF had slightly better OS than CMF (85% v 82%, HR = 1.19 for CMF v CAF; 95% CI, 0.99 to 1.43); values were statistically significant in the planned one-sided test (P = .03). Toxicity was greater with CAF and did not increase with TAM. Overall, TAM had no benefit (DFS, P = .16; OS, P = .37), but the TAM effect differed by HR groups. For HR-positive patients, TAM was beneficial (DFS, HR = 1.32 for no TAM v TAM; 95% CI, 1.09 to 1.61; P = .003; OS, HR = 1.26; 95% CI, 0.99 to 1.61; P = .03), but not for HR-negative patients (DFS, HR = 0.81 for no TAM v TAM; 95% CI, 0.64 to 1.03; OS, HR = 0.79; 95% CI, 0.60 to 1.05). CONCLUSION: CAF did not improve DFS compared with CMF; there was a slight effect on OS. Given greater toxicity, we cannot conclude CAF to be superior to CMF. TAM is effective in HR-positive disease, but not in HR-negative disease.     

Activity of first-line epirubicin and paclitaxel in metastatic breast cancer is independent of type of adjuvant therapy

To evaluate the impact of prior adjuvant chemotherapy on response rate (RR), progression-free (PFS) and overall survival (OS) of metastatic breast cancer patients treated with epirubicin/paclitaxel (ET) regimens. In all, 291 patients enrolled in five studies in metastatic breast cancer were analysed: 101 (35%) were chemonaive, 109 (37%) had received adjuvant CMF and 81 (28%) adjuvant anthracyclines. Response rate to ET was 66%. Response rate was 63% for cyclophosphamide plus methotrexate plus 5-fluorouracil (CMF), 67% for prior anthracyclines and 68% in chemonaive patients (P=0.5). By multivariate analysis, adjusted odds ratio for response was 0.81 (95% CI: 0.37-1.79) for CMF and 0.92 (95% CI 0.43-2.01) for anthracyclines (P=0.86). The CR rates were 14% for both CMF and anthracyclines and 22% for chemonaive patients (P=0.2). By multivariate analysis, the relative odds of CR for CMF or anthracyclines were 0.40 and 0.39 as compared to chemonaive patients (P=0.036). The median PFS was 11.0 months for prior CMF, 10.2 months for anthracyclines and 12.5 months in chemonaive patients (P=0.33). In multivariate Cox's model, a nonsignificant increase in the risk of progression was seen in patients treated with adjuvant CMF or anthracyclines. The median OS was 23.8 months for CMF, 20.2 months for anthracyclines and 27.5 months in chemonaive patients (P=0.61). The same, nonsignificant, association was seen in multivariate analysis. The ET regimens provide satisfactory results in metastatic breast cancer, regardless of previous adjuvant chemotherapy.     

Clinical role of multidrug resistance protein 1 expression in chemotherapy resistance in early-stage breast cancer: the Austrian Breast and Colorectal Cancer Study Group.

PURPOSE: The multidrug resistance protein 1 (MRP1) is expressed in human breast cancer cells and may contribute to the clinical drug resistance of breast cancer patients. Therefore, we determined the impact of MRP1 expression on the clinical outcome of adjuvant therapy in patients with early-stage breast cancer. PATIENTS AND METHODS: Immunostaining for MRP1 was performed on tissue sections from 516 premenopausal, hormone receptor-positive breast cancer patients with stage I and II disease. Statistical analyses were performed to assess the effect of MRP1 expression on survival and to test for interaction between MRP1 expression and treatment. RESULTS: MRP1 expression independently predicted shorter relapse-free survival (RFS) and overall survival (OS) in patients treated with cyclophosphamide, methotrexate, and fluorouracil (CMF; RFS: hazard ratio [HR] = 1.48; 95% CI, 1.16 to 1.88; P = .002; OS: HR = 1.82; 95% CI, 1.10 to 3.01; P = .02), but it did not predict shorter RFS and OS in patients who received tamoxifen plus goserelin (RFS: HR = 0.99; 95% CI, 0.74 to 1.31; P = .9; OS: HR = 0.68; 95% CI, 0.40 to 1.15; P = .1). Tests for interaction between MRP1 expression and treatment were statistically significant for both RFS (P = .04) and OS (P = .006). CONCLUSION: Our data suggest that MRP1 expression plays an important role in the clinical resistance to adjuvant CMF chemotherapy but does not seem to affect response to adjuvant endocrine treatment with tamoxifen plus goserelin. Thus, MRP1 may be a useful marker for the selection of patients with early-stage breast cancer for the appropriate adjuvant therapy after prospective confirmatory evaluation.     

Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5.

PURPOSE: Effective adjuvant treatment modalities in premenopausal breast cancer patients today include chemotherapy, ovariectomy, and tamoxifen administration. The purpose of Austrian Breast and Colorectal Cancer Study Group Trial 5 was to compare the efficacy of a combination endocrine treatment with standard chemotherapy. PATIENTS AND METHODS: Assessable trial subjects (N = 1,034) presenting with hormone-responsive disease were randomized to receive either 3 years of goserelin plus 5 years of tamoxifen or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Stratification criteria included tumor stage and grade, number of involved nodes, type of surgery, and steroid hormone receptor content. Relapse-free survival (RFS) was defined as time from randomization to first relapse, local recurrence, or contralateral incidence, and overall survival (OS) as time to date of death. RESULTS: With a 60-month median follow-up, 17.2% of patients in the endocrine group and 20.8% undergoing chemotherapy developed relapses. Local recurrences emerged in 4.7% and 8.0%, respectively. RFS and local recurrence-free survival differed significantly in favor of endocrine therapy (P =.037 and P =.015), with a similar trend observed in OS (P =.195). CONCLUSION: Overall, our data suggest that the goserelin-tamoxifen combination is significantly more effective than CMF in the adjuvant treatment of premenopausal patients with stage I and II breast cancer.     

Direct comparisons of adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy for operable breast cancer patients stratified by estrogen receptor and menopausal status

Based on estrogen receptor (ER) and menopausal status, operable breast cancer (UICC stage I, II, III-a) patients were randomized for adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy, and the effects on the relapse-free survival (RFS) and overall survival (OS) were compared. Tamoxifen (TAM) 20 mg/day was administered orally for 2 years after mastectomy as an adjuvant endocrine therapy in postmenopausal patients. In premenopausal patients, oophorectomy (OVEX) was performed before TAM administration. In the chemotherapy arm (CHEM), patients were given 0.06 mg/kg of body weight of mitomycin C (MMC) intravenously, followed by an oral administration of cyclophosphamide (CPA) 100 mg/day in an administration of a 3-month period and a 3-month intermission. This 6-month schedule was repeated 4 times in 2 years. The chemoendocrine arm (CHEM + TAM) was composed of TAM with MMC + CPA chemotherapy. The patients were randomized according to ER and menopausal status. ER-positive patients were randomized to three arms: OVEX ± TAM, CHEM, and CHEM + TAM. For ER-negative patients there were two arms: CHEM and CHEM + TAM. 1579 patients entered the trial between September 1978 and December 1991, with median follow-up of 8.2 years. In ER-positive, premenopausal patients, there were no significant differences in RFS or OS among OVEX ± TAM, MMC + CPA, TAM + MMC + CPA arms. On the contrary, in ER-positive, postmenopausal patients, the chemoendocrine therapy showed a significantly higher RFS (p = 0.0400) and OS (p=0.0187) as compared with TAM to chemotherapy alone. There were no significant differences in RFS or OS by addition of TAM on the chemotherapy, in both pre- and post-menopausal ER-negative patients. It was concluded that in ER-positive premenopausal breast cancer, endocrine therapy alone may be equivalent in prolonging RFS and OS to chemotherapy or chemoendocrine therapy, and that ER-positive postmenopausal breast cancer may be better controlled with the combination of TAM and chemotherapy, as compared to TAM or chemotherapy alone. The importance of stratification of operable breast cancer by ER and menopausal status, as well as the direct comparisons of different treatments, were stressed.This revised version was published online in October 2005 with corrections to the Cover Date.     

