TP53 status for prediction of sensitivity to taxane versus non-taxane neoadjuvant chemotherapy in breast cancer (EORTC 10994/BIG 1-00): a randomised phase 3 trial
Mené sur 1 856 patientes d'âge inférieur à 71 ans et atteintes d'un cancer du sein, cet essai de phase III évalue l'association entre la présence d'une mutation de TP53 et la réponse à une chimiothérapie néo-adjuvante à base de taxanes ou d'anthracyclines
TP53has a crucial role in the DNA damage response. We therefore tested the hypothesis that taxanes confer a greater advantage than do anthracyclines on breast cancers with mutatedTP53than in those with wild-typeTP53. In an open-label, phase 3 study, women (age <71 years) with locally advanced, inflammatory, or large operable breast cancers were randomly assigned in a 1:1 ratio to either a standard anthracycline regimen (six cycles of intravenous fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2every 21 days [FEC100], or fluorouracil 600 mg/m2, epirubicin 75 mg/m2, cyclophosphamide 900 mg/m2[tailored FEC] starting on day 1 and then every 21 days) or a taxane-based regimen (three cycles of docetaxel 100 mg/m2, intravenously infused over 1 h on day 1 every 21 days, followed by three cycles of intravenous epirubicin 90 mg/m2and docetaxel 75 mg/m2on day 1 every 21 days [T-ET]) at 42 centres in Europe. Randomisation was by use of a minimisation method that stratified patients by institution and initial tumour stage. The primary endpoint was progression-free survival (PFS) according toTP53status. Analysis was by intention to treat. This is the final analysis of this trial. The study is registered withClinicalTrials.gov, numberNCT00017095. 928 patients were enrolled in the FEC group and 928 in the T-ET group.TP53status was not assessable for 183 (20%) patients in the FEC group and 204 (22%) patients in the T-ET group mainly because of low tumour-cell content in the biopsy. 361 primary endpoint events were recorded in the FEC group and 314 in the T-ET group. In patients withTP53-mutated tumours, 5-year PFS was 59·5% (95% CI 53·4?65·1) in the T-ET group (n=326) and 55·3% (49·2?60·9) in the FEC group (n=318; hazard ratio 0·84, 98% CI 0·63?1·14; p=0·17). In patients withTP53wild-type tumours, 5-year PFS was 66·8% (95% CI 61·4?71·6) in the T-ET group (n=398) and 64·7% (59·6?69·4) in the FEC group (n=427; 0·89, 98% CI 0·68?1·18; p=0·35). For all patients, irrespective ofTP53status, 5-year PFS was 65·1% (95% CI 61·6?68·3) in the T-ET group and 60·8% (57·3?64·2) in the FEC group (0·85, 98% CI 0·71?1·02; p=0·035). At the sites using FEC100 versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (75 [9%] of 803vs173 [21%] of 809, respectively), and neutropenia (653 [81%]vs730 [90%], respectively). At the sites using tailored FEC versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (ten [8%] of 118vs26 [22%] of 116, respectively), and neutropenia (100 [85%]vs115 [99%], respectively). Two patients died of toxicity during or within 30 days of chemotherapy completion and without disease relapse (one in each group). AlthoughTP53status was prognostic for overall survival, it was not predictive of preferential sensitivity to taxanes.TP53status tested by use of the yeast assay in this patient population cannot be used to select patients for an anthracycline-based chemotherapy versus a taxane-based chemotherapy. US National Cancer Institute, La Ligue Nationale Contre le Cancer, European Union, Pharmacia, and Sanofi-Aventis.
The Lancet Oncology , résumé, 2010