International Agency for Research on Cancer, Lyon, France; Central Laboratory, Jinan Central Hospital, Jinan, China.
Department of Biostatistics, Gustave-Roussy, Paris, France; Inserm U1018, CESP, Paris-Sud and Paris-Saclay University, Villejuif, France; Ligue contre le Cancer, Paris, France.
J Thorac Oncol. 2016 Jun;11(6):850-61. doi: 10.1016/j.jtho.2016.02.002. Epub 2016 Feb 17.
Tumor protein p53 gene (TP53) mutations are common in stage I through III non-small cell lung cancer, but clinical trials have shown inconsistent results regarding their relationship to the effects of adjuvant therapy. The objective is to clarify their putative prognostic and predictive effects.
A pooled analysis of TP53 mutations (exons 5-8) was conducted in four randomized trials (the International Adjuvant Lung Cancer Trial, J BRonchus 10, Cancer and Leukemia Group B-9633, and Adjuvant Navelbine International Trialist Association trial) of platinum-based adjuvant chemotherapy (ACT) versus observation (OBS). Hazard ratios (HRs) and 95% confidence intervals (CIs) of mutant versus wild-type (WT) TP53 for overall survival (OS) and disease-free survival (DFS) were estimated using a multivariable Cox model stratified on trial and adjusted on sex, age, and clinicopathological variables. Predictive value was evaluated with an interaction between treatment and TP53.
A total of 1209 patients (median follow-up 5.5 years) were included. There were 573 deaths (47%) and 653 DFS events (54%). Mutations (434 [36%]) had no prognostic effect (OBS HROS = 0.99, 95% CI: 0.77-1.28, p = 0.95; HRDFS = 0.99, 95% CI: 0.78-1.25, p = 0.92) but were marginally predictive of benefit from ACT for OS (test for interaction: OS, p = 0.06; DFS, p = 0.11). Patients with WT TP53 had a tendency toward better outcomes with ACT than did those in the OBS group (HROS = 0.77, 95% CI: 0.62-0.95, p = 0.02; HRDFS = 0.75, 95% CI: 0.62-0.92, p = 0.005). In the ACT arm, a deleterious effect of mutant versus WT TP53 was observed (HROS = 1.40, 95% CI: 1.10-1.78, p = 0.006; HRDFS = 1.31, 95% CI: 1.04-1.64, p = 0.02).
TP53 mutation had no prognostic effect but was marginally predictive for survival from ACT. In patients who received ACT, TP53 mutation tended to be associated with shorter survival than wild-type TP53.
肿瘤蛋白 p53 基因（TP53）突变常见于 I 期至 III 期非小细胞肺癌，但临床试验表明其与辅助治疗效果的关系并不一致。本研究旨在明确其潜在的预后和预测作用。
对四项随机临床试验（国际辅助肺癌试验、J BRonchus 10 试验、癌症和白血病组 B-9633 试验和辅助长春瑞滨国际试验者协会试验）中基于铂的辅助化疗（ACT）与观察（OBS）比较的 TP53 突变（外显子 5-8）进行了汇总分析。使用多变量 Cox 模型，按试验分层并调整性别、年龄和临床病理变量，估计突变型与野生型（WT）TP53 的总生存期（OS）和无病生存期（DFS）的风险比（HRs）和 95%置信区间（CIs）。通过治疗与 TP53 之间的交互作用评估预测价值。
共纳入 1209 例患者（中位随访 5.5 年），其中 573 例死亡（47%）和 653 例DFS 事件（54%）。突变（434 [36%]）无预后作用（OBS HROS=0.99，95%CI：0.77-1.28，p=0.95；HRDFS=0.99，95%CI：0.78-1.25，p=0.92），但对 OS 获益的 ACT 有一定的预测作用（检验交互作用：OS，p=0.06；DFS，p=0.11）。与 OBS 组相比，WT TP53 患者接受 ACT 的结局更好（HROS=0.77，95%CI：0.62-0.95，p=0.02；HRDFS=0.75，95%CI：0.62-0.92，p=0.005）。在 ACT 组中，观察到突变型与 WT TP53 相比生存获益较差（HROS=1.40，95%CI：1.10-1.78，p=0.006；HRDFS=1.31，95%CI：1.04-1.64，p=0.02）。
TP53 突变无预后作用，但对 ACT 生存有一定的预测作用。在接受 ACT 的患者中，TP53 突变与 WT TP53 相比，其生存时间往往更短。
