Summary Background Trastuzumab has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. The standard of care is 1 year of adjuvant trastuzumab, but ...the optimum duration of treatment is unknown. We compared 2 years of treatment with trastuzumab with 1 year of treatment, and updated the comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years, for patients enrolled in the HERceptin Adjuvant (HERA) trial. Methods The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant chemotherapy, adjuvant chemotherapy, or both in 5102 patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. The comparison of 2 years versus 1 year of trastuzumab treatment involved a landmark analysis of 3105 patients who were disease-free 12 months after randomisation to one of the trastuzumab groups, and was planned after observing at least 725 disease-free survival events. The updated intention-to-treat comparison of 1 year trastuzumab treatment versus observation alone in 3399 patients at a median follow-up of 8 years (range 0–10) is also reported. This study is registered with ClinicalTrials.gov , number NCT00045032. Findings We recorded 367 events of disease-free survival in 1552 patients in the 1 year group and 367 events in 1553 patients in the 2 year group (hazard ratio HR 0·99, 95% CI 0·85–1·14, p=0·86). Grade 3–4 adverse events and decreases in left ventricular ejection fraction during treatment were reported more frequently in the 2 year treatment group than in the 1 year group (342 20·4% vs 275 16·3% grade 3–4 adverse events, and 120 7·2% vs 69 4·1% decreases in left ventricular ejection fraction, respectively). HRs for a comparison of 1 year of trastuzumab treatment versus observation were 0·76 (95% CI 0·67–0·86, p<0·0001) for disease-free survival and 0·76 (0·65–0·88, p=0·0005) for overall survival, despite crossover of 884 (52%) patients from the observation group to trastuzumab therapy. Interpretation 2 years of adjuvant trastuzumab is not more effective than is 1 year of treatment for patients with HER2-positive early breast cancer. 1 year of treatment provides a significant disease-free and overall survival benefit compared with observation and remains the standard of care. Funding F Hoffmann-La Roche (Roche).
The PACS 01 trial compared six cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) with a sequential regimen of three cycles of FEC followed by three cycles of docetaxel (FEC-D) as ...adjuvant treatment for women with node-positive early breast cancer.
Between June 1997 and March 2000, 1,999 patients with operable node-positive breast cancer were randomly assigned to either FEC every 21 days for six cycles, or three cycles of FEC followed by three cycles of docetaxel, both given every 21 days. Hormone-receptor-positive patients received tamoxifen for 5 years after chemotherapy. The primary end point was 5-year disease-free survival (DFS).
Median follow-up was 60 months. Five-year DFS rates were 73.2% with FEC and 78.4% with FEC-D (unadjusted P = .011; adjusted P = .012). Multivariate analysis adjusted for prognostic factors showed an 18% reduction in the relative risk of relapse with FEC-D. Five-year overall survival rates were 86.7% with FEC and 90.7% with FEC-D, demonstrating a 27% reduction in the relative risk of death (unadjusted P = .014; adjusted P = .017). The incidence of grade 3 to 4 neutropenia, the need for hematopoietic growth factor, and incidence of nausea/vomiting were higher with FEC. Docetaxel was associated with more febrile neutropenia in the fourth cycle, stomatitis, edema, and nail disorders. Though rare overall, there were fewer cardiac events after FEC-D (P = .03), attributable mainly to the lower anthracycline cumulative dose.
Sequential adjuvant chemotherapy with FEC followed by docetaxel significantly improves disease-free and overall survival in node-positive breast cancer patients and has a favorable safety profile.
Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen ...receptor (ER) -negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-α (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines.
The TOP trial included 149 patients, 139 of whom were evaluable for response prediction analyses. The primary end point was pathologic complete response (pCR). TOP2A and gene expression profiles were evaluated using pre-epirubicin biopsies. Gene expression data from ER-negative samples of the EORTC (European Organisation for Research and Treatment of Cancer) 10994/BIG (Breast International Group) 00-01 and MDACC (MD Anderson Cancer Center) 2003-0321 neoadjuvant trials were used for validation purposes.
