Molecular Carcinogenesis Group, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 8, France.
Breast Cancer Res. 2012 May 2;14(3):R70. doi: 10.1186/bcr3179.
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.
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.
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.
p53 truncating mutations were uncommon but associated with poor prognosis. No significant predictive role for p53 status was detected.
ClinicalTrials.gov NCT00174655.
临床前数据表明，p53 依赖性蒽环类药物诱导的细胞凋亡和 p53 非依赖性紫杉烷活性。然而，专门的临床研究尚未确定 TP53 基因突变的预测作用。本研究的目的是回顾性探讨 BIG 02-98 随机 III 期临床试验中 TP53 体细胞突变的预后和预测价值，该试验中，淋巴结阳性乳腺癌患者接受辅助多柔比星为基础的化疗，联合或不联合多西紫杉醇。
通过基因测序在外显子 5 至 8 中分析 TP53 的预后和预测价值。根据从 TP53 基因序列预测的 p53 蛋白状态，将患者分为野生型（无 TP53 变异或预测不改变 p53 蛋白序列的 TP53 变异）或突变型（p53 非同义突变）。根据错义或截断突变对突变进行亚分类。使用 Kaplan-Meier 方法和对数秩检验进行生存分析。Cox 回归分析用于确定预后的独立预测因素。
在 BIG 02-98 中入组的 2887 名女性中有 18%（520 名）确定了 TP53 基因状态。在 520 名患者中发现了 17%（90 名）的 TP53 基因变异。发现 16.3%（520 名中的 85 名）存在非同义 p53 突变，与年龄较大、导管形态、更高的分级和激素受体阴性相关。在非同义突变中，12.3%（520 名中的 64 名）为错义突变，3.6%为截断突变（520 名中的 19 名）。只有截断突变具有显著的独立预后价值，与非修饰 p53 蛋白的患者相比，复发风险增加（风险比=3.21，95%置信区间=1.740 至 5.935，P=0.0002）。p53 状态对多西紫杉醇的反应无显著预测价值。
p53 截断突变很少见，但与预后不良相关。未检测到 p53 状态的显著预测作用。
ClinicalTrials.gov NCT00174655。
