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 Fernandez-Cuesta,Catherine Oakman,Priscila Falagan-Lotsch,Ke-seay Smoth,E. 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 +16 more
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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 were explored.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.read more
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TP53 Mutation Spectrum in Breast Cancer Is Subtype Specific and Has Distinct Prognostic Relevance
Laxmi Silwal-Pandit,Hans Kristian Moen Vollan,Suet-Feung Chin,Oscar M. Rueda,Steven McKinney,Tomo Osako,David A. Quigley,Vessela N. Kristensen,Samuel Aparicio,Anne Lise Børresen-Dale,Carlos Caldas,Anita Langerød +11 more
TL;DR: This study reveals that TP53 mutations have different clinical relevance in molecular subtypes of breast cancer, and suggests diverse roles for TP53 in the biology underlying breast cancer development.
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Sequential Adjuvant Epirubicin-Based and Docetaxel Chemotherapy for Node-Positive Breast Cancer Patients:The FNCLCC PACS 01 Trial
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Somatic TP53 Mutations in the Era of Genome Sequencing.
Pierre Hainaut,Gerd P. Pfeifer +1 more
TL;DR: The clinical significance of TP53 mutation is dependent on tumor subtype and context, and understanding the clinical impact of mutation will require integrating mutation-specific information (type, frequency, and predicted impact) with data on haplotypes and on loss of heterozygosity.
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Mutant p53 in breast cancer: potential as a therapeutic target and biomarker.
TL;DR: Since p53 is mutated in the vast majority of TN breast cancers, compounds such as APR-246, PK11007, and COTI-2 are potential treatments for patients with this subform of the disease.
References
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Journal ArticleDOI
p53, the Cellular Gatekeeper for Growth and Division
TL;DR: The author regrets the lack of citations for many important observations mentioned in the text, but their omission is made necessary by restrictions in the preparation of review manuscripts.
Journal ArticleDOI
Blinded by the Light: The Growing Complexity of p53
Karen H. Vousden,Carol Prives +1 more
TL;DR: Control of p53's transcriptional activity is crucial for determining which p53 response is activated, a decision that must be understood if the next generation of drugs that selectively activate or inhibit p53 are to be exploited efficiently.
Journal ArticleDOI
Ki67 Index, HER2 Status, and Prognosis of Patients With Luminal B Breast Cancer
Maggie C.U. Cheang,Stephen Chia,David Voduc,Dongxia Gao,Samuel Leung,Jacqueline E. Snider,Mark A. Watson,Sherri R. Davies,Philip S. Bernard,Joel S. Parker,Charles M. Perou,Matthew J. Ellis,Torsten O. Nielsen +12 more
TL;DR: Luminal B and luminal–HER2-positive breast cancers were statistically significantly associated with poor breast cancer recurrence-free and disease-specific survival in all adjuvant systemic treatment categories.
Journal ArticleDOI
Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database.
Audrey Petitjean,Ewy Mathé,Ewy Mathé,Shunsuke Kato,Chikashi Ishioka,Sean V. Tavtigian,Pierre Hainaut,Magali Olivier +7 more
TL;DR: It is shown that loss of transactivation capacity is a key factor for the selection of missense mutations, and that difference in mutation frequencies is closely related to nucleotide substitution rates along TP53 coding sequence, which provides new insights into the factors that shape mutation patterns and influence mutation phenotype.
Journal ArticleDOI
An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival
Lance D. Miller,Johanna Smeds,Joshy George,Vinsensius B. Vega,Liza A. Vergara,Alexander Ploner,Yudi Pawitan,Per Hall,Sigrid Klaar,Edison T. Liu,Jonas Bergh +10 more
TL;DR: The p53 signature identified a subset of aggressive tumors absent of sequence mutations in p53 yet exhibiting expression characteristics consistent with p53 deficiency because of attenuated p53 transcript levels, showing the primary importance of p53 functional status in predicting clinical breast cancer behavior.
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