A pCR was obtained in 14% of the evaluable patients in the TOP trial. TOP2A amplification, but not protein overexpression, was significantly associated with pCR (P ≤ .001 v P ≤ .33). We developed an anthracycline-based score (A-Score) combining three signatures: a TOP2A gene signature and two previously published signatures related to tumor invasion and immune response. The A-Score was characterized by a high negative predictive value (NPV; NPV, 0.98; 95% CI, 0.90 to 1.00) overall and in the human epidermal growth factor receptor 2 (HER2) -negative and HER2-positive subpopulations. Its performance was independently confirmed in the anthracycline-based arms of the two validation trials (BIG 00-01: NPV, 0.83; 95% CI, 0.64 to 0.94 and MDACC 2003-0321: NPV, 1.00; 95% CI, 0.80 to 1.00).
Given its high NPV, the A-Score could become, if further validated, a useful clinical tool to identify those patients who do not benefit from anthracyclines and could therefore be spared the non-negligible adverse effects.
To compare a full-dose epirubicin-cyclophosphamide (HEC) regimen with classical cyclophosphamide, methotrexate, and fluorouracil (CMF) therapy and with a moderate-dose epirubicin-cyclophosphamide ...regimen (EC) in the adjuvant therapy of node-positive breast cancer.
Node-positive breast cancer patients who were aged 70 years or younger were randomly allocated to one of the following treatments: CMF for six cycles (oral cyclophosphamide); EC for eight cycles (epirubicin 60 mg/m(2), cyclophosphamide 500 mg/m(2); day 1 every 3 weeks); and HEC for eight cycles (epirubicin 100 mg/m(2), cyclophosphamide 830 mg/m(2); day 1 every 3 weeks).
Two hundred fifty-five, 267, and 255 eligible patients were treated with CMF, EC, and HEC, respectively. Patient characteristics were well balanced among the three arms. One and three cases of congestive heart failure were reported in the EC and HEC arms, respectively. Three cases of acute myeloid leukemia were reported in the HEC arm. After 4 years of median follow-up, no statistically significant differences were observed between HEC and CMF (event-free survival EFS: hazards ratio HR = 0.96, 95% confidence interval CI, 0.70 to 1.31, P =.80; distant-EFS: HR = 0.97, 95% CI, 0.70 to 1.34, P =.87; overall survival OS: HR = 0.97, 95% CI, 0.65 to 1.44, P =.87). HEC is more effective than EC (EFS: HR = 0.73, 95% CI, 0.54 to 0.99, P =.04; distant-EFS: HR = 0.75, 95% CI, 0.55 to 1.02, P =.06; OS HR = 0.69, 95% CI, 0.47 to 1.00, P =.05).
This three-arm study does not show an advantage in favor of an adequately dosed epirubicin-based regimen over classical CMF in the adjuvant therapy of node-positive pre- and postmenopausal women with breast cancer. Moreover, this study confirms that there is a dose-response curve for epirubicin in breast cancer adjuvant therapy.
The 4-year results of this trial demonstrated that a higher dose of epirubicin with cyclophosphamide (HEC) is superior to a lower dose of epirubicin, 60 mg/m(2) (EC), for event-free survival (EFS; ...27% reduction), but is not superior to classical oral cyclophosphamide, methotrexate, and fluorouracil (CMF) in the adjuvant treatment of node-positive breast cancer. Herein we report the 15-year data on efficacy and long-term toxicity of this three-arm Belgian multicenter trial.
Between March 1988 and December 1996, 777 eligible patients were randomly assigned to six cycles of CMF, eight cycles of EC, or eight cycles HEC.