A comparison of the outcomes of non-randomised chemotherapy regimens in node positive breast cancer

Adjuvant chemotherapy increases disease-free survival (DFS) and overall survival (OS) following surgery for breast cancer. However, debates concerning the type of adjuvant chemotherapy continue. The effect of adjuvant chemotherapy on loco-regional recurrence-free survival (LFS) was also reported. The present study was undertaken to compare the results of adjuvant FAC (5-fluorouracil, Doxorubicin, Cyclophosphamide) and CMF (Cyclophosphamide, Methotrexate, 5-fluorouracil) chemotherapy on DFS, OS and LFS for node positive breast carcinoma treated with mastectomy in a non-randomised setting. Data from 688 consecutive lymph node positive breast cancer patients who underwent radical or modified radical mastectomy and received adjuvant FAC (600/60/600 mgr/m2 for 6 cycles every three weeks) or CMF (600/40/600 mgr/m2 for 6 cycles on days land 8 every four weeks) chemotherapy were reviewed. The effect of FAC on DFS, OS and LFS as compared with CMF was analysed. Survival curves were generated by the Kaplan-Meier method, and a multivariate analysis was performed by the Cox proportional hazard model. Adjuvant FAC was found to improve DFS, OS and LFS. 5-year DFS, OS and LFS were longer for patients treated with FAC as compared to CMF (67% versus 53%, p < 0.001; 77% versus 66%, p < 0.001, and 97% versus 91%). Adjusted hazard ratio (HR) for potential risk factors and tamoxifen treatment showed that FAC treated patients much benefitted in terms of survival as compared to CMF treated patients (HR 0.53, CI 0.40-0.69 for DFS; HR 0.48, CI 0.35-0.65 for OS, and HR 0.33, CI 0.16-0.65 for LFS). In conclusion, adjuvant FAC improves DFS, OS and LFS as compared to CMF in node positive breast carcinoma patients treated with mastectomy.     

A randomized study of adjuvant treatments for operable breast cancer patients stratified by estrogen receptor and menopausal status

According to estrogen receptor (ER) and menopausal status, operable breast cancer patients were randomized for adjuvant endocrine therapy with tamoxifen (TAM) in premenopausal patients, after oophorectomy (OVEX), chemotherapy, CHEM (mitomycin C+ oral cyclophosphamide), or chemo-endocrine therapy (TAM + CHEM). Some 1579 patients were entered in the trial between 9, 1978 and 12, 1991, with a median follow-up of 10 years. In ER-positive, premenopausal patients there were no significant differences in relapse-free (RFS) or overall survival (OS) among the OVEX + TAM, CHEM, and CHEM + TAM arms. On the contrary, in ER-positive, post-menopausal patients, the chemoendocrine therapy showed a significantly better OS (p = 0.0254) with a trend of better RFS (p = 0.0674), as compared with TAM or CHEM groups. ER-negative, premenopausal patients showed no significant differences in RFS or OS between CHEM and CHEM + TAM arms. In ER-negative, postmenopausal patients, there was a non-significantly better RFS (p = 0.0888) and a significantly better OS (p = 0.0332) in CHEM + TAM group than in the CHEM alone group. These results suggest that ER and menopausal status are important criteria to select early breast cancer patients for adjuvant treatments.     

Chemotherapy-induced amenorrhea and other clinical and pathological parameters in the prognosis of breast cancer patients.

147 stage II pre- and perimenopausal breast cancer patients were treated with cyclophosphamide-methotrexate-5-fluorouracil (CMF)- based adjuvant regimens. 103 (72%) patients became amenorrheic during or immediately after the end of the chemotherapy program. Univariate analyses for age, menstrual status, nodal involvement, grading, estrogen and progesterone receptor status indicated no correlation between induction of amenorrhea and a significant prolongation of overall and disease-free survival. Multivariate analyses confirmed that young age at diagnosis, increasing number of infiltrated nodes, negative progesterone receptor status and grade 3 tumors are associated with a worse prognosis. Our results suggest that no benefit is expected in women with drug induced amenorrhea after CMF adjuvant treatment.     

Anemia is a significant prognostic factor in local relapse-free survival of premenopausal primary breast cancer patients receiving adjuvant cyclophosphamide/methotrexate/5-fluorouracil chemotherapy.

