TP53突变与接受一线化疗加贝伐单抗的卵巢癌患者生存分析：MITO16A/MaNGO OV-2研究结果

TP53 mutations and survival in ovarian carcinoma patients receiving first-line chemotherapy plus bevacizumab: Results of the MITO16A/MaNGO OV-2 study

INTERNATIONAL JOURNAL OF CANCER

影响因子:4.7

分区:医学2区 / 肿瘤学2区

发表日期:2025 Mar 01

作者: Eliana Bignotti, Vittorio Simeon, Laura Ardighieri, Elisabetta Kuhn, Sergio Marchini, Daniela Califano, Sabrina Chiara Cecere, Mattia Bugatti, Anna Spina, Giosuè Scognamiglio, Lara Paracchini, Daniela Russo, Laura Arenare, Germana Tognon, Domenica Lorusso, Luca Beltrame, Maurizio D'Incalci, Enrico Sartori, Andrea De Censi, Franco Odicino, Francesco Perrone, Paolo Chiodini, Sandro Pignata

DOI: 10.1002/ijc.35203

摘要

目前尚无生物标志物能明确界定对贝伐单抗（BEV）反应的患者亚群，后者是晚期卵巢癌（OC）一种有效的治疗选择。在MITO16A/MaNGO OV-2试验——一项针对晚期OC一线化疗联合BEV的IV期临床研究中，我们通过新一代测序评估了202例样本中的TP53突变情况，并利用免疫组化（IHC）检测了311例样本中的p53表达。我们进一步分析了TP53突变的类型、功能和位置，并结合患者的临床病理特征和生存数据。发现未知功能的TP53错义突变（归类为未分类突变）在我们的患者群中占主导（44.4%），且与显著改善的总生存期（OS）相关（单变量分析HR=0.43，95% CI=0.20-0.92，p=.03；多变量分析HR=0.39，95% CI=0.18-0.86，p=.02）。TP53突变分析与IHC检测的一致率为91%。观察到p53过表达组的OS风险比野生型低（HR=0.70），但未达到统计学显著性（p=.31，95% CI=0.36-1.38）。结果显示，未分类TP53突变在接受贝伐单抗联合化疗的OC患者中具有良好的预后意义，特别是这类突变代表一部分具有明显生存优势的患者群体，其预后与其他临床病理特征无关。这些发现提示未来需要更多研究以确认TP53突变在贝伐单抗治疗的OC患者中的预后作用，并值得在未来随机对照临床试验中评估其潜在的预测价值。

Abstract

To date, there are no biomarkers that define a patient subpopulation responsive to bevacizumab (BEV), an effective treatment option for advanced ovarian carcinoma (OC). In the context of the MITO16A/MaNGO OV-2 trial, a Phase IV study of chemotherapy combined with BEV in first-line treatment of advanced OC, we evaluated TP53 mutations by next-generation sequencing and p53 expression by immunohistochemistry (IHC) on 202 and 311 cases, respectively. We further correlated TP53 mutations in terms of type, function, and site, and IHC data with patients' clinicopathological characteristics and survival. TP53 missense mutations of unknown function (named unclassified) represented the majority of variants in our population (44.4%) and were associated with a significantly improved overall survival (OS) both in univariable (hazard ratio [HR] = 0.43, 95% confidence interval [CI] = 0.20-0.92, p = .03) and multivariable analysis (HR = 0.39, 95% CI = 0.18-0.86, p = .02). Concordance between TP53 mutational analysis and IHC was 91%. We observed an HR of 0.70 for OS in patients with p53 IHC overexpression compared to p53 wild-type, which however did not reach statistical significance (p = .31, 95% CI = 0.36-1.38). Our results indicate that the presence of unclassified TP53 mutations has favorable prognostic significance in patients with OC receiving upfront BEV plus chemotherapy. In particular, unclassified missense TP53 mutations characterize a subpopulation of patients with a significant survival advantage, independently of clinicopathological characteristics. Our findings warrant future investigations to confirm the prognostic impact of TP53 mutations in BEV-treated OC patients and deserve to be assessed for their potential predictive role in future randomized clinical studies.