The 15-year EFS was 45% for patients who received CMF, 39% for patients who received EC, and 50% for patients who received HEC. The hazard ratios (HR) were 0.77 for HEC versus EC (95% CI, 0.60 to 0.98; P = .03), 0.90 for HEC versus CMF (P = .39), and 0.86 for EC versus CMF (P = .21). No difference in overall survival (OS) was seen. Cardiac toxicity was more frequent with HEC than with CMF (11 patients v 1 patient; P = .006), but no more than with EC (P = .21).
Treatment with HEC demonstrated superior EFS when compared with lower-dose epirubicin. However, we do not recommend the use of HEC regimen in daily clinical practice, mainly because of the higher risk of cardiotoxicity related to the cumulative doses of epirubicin and the lack of superiority of anthracyclines over CMF in our study.
Fulvestrant (Faslodex™) is a new estrogen receptor (ER) antagonist with no agonist effects that is licensed for the treatment of postmenopausal women with hormone-sensitive advanced breast cancer ...(ABC) who have progressed/recurred on prior antiestrogen therapy. The Faslodex™ Compassionate Use Program (CUP) provides expanded access to fulvestrant in countries where it is not yet available for patients who are not eligible to enter clinical trials. This analysis pools data from 402 patients who received fulvestrant as part of the CUP in Belgium, predominantly as 3rd- to 5th-line endocrine therapy for ABC. Two patients experienced partial responses and 118 experienced stable disease lasting ≥6 months, resulting in an overall clinical benefit rate of 29.9%. Fulvestrant was active in patients with multiple sites of metastases, visceral metastases, human epidermal growth factor receptor 2-positive disease and after heavy endocrine pre-treatment. Fulvestrant was well tolerated, with only six patients (1.5%) discontinuing treatment following adverse events. These data support the findings of previous CUP analyses and Phase II and III trials, suggesting that fulvestrant is a valuable addition to the treatment sequence for postmenopausal women with ABC who have progressed/recurred on prior endocrine therapy.
Highlights • 82 patients (30%) out of 269 eligible patients accepted to participate. • This is one of the longest follow-up (median 18 years) in breast cancer patients. • Epirubicin-treated patients ...had significantly higher heart rate, more abnormal US and lower LVEF by MRI. • A trend towards higher BNP was also observed in the anthracycline-treated group. • No differences were observed in LVEF assessed by echocardiogram or troponin T levels.
Abstract Background The MINDACT (Microarray In Node-negative and 1–3 node positive Disease may Avoid ChemoTherapy) trial investigates the clinical utility of the 70-gene profile (MammaPrint) for the ...selection of breast cancer patients for adjuvant chemotherapy (CT) together with standard clinicopathological criteria. We present the results of the pilot phase consisting of first 800 patients included. Methods MINDACT has enrolled 6600 patients, classified into high or low risk by MammaPrint and clinicopathological risk through Adjuvant! Online. Patients with both clinical (C) and genomic (G) high risks are offered adjuvant CT; those with both C and G low risks do not receive CT; patients with discordant risk are randomised for the decision of adjuvant CT based on C or G risk. CT randomisation of anthracycline-based versus docetaxel/capecitabine and endocrine therapy randomisation between letrozole and tamoxifen → letrozole are offered. Results During the pilot phase 46% of screened patients were enrolled. Main reasons for non-enrolment were node positivity before trial amendment, sample quality problems and failure to meet logistic settings. Among the 800 patients, 386 (48%) were C-low/G-low, 198 (24.8%) as C-high/G-high, 75 (9.4%) as C-low/G-high and 141 (17.6%) as C-high/G-low. In total 216 (27%) cases were discordant. The difference between patients with C-high (42%) and G-high risk (34%) is 8.25% (95% confidence interval (CI), 4.7–11.8%; P < .0001). Compliance with the treatment decision was high (>92%). Conclusions The logistically complex MINDACT trial is feasible in a multinational setting. The proportion of discordant patients, the potential reduction in CT by using the genomic signature and compliance to treatment assignment are in accordance with the trial hypotheses.
