Predictive and prognostic impact of TP53 mutations and MDM2 promoter genotype in primary breast cancer patients treated with epirubicin or paclitaxel.
Predictive and prognostic impact of TP53 mutations and MDM2 promoter genotype in primary breast cancer patients treated with epirubicin or paclitaxel.
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DOI：
10.1371/journal.pone.0019249
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发表时间：
2011-04-27
期刊：
影响因子：
3.7
通讯作者：
Lønning PE
中科院分区：
文献类型：
--
作者：
Chrisanthar R;Knappskog S;Løkkevik E;Anker G;Ostenstad B;Lundgren S;Risberg T;Mjaaland I;Skjønsberg G;Aas T;Schlichting E;Fjösne HE;Nysted A;Lillehaug JR;Lønning PE
TP 53突变与乳腺癌患者对蒽环类药物的耐药性有关，但与紫杉烷类药物无关。MDM 2启动子单核苷酸多态性（SNP）T309 G增加MDM 2活性，并可能降低野生型p53蛋白活性。在此，我们探讨了TP 53和CHEK 2突变状态以及MDM 2 SNP 309基因型在接受紫杉醇或表阿霉素单药治疗的III期乳腺癌患者中的预测和预后价值。每例患者随机分为两组，分别给予表阿霉素90 mg/m2（n = 109）和紫杉醇200 mg/m2（n = 114），每3周1次，治疗4-6个周期。 需要进一步化疗的一线治疗获得次优缓解的患者接受相反的方案。从末例患者入选到随访删失的时间为69个月。每例患者在开始化疗前采集了速冻肿瘤组织标本。虽然TP 53和CHEK 2突变预测了对表阿霉素的耐药性，但MDM 2状态不能。TP 53/CHEK 2突变和MDM 2状态均与紫杉醇反应无关。值得注意的是，TP 53突变（p = 0.007）以及MDM 2 309 TG/GG基因型状态（p = 0.012）与接受紫杉醇治疗的患者的疾病特异性生存率差相关，但与接受表阿霉素一线治疗的患者无关。 在携带野生型TP 53的个体中观察到MDM 2状态的影响（p = 0.039），但在具有TP 53突变肿瘤的个体中未观察到MDM 2状态的影响（p>0.5）。 TP 53和CHEK 2突变与表阿霉素单药治疗无效相关。相比之下，TP 53突变和MDM 2 309 G等位基因状态使接受紫杉醇治疗而非表阿霉素单药治疗的患者的疾病特异性生存率较差。
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 wild-type 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. 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. 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). 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.
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