Dataset Information

Prognostic and predictive value of TP53 mutations in node-positive breast cancer patients treated with anthracycline- or anthracycline/taxane-based adjuvant therapy: results from the BIG 02-98 phase III trial.

ABSTRACT:

Introduction

Pre-clinical data suggest p53-dependent anthracycline-induced apoptosis and p53-independent taxane activity. However, dedicated clinical research has not defined a predictive role for TP53 gene mutations. The aim of the current study was to retrospectively explore the prognosis and predictive values of TP53 somatic mutations in the BIG 02-98 randomized phase III trial in which women with node-positive breast cancer were treated with adjuvant doxorubicin-based chemotherapy with or without docetaxel.

Methods

The prognostic and predictive values of TP53 were analyzed in tumor samples by gene sequencing within exons 5 to 8. Patients were classified according to p53 protein status predicted from TP53 gene sequence, as wild-type (no TP53 variation or TP53 variations which are predicted not to modify p53 protein sequence) or mutant (p53 nonsynonymous mutations). Mutations were subcategorized according to missense or truncating mutations. Survival analyses were performed using the Kaplan-Meier method and log-rank test. Cox-regression analysis was used to identify independent predictors of outcome.

Results

TP53 gene status was determined for 18% (520 of 2887) of the women enrolled in BIG 02-98. TP53 gene variations were found in 17% (90 of 520). Nonsynonymous p53 mutations, found in 16.3% (85 of 520), were associated with older age, ductal morphology, higher grade and hormone-receptor negativity. Of the nonsynonymous mutations, 12.3% (64 of 520) were missense and 3.6% were truncating (19 of 520). Only truncating mutations showed significant independent prognostic value, with an increased recurrence risk compared to patients with non-modified p53 protein (hazard ratio = 3.21, 95% confidence interval = 1.740 to 5.935, P = 0.0002). p53 status had no significant predictive value for response to docetaxel.

Conclusions

p53 truncating mutations were uncommon but associated with poor prognosis. No significant predictive role for p53 status was detected.

Trial registration

ClinicalTrials.gov NCT00174655.

SUBMITTER: Fernandez-Cuesta L

PROVIDER: S-EPMC3446332 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Publications

Prognostic and predictive value of TP53 mutations in node-positive breast cancer patients treated with anthracycline- or anthracycline/taxane-based adjuvant therapy: results from the BIG 02-98 phase III trial.

Fernández-Cuesta Lynnette L Oakman Catherine C Falagan-Lotsch Priscila P Smoth Ke-Seay KS Quinaux Emmanuel E Buyse Marc M Dolci M Stella MS Azambuja Evandro De ED Hainaut Pierre P Dell'orto Patrizia P Larsimont Denis D Francis Prudence A PA Crown John J Piccart-Gebhart Martine M Viale Giuseppe G Leo Angelo Di AD Olivier Magali M

Breast cancer research : BCR 20120502 3

<h4>Introduction</h4>Pre-clinical data suggest p53-dependent anthracycline-induced apoptosis and p53-independent taxane activity. However, dedicated clinical research has not defined a predictive role for TP53 gene mutations. The aim of the current study was to retrospectively explore the prognosis and predictive values of TP53 somatic mutations in the BIG 02-98 randomized phase III trial in which women with node-positive breast cancer were treated with adjuvant doxorubicin-based chemotherapy wi ...[more]

PMID: 22551440

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Project description:BackgroundTriple-negative breast cancer (TNBC) is a subtype of breast cancer associated with an aggressive clinical course. Adjuvant chemotherapy reduces the risk of recurrence and improves survival in patients with node-positive TNBC. The benefit of anthracycline plus taxane (ATAX) regimens compared with non-anthracycline-containing, taxane-based regimens (TAX) in older women with node-positive TNBC is not well characterised.MethodsUsing the Surveillance, Epidemiology, and End Results-Medicare database, we identified 1106 women with node-positive TNBC diagnosed at age 66 years and older between 2010 and 2015. We compared patient clinical characteristics according to adjuvant chemotherapy regimen (chemotherapy versus no chemotherapy and ATAX versus TAX). Logistic regression was performed to estimate the odds ratios (OR) and 95% confidence intervals (CIs). Kaplan-Meier survival curves were generated to estimate 3-year overall survival (OS) and cancer-specific survival (CSS). Cox proportional hazard models were used to analyse OS and CSS while controlling for patient and tumour characteristics.ResultsOf the 1106 patients in our cohort, 767 (69.3%) received adjuvant chemotherapy with ATAX (364/767, 47.5%), TAX (297/767, 39%) or other regimens (106/767, 13.8%). Independent predictors of which patients were more likely to receive ATAX versus TAX included more extensive nodal involvement (≥4), age, marital/partner status and non-cardiac comorbidities. There was a statistically significant improvement in 3-year CSS (81.8% versus 71.4%) and OS (70.7% versus 51.3%) with the use of any chemotherapy in our cohort (P < 0.01). Three-year CSS and OS for patients who received ATAX versus TAX were similar at 82.8% versus 83.7% (P = 0.80) and 74.2% versus 72.7% (P = 0.79), respectively. There was a trend towards improved CSS and OS in patients with four or more positive lymph nodes who received ATAX versus TAX (hazard ratio 0.66, 95% CI: 0.36-1.23, P = 0.19 and hazard ratio 0.68, 95% CI: 0.41-1.14, P = 0.14, respectively).ConclusionAmong older women with node-positive TNBC, a majority of patients received adjuvant chemotherapy, which was associated with an improvement in CSS and OS. When compared with TAX chemotherapy, there was a trend towards better outcomes with ATAX for patients with ≥4 nodes.

Project description: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.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 NCT00017095.928 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).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.US National Cancer Institute, La Ligue Nationale Contre le Cancer, European Union, Pharmacia, and Sanofi-Aventis.

Dataset Information

Prognostic and predictive value of TP53 mutations in node-positive breast cancer patients treated with anthracycline- or anthracycline/taxane-based adjuvant therapy: results from the BIG 02-98 phase III trial.

Introduction

Methods

Results

Conclusions

Trial registration

Publications

Prognostic and predictive value of TP53 mutations in node-positive breast cancer patients treated with anthracycline- or anthracycline/taxane-based adjuvant therapy: results from the BIG 02-98 phase III trial.

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