•82 patients (30%) out of 269 eligible patients accepted to participate.•This is one of the longest follow-up (median 18 years) in breast cancer patients.•Epirubicin-treated patients had ...significantly higher heart rate, more abnormal US and lower LVEF by MRI.•A trend towards higher BNP was also observed in the anthracycline-treated group.•No differences were observed in LVEF assessed by echocardiogram or troponin T levels.
Epirubicin-based chemotherapy improves the outcome of early breast cancer (BC) patients. However, cardiotoxicity remains an important side effect.
We re-consented node-positive BC patients enrolled in a phase III trial between 1988 and 1996 which compared six cycles of oral cyclophosphamide, methotrexate, fluorouracil (CMF) versus two epirubicin–cyclophosphamide regimens differing by the anthracycline cumulative dose standard-dose epirubicin and cyclophosphamide (SDE) (8×60mg/m2) and higher-dose epirubicin and cyclophosphamide (HDE) (8×100mg/m2). Eligible patients were those who were alive and free of disease and had no contra-indications to the proposed tests (cardiac evaluation). Cardiotoxicity was defined as asymptomatic systolic dysfunction (left ventricular ejection fraction (LVEF)<50%, New York Heart Association (NYHA) Class I) or symptomatic heart failure (NYHA Class II–IV).
Differences in cardiotoxicity between CMF and SDE/HDE were assessed using chi-square and Fisher Exact tests for binary variables and t-test and Wilcoxon test for continuous variables.
Among the 777 patients, 20 cases of CHF were reported (CMF=1, SDE=5, HDE=14; p<0.001). Between September 2010 and June 2013, 82 patients (30%) out of 269 eligible patients accepted to participate in this substudy. Median follow-up was 18years (range 15–24). Epirubicin-treated patients had significantly higher heart rate, more abnormal echocardiograms and LVEF by magnetic resonance imaging (MRI) compared to CMF-treated ones. A trend towards higher BNP was also observed in the SDE/HDE group (P=0.08). No differences were observed in LVEF assessed by echocardiogram or troponin T levels.
Participation rate in this substudy was lower than expected highlighting the complexity of re-calling patients several years after the initial BC diagnosis. After 18years, epirubicin-treated patients had a lower LVEF by MRI, more abnormal echocardiograms, higher heart rates compared to patients treated with CMF. However, no major delayed cardiotoxicity was observed.
Abstract Aim Trastuzumab (T), a humanised monoclonal antibody against HER-2, is active in HER-2-positive MBC patients. However, nearly 60% of the patients do not benefit from T, stressing the need ...for additional predictive markers. The following markers could be implicated in response to T: (1) the magnitude of Her-2 gene amplification; (2) the co-expression of the other HER family receptors, possibly responsible for HER-2 trans-activation; (3) the activated status of HER-2; (4) the activated status of downstream effectors as mitogen-activated protein kinases (MAPKs), p38 and p27. Methods Medical files of patients with MBC treated with T either as a single agent or in combination with chemotherapy (CT) were reviewed. HER family members (EGFR, HER-2, HER-3, HER-4), the phosphorylated forms of EGFR (p-EGFR), HER-2 (p-HER-2) and of the downstream effectors were evaluated in the archival tumours. The correlation between clinical outcome and the expression of these markers was investigated. Results (1) Increasing values of Her-2 amplification were associated with a higher probability of achieving an objective response; (2) no statistical significant correlation between the expression of the HER family receptors was found; (3) p-HER-2 was predictive of response in patients treated with T + CT; (4) a statistically significant correlation between p-ERK 1/2, p-p38 and p-HER-2 emerged, pointing to the activated vertical pathway p-HER-2 → p-MAPKs. Conclusions p-HER-2 and the magnitude of Her-2 amplification were predictive of response to T and their role deserves to be analysed in larger and more homogenous T-treated populations such as those from large phase III trials.
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