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

Abstract

Background: TP53 has 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 mutated TP53 than in those with wild-type TP53.

Methods: 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/m² every 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/m² and docetaxel 75 mg/m² on 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 to TP53 status. Analysis was by intention to treat. This is the final analysis of this trial. The study is registered with ClinicalTrials.gov, number NCT00017095.

Findings: 928 patients were enrolled in the FEC group and 928 in the T-ET group. TP53 status 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 with TP53-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 with TP53 wild-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 of TP53 status, 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 803 vs 173 [21%] of 809, respectively), and neutropenia (653 [81%] vs 730 [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 118 vs 26 [22%] of 116, respectively), and neutropenia (100 [85%] vs 115 [99%], respectively). Two patients died of toxicity during or within 30 days of chemotherapy completion and without disease relapse (one in each group).

Interpretation: Although TP53 status was prognostic for overall survival, it was not predictive of preferential sensitivity to taxanes. TP53 status 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.

Funding: US National Cancer Institute, La Ligue Nationale Contre le Cancer, European Union, Pharmacia, and Sanofi-Aventis.

Conflict of interest statement

Conflicts of interest

The other authors declare that they have no conflicts of interest.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Outline of the assay p53 mRNA is extracted from the tumour biopsies, converted to cDNA, and amplified by PCR. The p53 PCR product is transfected into yeast, where it is cloned into a yeast expression vector by homologous recombination. Every yeast colony contains the progeny of a single p53 mRNA. P53 is a transcription factor. When wild type p53 protein is expressed within the yeast cell, it binds to a p53 binding site in a p53 responsive promoter in an ADE2 reporter gene and activates expression of Ade2 protein. Mutant p53 is unable to bind to DNA and fails to induce Ade2 expression. Yeast containing Ade2 protein form white colonies. Yeast lacking Ade2 form red colonies.

Figure 2

CONSORT diagram Abbreviations: FEC100: 5-fluorouracil 500mg/m2, epirubicin 100mg/m2, cyclophosphamide 500mg/m2 all intravenously every 21 days for 6 cycles; Tailored FEC: first cycle on day 1 with 5-fluorouracil 600 mg/m2, epirubicin 75 mg/m2, cyclophosphamide 900 mg/m2, all intravenously every 21 days, with granulocyte colony-stimulating factor (G-CSF) 5 ug/kg on days 5–12 and ciprofloxacin orally 500 mg twice daily on days 2–15, subsequent cycles were modified for each individual as previously described for 6 cycles (maximal epirubicin dose 120 mg/m2/cycle and cyclophosphamide dose 1200 mg/m2/cycle); T-ET: docetaxel 100mg/m2 every 21 days for 3 cycles followed by epirubicin 90mg/m2 and docetaxel 75mg/m2 every 21 days without G-CSF for 3 cycles; pts: patients; CT: chemotherapy.

Figure 3

Trial profile Abbreviations: (1) Most important reasons for ineligibility (total=22): Clinical : T1, N0–1 = 3; M1 = 6 ; Psychiatric disorder = 2 ; Inappropriate type of cancer = 2 ; Bilateral BC = 7 ; Prior treatment not allowed = 1 ; Withdrawn consent = 1 (2) Reasons for inability to include patients in the planned testing (total=370): No sample = 67; Not assessable = 6; Samples that could not be tested because

Figure 4

Distribution of the percentage (%) of red colonies The percentage of red colonies depends on the amount of mutant mRNA in the tumour cells in the biopsy, the amount of wild type mRNA in the normal cells in the biopsy, and the background. The distribution is modeled as three peaks. The peak on the left corresponds to samples containing only wild type p53 (the background in the assay is thus 11% ± 4%; the main cause is PCR mutations. The peak on the right corresponds to tumours with homozygous p53 mutations (76% ± 14%). The mean wild type p53 mRNA content in the homozygous group is thus ~27% (24% plus the background). Between the wild type and homozygous peaks there is a third peak that is best explained by nonsense p53 mutations or heterozygous (particularly dominant negative) missense p53 mutations, but could potentially be explained by intra-tumoural heterogeneity, an intense inflammatory infiltrate or a florid stromal reaction.

Figure 5

(a) Progression-free survival and (b) Overall survival in the 3 groups by treatment arm: p53 mutated group, p53 wild type group and all patients Abbreviations HR: hazard ratio; 5 yr PFS: 5 year progression-free survival; 5yr OS: 5 year overall survival; CI: confidence interval; FEC: 5-fluorouracil, epirubicin, and cyclophosphamide; T-ET: docetaxel followed by epirubicin and docetaxel.

Figure 5

(a) Progression-free survival and (b) Overall survival in the 3 groups by treatment arm: p53 mutated group, p53 wild type group and all patients Abbreviations HR: hazard ratio; 5 yr PFS: 5 year progression-free survival; 5yr OS: 5 year overall survival; CI: confidence interval; FEC: 5-fluorouracil, epirubicin, and cyclophosphamide; T-ET: docetaxel followed by epirubicin and docetaxel.

Figure 6

Hazard ratios for progression-free survival by clinical characteristics, choice of regimen, biological markers, and simplified subtypes Abbreviations LA: locally advanced; LO: large operable; Menop. > CT: menopausal status post chemotherapy; Miss: missing; ER: estrogen receptor; PgR: progesterone receptor; HER2: human epidermal growth factor receptor 2; +: positive; −: negative; trip. Neg: triple negative; T-ET: docetaxel followed by epirubicin and docetaxel; FEC: 5-fluorouracil, epirubicin, and cyclophosphamide; HR: hazard ratio; CI: confidence interval.