Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Clin Cancer Res. 2022 Jun 13;28(12):2669-2678. doi: 10.1158/1078-0432.CCR-21-4016.
In patients with locally advanced esophageal adenocarcinoma, response to neoadjuvant therapy strongly predicts survival, but robust molecular predictors of response have been lacking. We therefore sought to discover meaningful predictors of response in these patients.
We retrospectively identified all patients with adenocarcinoma of the lower esophagus or gastroesophageal junction who (i) were treated with multimodality therapy with curative intent at our institution from 2014 through 2020 and (ii) underwent prospective sequencing by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. Clinicopathologic and genomic data were analyzed to identify potential genomic features, somatic alterations, and oncogenic pathways associated with treatment response.
In total, 237 patients were included. MDM2 amplification was independently associated with poor response to neoadjuvant therapy [OR, 0.10 (95% confidence interval, 0.01-0.55); P = 0.032], when accounting for significant clinicopathologic variables, including clinical stage, tumor grade, and chemotherapy regimen. Moreover, TP53 pathway alterations, grouped according to inferred severity of TP53 dysfunction, were significantly associated with response to neoadjuvant therapy (P = 0.004, q = 0.07). Patients with MDM2 amplifications or truncating biallelic TP53 mutations had similar outcomes in terms of poor responses to neoadjuvant therapy and, consequently, shorter progression-free survival, compared with patients with TP53 pathway wild-type tumors. Thus, worsening TP53 dysfunction was directly correlated with worse outcomes.
MDM2 amplification and TP53 status are associated with response to therapy in patients with esophageal adenocarcinoma. Given the dearth of actionable targets in esophageal adenocarcinoma, MDM2 inhibition, in combination with cytotoxic chemotherapy, may represent an important therapeutic strategy to overcome treatment resistance and improve outcomes in these patients.
在局部晚期食管腺癌患者中，对新辅助治疗的反应强烈预测生存，但缺乏反应的强大分子预测因子。因此，我们试图在这些患者中发现有意义的反应预测因子。
我们回顾性地确定了所有在我们机构接受根治性多模式治疗的下段食管或胃食管交界处腺癌患者（i）于 2014 年至 2020 年期间接受前瞻性测序，并进行了前瞻性测序通过纪念斯隆凯特琳综合行动癌症靶点突变分析。分析临床病理和基因组数据，以确定与治疗反应相关的潜在基因组特征、体细胞改变和致癌途径。
共纳入 237 例患者。MDM2 扩增与新辅助治疗的不良反应独立相关[OR，0.10（95%置信区间，0.01-0.55）；P = 0.032]，当考虑到显著的临床病理变量，包括临床分期、肿瘤分级和化疗方案。此外，根据推测的 TP53 功能障碍严重程度分组的 TP53 通路改变与新辅助治疗的反应显著相关（P = 0.004，q = 0.07）。与 TP53 通路野生型肿瘤相比，MDM2 扩增或双等位 TP53 突变截断的患者对新辅助治疗的反应较差，因此无进展生存期较短，结果相似。因此，TP53 功能障碍的恶化与较差的结果直接相关。
MDM2 扩增和 TP53 状态与食管腺癌患者的治疗反应相关。鉴于食管腺癌中缺乏可操作的靶点，MDM2 抑制联合细胞毒性化疗可能代表一种重要的治疗策略，可以克服治疗耐药性，改善这些患者的预后。
