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

Lynnette Fernández-Cuesta, Catherine Oakman, Priscila Falagan-Lotsch, Ke-Seay Smoth, Emmanuel Quinaux, Marc Buyse, M Stella Dolci, Evandro De Azambuja, Pierre Hainaut, Patrizia Dell'orto, Denis Larsimont, Prudence A Francis, John Crown, Martine Piccart-Gebhart, Giuseppe Viale, Angelo Di Leo, Magali Olivier

Research output: Contribution to journalArticle

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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.
LanguageEnglish
Article numberR70
Number of pages13
JournalBreast Cancer Research
Volume14
Issue number3
DOIs
Publication statusPublished - 2 May 2012

Fingerprint

Anthracyclines
Breast Neoplasms
Mutation
p53 Genes
docetaxel
Therapeutics
taxane
Proteins
Survival Analysis
Doxorubicin
Exons
Regression Analysis
Hormones
Confidence Intervals
Apoptosis
Recurrence
Drug Therapy

Keywords

  • young adult
  • disease-free survival
  • Ki-67 antigen
  • tumor suppressor protein p53
  • apoptosis
  • antineoplastic agents
  • lymphatic metastasis
  • humans
  • retrospective studies
  • aged
  • genes, p53
  • adult
  • antineoplastic combined chemotherapy protocols
  • adolescent
  • ahemotherapy, adjuvant
  • survival analysis
  • sequence deletion
  • receptor, erbB-2
  • breast neoplasms
  • taxoids
  • sequence analysis, DNA
  • mutation, missense
  • doxorubicin
  • base sequence
  • receptors, progesterone
  • middle aged
  • adenocarcinoma
  • female
  • receptors, estrogen

Cite this

Fernández-Cuesta, Lynnette ; Oakman, Catherine ; Falagan-Lotsch, Priscila ; Smoth, Ke-Seay ; Quinaux, Emmanuel ; Buyse, Marc ; Dolci, M Stella ; Azambuja, Evandro De ; Hainaut, Pierre ; Dell'orto, Patrizia ; Larsimont, Denis ; Francis, Prudence A ; Crown, John ; Piccart-Gebhart, Martine ; Viale, Giuseppe ; Leo, Angelo Di ; Olivier, Magali. / 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. In: Breast Cancer Research. 2012 ; Vol. 14, No. 3.
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title = "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.",
keywords = "young adult, disease-free survival, Ki-67 antigen, tumor suppressor protein p53, apoptosis, antineoplastic agents, lymphatic metastasis, humans, retrospective studies, aged, genes, p53, adult, antineoplastic combined chemotherapy protocols, adolescent, ahemotherapy, adjuvant, survival analysis, sequence deletion, receptor, erbB-2, breast neoplasms, taxoids, sequence analysis, DNA, mutation, missense, doxorubicin, base sequence, receptors, progesterone, middle aged, adenocarcinoma, female, receptors, estrogen",
author = "Lynnette Fern{\'a}ndez-Cuesta and Catherine Oakman and Priscila Falagan-Lotsch and Ke-Seay Smoth and Emmanuel Quinaux and Marc Buyse and Dolci, {M Stella} and Azambuja, {Evandro De} and Pierre Hainaut and Patrizia Dell'orto and Denis Larsimont and Francis, {Prudence A} and John Crown and Martine Piccart-Gebhart and Giuseppe Viale and Leo, {Angelo Di} and Magali Olivier",
year = "2012",
month = "5",
day = "2",
doi = "10.1186/bcr3179",
language = "English",
volume = "14",
journal = "Breast Cancer Research",
issn = "1465-5411",
number = "3",

}

Fernández-Cuesta, L, Oakman, C, Falagan-Lotsch, P, Smoth, K-S, Quinaux, E, Buyse, M, Dolci, MS, Azambuja, ED, Hainaut, P, Dell'orto, P, Larsimont, D, Francis, PA, Crown, J, Piccart-Gebhart, M, Viale, G, Leo, AD & Olivier, M 2012, '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' Breast Cancer Research, vol. 14, no. 3, R70. https://doi.org/10.1186/bcr3179

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; Oakman, Catherine; Falagan-Lotsch, Priscila; Smoth, Ke-Seay; Quinaux, Emmanuel; Buyse, Marc; Dolci, M Stella; Azambuja, Evandro De; Hainaut, Pierre; Dell'orto, Patrizia; Larsimont, Denis; Francis, Prudence A; Crown, John; Piccart-Gebhart, Martine; Viale, Giuseppe; Leo, Angelo Di; Olivier, Magali.

In: Breast Cancer Research, Vol. 14, No. 3, R70, 02.05.2012.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Prognostic and predictive value of TP53 mutations in node-positive breast cancer patients treated with anthracycline- or anthracycline/taxane-based adjuvant therapy

T2 - Breast Cancer Research

AU - Fernández-Cuesta, Lynnette

AU - Oakman, Catherine

AU - Falagan-Lotsch, Priscila

AU - Smoth, Ke-Seay

AU - Quinaux, Emmanuel

AU - Buyse, Marc

AU - Dolci, M Stella

AU - Azambuja, Evandro De

AU - Hainaut, Pierre

AU - Dell'orto, Patrizia

AU - Larsimont, Denis

AU - Francis, Prudence A

AU - Crown, John

AU - Piccart-Gebhart, Martine

AU - Viale, Giuseppe

AU - Leo, Angelo Di

AU - Olivier, Magali

PY - 2012/5/2

Y1 - 2012/5/2

N2 - 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.

AB - 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.

KW - young adult

KW - disease-free survival

KW - Ki-67 antigen

KW - tumor suppressor protein p53

KW - apoptosis

KW - antineoplastic agents

KW - lymphatic metastasis

KW - humans

KW - retrospective studies

KW - aged

KW - genes, p53

KW - adult

KW - antineoplastic combined chemotherapy protocols

KW - adolescent

KW - ahemotherapy, adjuvant

KW - survival analysis

KW - sequence deletion

KW - receptor, erbB-2

KW - breast neoplasms

KW - taxoids

KW - sequence analysis, DNA

KW - mutation, missense

KW - doxorubicin

KW - base sequence

KW - receptors, progesterone

KW - middle aged

KW - adenocarcinoma

KW - female

KW - receptors, estrogen

UR - http://breast-cancer-research.com/

U2 - 10.1186/bcr3179

DO - 10.1186/bcr3179

M3 - Article

VL - 14

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 3

M1 - R70

ER -