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

Hdl Handle:
http://hdl.handle.net/10147/226895
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
Authors:
Fernandez-Cuesta, Lynnette; Oakman, Catherine; Falagan-Lotsch, Priscila; Smoth, Ke-seay; Quinaux, Emmanuel; Buyse, Marc; Dolci, M STELLA; De Azambuja, Evandro; Hainaut, Pierre; Dell'Orto, Patrizia; Larsimont, Denis; Francis, Prudence A; Crown, John; Piccart-Gebhart, Martine; Viale, Giuseppe; Di Leo, Angelo; Olivier, Magali
Citation:
Breast Cancer Research. 2012 May 02;14(3):R70
Issue Date:
2-May-2012
URI:
http://dx.doi.org/10.1186/bcr3179; http://hdl.handle.net/10147/226895
Abstract:
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
Item Type:
Journal Article

Full metadata record

DC FieldValue Language
dc.contributor.authorFernandez-Cuesta, Lynnette-
dc.contributor.authorOakman, Catherine-
dc.contributor.authorFalagan-Lotsch, Priscila-
dc.contributor.authorSmoth, Ke-seay-
dc.contributor.authorQuinaux, Emmanuel-
dc.contributor.authorBuyse, Marc-
dc.contributor.authorDolci, M STELLA-
dc.contributor.authorDe Azambuja, Evandro-
dc.contributor.authorHainaut, Pierre-
dc.contributor.authorDell'Orto, Patrizia-
dc.contributor.authorLarsimont, Denis-
dc.contributor.authorFrancis, Prudence A-
dc.contributor.authorCrown, John-
dc.contributor.authorPiccart-Gebhart, Martine-
dc.contributor.authorViale, Giuseppe-
dc.contributor.authorDi Leo, Angelo-
dc.contributor.authorOlivier, Magali-
dc.date.accessioned2012-05-31T13:43:14Z-
dc.date.available2012-05-31T13:43:14Z-
dc.date.issued2012-05-02-
dc.identifier.citationBreast Cancer Research. 2012 May 02;14(3):R70-
dc.identifier.urihttp://dx.doi.org/10.1186/bcr3179-
dc.identifier.urihttp://hdl.handle.net/10147/226895-
dc.description.abstractAbstract 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-
dc.titlePrognostic 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-
dc.typeJournal Article-
dc.language.rfc3066en-
dc.rights.holderFernandez-Cuesta et al.; licensee BioMed Central Ltd.-
dc.description.statusPeer Reviewed-
dc.date.updated2012-05-28T19:02:45Z-
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