Predictive and Prognostic Impact of TP53 Mutations and MDM2 Promoter Genotype in Primary Breast Cancer Patients Treated with Epirubicin or Paclitaxel
| Autor: | Bjørn Østenstad, Per Eystein Lønning, Ellen Schlichting, Gudbrand Skjønsberg, Terje Risberg, Gun Anker, Johan R. Lillehaug, Ingvil Mjaaland, Ranjan Chrisanthar, Erik Løkkevik, Arne Nysted, Turid Aas, Hans E. Fjøsne, Stian Knappskog, Steinar Lundgren |
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| Přispěvatelé: | Norges teknisk-naturvitenskapelige universitet, Det medisinske fakultet, Institutt for kreftforskning og molekylær medisin |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Oncology
medicine.medical_treatment Cancer Treatment lcsh:Medicine Cohort Studies chemistry.chemical_compound Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762 [VDP] Breast Tumors Genotype lcsh:Science Promoter Regions Genetic skin and connective tissue diseases Multidisciplinary Obstetrics and Gynecology Proto-Oncogene Proteins c-mdm2 Prognosis Paclitaxel Medicine Female Research Article Epirubicin medicine.drug medicine.medical_specialty VDP::Medisinske Fag: 700::Basale medisinske odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 Antineoplastic Agents Breast Neoplasms VDP::Medical disciplines: 700::Basic medical dental and veterinary science disciplines: 710::Medical genetics: 714 Polymorphism Single Nucleotide Breast cancer Internal medicine Breast Cancer Genetics Cancer Genetics medicine Humans Biology CHEK2 neoplasms Survival analysis DNA Primers Chemotherapy Base Sequence business.industry VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762 lcsh:R Cancers and Neoplasms Chemotherapy and Drug Treatment Genes p53 medicine.disease Survival Analysis VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762 Regimen chemistry Mutation Cancer research lcsh:Q business |
| Zdroj: | PLoS ONE PLoS ONE, Vol 6, Iss 4, p e19249 (2011) |
| Popis: | Background: TP53 mutations have been associated with resistance to anthracyclines but not to taxanes in breast cancer patients. The MDM2 promoter single nucleotide polymorphism (SNP) T309G increases MDM2 activity and may reduce wildtype p53 protein activity. Here, we explored the predictive and prognostic value of TP53 and CHEK2 mutation status together with MDM2 SNP309 genotype in stage III breast cancer patients receiving paclitaxel or epirubicin monotherapy. Experimental Design: Each patient was randomly assigned to treatment with epirubicin 90 mg/m2 (n= 109) or paclitaxel 200 mg/m2 (n = 114) every 3rd week as monotherapy for 4–6 cycles. Patients obtaining a suboptimal response on first-line treatment requiring further chemotherapy received the opposite regimen. Time from last patient inclusion to follow-up censoring was 69 months. Each patient had snap-frozen tumor tissue specimens collected prior to commencing chemotherapy. Principal Findings: While TP53 and CHEK2 mutations predicted resistance to epirubicin, MDM2 status did not. Neither TP53/ CHEK2 mutations nor MDM2 status was associated with paclitaxel response. Remarkably, TP53 mutations (p = 0.007) but also MDM2 309TG/GG genotype status (p = 0.012) were associated with a poor disease-specific survival among patients having paclitaxel but not patients having epirubicin first-line. The effect of MDM2 status was observed among individuals harbouring wild-type TP53 (p = 0.039) but not among individuals with TP53 mutated tumors (p.0.5). Conclusion: TP53 and CHEK2 mutations were associated with lack of response to epirubicin monotherapy. In contrast, TP53 mutations and MDM2 309G allele status conferred poor disease-specific survival among patients treated with primary paclitaxel but not epirubicin monotherapy. publishedVersion |
| Databáze: | OpenAIRE |
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