Predictive and Prognostic Impact of TP53 Mutations and MDM2 Promoter Genotype in Primary Breast Cancer Patients Treated with Epirubicin or Paclitaxel

et al. (2011) Predictive and Prognostic Impact of TP53 Mutations and MDM2 Promoter Genotype in Primary Breast Cancer Patients Treated with Epirubicin or Paclitaxel. PLoS ONE 6(4): e19249. doi:10.1371/journal.pone.0019249 Predictive and Prognostic Impact of TP53 Mutations and MDM2 Promoter Genotype in Primary Breast Cancer Patients Treated with Epirubicin or Paclitaxel Ranjan Chrisanthar 0 Stian Knappskog 0 Erik Lkkevik 0 Gun Anker 0 Bjrn stenstad 0 Steinar Lundgren 0 Terje Risberg 0 Ingvil Mjaaland 0 Gudbrand Skjnsberg 0 Turid Aas 0 Ellen Schlichting 0 Hans E. Fjo sne 0 Arne Nysted 0 Johan Richard Lillehaug 0 Per Eystein Lnning 0 Hava Karsenty Avraham, Beth Israel Deaconess Medical Center, United States of America 0 1 Section of Oncology, Institute of Medicine, University of Bergen , Bergen , Norway , 2 Department of Oncology, Haukeland University Hospital , Bergen , Norway , 3 Department of Molecular Biology, University of Bergen , Bergen , Norway , 4 Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital , Oslo , Norway , 5 Department of Oncology, Oslo University Hospital , Ullevaal, Oslo , Norway , 6 Department of Oncology, St. Olavs University Hospital , Trondheim , Norway , 7 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology , Trondheim , Norway , 8 Department of Oncology, University Hospital of Northern Norway and Institute of Clinical Medicine, University of Troms , Troms , Norway , 9 Division of Hematology and Oncology, Stavanger University Hospital , Stavanger , Norway , 10 Department of Surgery, Oslo University Hospital, The Norwegian Radium Hospital , Oslo , Norway , 11 Department of Surgery, Haukeland University Hospital , Bergen , Norway , 12 Department of Breast and Endocrine Surgery, Oslo University Hospital , Ullevaal, Oslo , Norway , 13 Department of Surgery, St. Olavs University Hospital , Trondheim , Norway , 14 Department of Surgery, Stavanger University Hospital , Stavanger , Norway 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. - Funding: The study was supported by grants from the Norwegian Cancer Society, The Norwegian Health Region West (Helse Vest) and Norwegian Research Council. Part of the work was performed in the Mohn laboratory for Cancer Research and Haukeland University Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Anthracyclines and taxanes are the chemotherapeutic agents most frequently used in patients with primary as well as metastatic breast cancer. So far, we have a limited understanding of the mechanisms conferring chemoresistance to both drugs in vivo, and we lack suitable predictive factors to select optimal therapy. Previously, we [1,2,3] and others [4] have reported mutations in the TP53 gene (encoding the tumor suppressor protein p53), with mutations affecting the DNA-binding domains L2/L3 of p53 in particular, to be associated with resistance to anthracyclines in breast cancer patients. While in vitro studies have provided conflicting data suggesting a role of p53 to taxane sensitivity [5,6], the result from the only clinical study available evaluating TP53 status with respect to paclitaxel sensitivity revealed no correlation [4]. MDM2 (Mouse Double Minute 2 homolog) is an important regulator of p53 and function by suppressing p53 transcriptional activity [7]. Further, MDM2 amplifications and over-expression have been considered an alternative mechanism of p53 inactivation in several tumor forms [8]. Recently, a single nucleotide polymorphism (SNP) 309 T.G in the MDM2 intronic promoter (rs = 2279744, referred to as SNP309 in this paper) was found associated with increased MDM2 mRNA and protein levels [9]. Subsequently, conflicting evidence has linked the SNP 309G variant to enhanced risk of different cancer forms [10]. The predictive value of TP53 and CHEK2 mutations on response to chemotherapy in the epirubicin arm of this study has previously been reported [3]. Here, we report the effect of TP53 and CHEK2 mutation status on response to paclitaxel. Further, we report the predictive value of MDM2 SNP309 genotype on response to epirubicin as well as paclitaxel treatment together with long-term follow-up data with respect to disease-specific survival (DSS) for patients in both arms up to a cut-off day 5 year 8 months after the final date of randomization. Materials and Methods Ethics Considerations The study protocol was approved by the Regional Ethical Committee (Norwegian Health Region III), including formal Biobank registration in accordance to Norwegian law. The study and protocol is registered under the Norwegian Social Science Data services ((www.nsd/uib/personvern/database/), University of Bergen project no 16297 and Helse Bergen project no 13025). Each patient gave written informed consent. Patients This study enrolled a total of 223 patients with primary stage III breast cancers. Recruitment period was between November 24, 1997 and December 16, 2003. The median age was 51 years (range 2570). Forty-two patients had a T4 tumor, 177 patients had T (...truncated)