PURPOSE: To determine the effects of anemia on local relapse-free, relapse-free, and overall survival (LRFS, RFS, and OS, respectively) in premenopausal, primary breast cancer patients receiving adjuvant polychemotherapy, and to determine which conventional prognostic factors affected these outcomes. EXPERIMENTAL DESIGN: Four hundred twenty-four premenopausal patients with early-stage primary breast cancer and hormone receptor-expressing tumors were treated with i.v. cyclophosphamide/methotrexate/5-fluorouracil (CMF) polychemotherapy as part of an adjuvant phase III trial (Austrian Breast and Colorectal Cancer Study Group Trial 5). The influence of anemia (hemoglobin <12 g/dL) on LRFS, RFS, and OS was evaluated in a retrospective analysis. RESULTS: Of 424 patients, 77 (18.2%) developed anemia on CMF chemotherapy. After a median follow-up time of 5 years, 8.9% of nonanemic patients had local relapse compared with 19.6% of anemic patients (P=0.0006). Although mastectomy was associated with anemia (26% versus 13.7% in breast conserving surgery; P=0.002), multivariate analysis did not show mastectomy per se to be a significant risk factor for LRFS. Age, lymph node status, and hemoglobin had an independent significant influence on LRFS (P<0.005). Anemic patients had a relative risk of 2.96 (95% confidence interval, 1.41-6.23) for developing local relapse in comparison with nonanemic patients. CONCLUSION: Premenopausal breast cancer patients who developed anemia during the CMF regimen had significantly worse LRFS. In Austrian Breast and Colorectal Cancer Study Group Trial 5, anemia may have contributed to an almost doubled incidence of local recurrence in the chemotherapy arm. Molecular targets associated with tumor hypoxia and distinct from erythropoiesis should receive further attention in experimental and clinical settings.     

Leucocyte nadir as a marker for chemotherapy efficacy in node-positive breast cancer treated with adjuvant CMF.

The purpose of this study was to examine the association between the leucocyte nadir and prognosis in breast cancer patients receiving adjuvant chemotherapy consisting of cyclophosphamide, methotrexate and fluorouracil (CMF). Three hundred and sixty-eight patients with node-positive breast cancer without distant metastases were treated with six cycles of adjuvant CMF. Some patients (n = 60) also received tamoxifen. All patients underwent surgery and received radiotherapy to the axillary and supraclavicular lymph nodes and the chest wall. The effect of leucopenia caused by CMF on distant disease-free survival (DDFS) and overall survival (OS) was assessed. A low leucocyte nadir during the chemotherapy was associated with a long DDFS in univariate analysis when tested as a continuous variable (the relative risk (RR) 1.3, 95% confidence interval (CI) 1.04-1.06, P = 0.02). Similarly, when the leucocyte nadir count was divided into tertiles, the patients who had the highest nadir values during the six-cycle treatment had worst outcome (RR 1.6, 95% CI 1.07-2.5, P = 0.02). However, in a multivariate analysis only the number of affected lymph nodes, tumour size, progesterone receptor status, surgical procedure, age and adjuvant tamoxifen therapy retained prognostic significance, whereas the leucocyte nadir count did not. A low leucocyte nadir during the adjuvant CMF chemotherapy is associated with favourable DDFS and it may be a useful biological marker for chemotherapy efficacy.     

The prognostic significance of expression of the multidrug resistance-associated protein (MRP) in primary breast cancer.

In the present study, we determined the frequency and intensity of MRP protein expression by monoclonal antibody immunohistochemistry in a series of 259 resected invasive primary breast carcinomas, and we evaluated MRP immunoreactivity in relation to patient and tumour characteristics, relapse-free (RFS) and overall survival (OS). The immunostaining was graded on a semiquantitative scale that ranged from (-) to ( ). Overall, 34% of the tumours were positive for anti-MRP antibody: 19% showed weak cytoplasmic staining (+), 14% had clear cytoplasmic staining (++) and only 1% of the tumours had a strong cytoplasmic as well as membranous staining ( ). MRP expression was not related to patient''s age, menopausal status, tumour size, differentiation grade, oestrogen and progesterone receptor level or lymph node involvement. In an exploratory univariate analysis of all patients, only primary tumour size and number of lymph nodes involved were significantly associated with shortened RFS (P < 0.001 and P < 0.001 respectively) and OS (P = 0.02 and P < 0.001 respectively). In Cox univariate analysis for RFS in subgroups of patients stratified by menopausal status, tumour size, nodal status, adjuvant systemic therapy and oestrogen and progesterone receptor status, MRP expression was associated with increased risk for failure in patients with small tumours (T1), in node-negative patients and in node-positive patients who received adjuvant systemic chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF); the relative hazard rate (RHR) for relapse was increased in the presence of MRP, with RHR values with 95% confidence limits (CL) of 2.8 (1.2-6.9), 2.1 (1.0-4.2) and 2.8 (0.8-9.9) respectively. In analysis for OS, expression of MRP was also associated with increased risk for failure in patients with small tumours (T1) [RHR (95% CL) 2.3 (0.9-6.0)] and in node-positive patients who received adjuvant systemic chemotherapy with CMF [RHR (95% CL) 3.7 (0.8-17.1)] but not in node-negative patients [RHR (95% CL) 1.1 (0.4-2.6)]. In conclusion, our results show that MRP is frequently overexpressed in primary breast cancer and suggest that MRP expression might be of prognostic significance in the subgroups of patients with the more favourable prognosis, i.e. patients with small tumours and node-negative patients, as well as in the setting of adjuvant systemic chemotherapy. In primary breast cancer, MRP might be related to altered cell biological behaviour, including a more aggressive phenotype, and resistance to adjuvant systemic chemotherapy.     

Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23.

PURPOSE: Uncertainty about the relative worth of doxorubicin/cyclophosphamide (AC) and cyclophosphamide/methotrexate/fluorouracil (CMF), as well as doubt about the propriety of giving tamoxifen (TAM) with chemotherapy to patients with estrogen receptor-negative tumors and negative axillary nodes, prompted the National Surgical Adjuvant Breast and Bowel Project to initiate the B-23 study. PATIENTS AND METHODS: Patients (n = 2,008) were randomly assigned to CMF plus placebo, CMF plus TAM, AC plus placebo, or AC plus TAM. Six cycles of CMF were given for 6 months; four cycles of AC were administered for 63 days. TAM was given daily for 5 years. Relapse-free survival (RFS), event-free survival (EFS), and survival (S) were determined by using life-table estimates. Tests for heterogeneity of outcome used log-rank statistics and Cox proportional hazards models to detect differences across all groups and according to chemotherapy and hormonal therapy status. RESULTS: No significant difference in RFS, EFS, or S was observed among the four groups through 5 years (P =.96,.8, and.8, respectively), for those aged < or = 49 years (P =.97,.5, and.9, respectively), or for those aged > or = 50 years (P =.7,.6, and.6, respectively). A comparison between all CMF- and all AC-treated patients demonstrated no significant differences in RFS (87% at 5 years in both groups, P =.9), EFS (83% and 82%, P =.6), or S (89% and 90%, P =.4). There were no significant differences in RFS, EFS, or S between CMF and AC in patients aged < or = 49 or > or = 50 years. No significant difference in any outcome was observed when chemotherapy-treated patients who received placebo were compared with those given TAM. RFS in both groups was 87% (P =.6), 87% in patients aged < or = 49 (P =.9), and 88% and 87%, respectively (P =.4), in those aged > or = 50 years. CONCLUSION: There was no significant difference in the outcome of patients who received AC or CMF. TAM with either regimen resulted in no significant advantage over that achieved from chemotherapy alone.     

TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients

HER2 amplification, TOP2A aberrations, and absence of tissue inhibitor of metalloproteinase (TIMP-1) expression in breast carcinomas have been shown to be associated with incremental benefit from anthracycline-containing adjuvant chemotherapy, and this study was undertaken to validate these findings in a similar, but independent, randomized clinical trial. TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to cyclophosphamide, epirubicin, and fluorouracil (CEF) or cyclophosphamide, methotrexate, and fluorouracil (CMF) in the MA.5 trial. Ninety-eight (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. Forty-four percentage was classified as HT responsive (HER2 amplified and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT-responsive patients, CEF was superior to CMF with an improved RFS (adjusted HR, 0.64; 95% CI, 0.42-0.97), but this was not significant for OS (adjusted HR, 0.66; 95% CI, 0.42-1.04). A significant HT profile versus treatment interaction was detected for OS (P = 0.03). In 2T-responsive patients, CEF seemed to improve RFS compared to CMF (adjusted HR, 0.67; 95% CI, 0.43-1.03) and improved OS (adjusted HR, 0.58; 95% CI, 0.36-0.93). A significant 2T profile versus treatment interaction was detected for OS (P = 0.01). With this study, we validate a more substantial reduction in mortality by CEF compared to CMF in patients with an HT- or 2T-responsive profile; however, we could not show a similarly significant reduction in RFS events, where a benefit of CEF over CMF was found irrespective of TIMP-1 status. Further studies are necessary before the HT and 2T profiles may be used to direct the use of anthracyclines.