同源重组缺陷（HRD）可预测 NSCLC 患者免疫新辅助治疗的疗效。
Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients.
机构信息
Department of Medical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
出版信息
J Hematol Oncol. 2022 May 18;15(1):62. doi: 10.1186/s13045-022-01283-7.
BACKGROUND
Neoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer, but study to unearth effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between non-small cell lung cancer (NSCLC) patients with varied response to neoadjuvant immunotherapy and discovered highly potential biomarkers with indicative capability in predicting outcomes.
METHODS
In this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimens followed by surgical resection. Treatment-naive FFPE or fresh tissues and blood samples were subjected to whole-exome sequencing (WES). Genetic alternations were compared between differently-responded patients. Findings were further validated in multiple public cohorts.
RESULTS
DNA damage repair (DDR)-related InDel signatures and DDR-related gene mutations were enriched in better-responded patients, i.e., major pathological response (MPR) group. Besides, MPR patients exhibited provoked genome instability and unique homologous recombination deficiency (HRD) events. By further inspecting alternation status of homology-dependent recombination (HR) pathway genes, the clonal alternations were exclusively enriched in MPR group. Additionally, associations between HR gene alternations, percentage of viable tumor cells and HRD event were identified, which orchestrated tumor mutational burden (TMB), mutational intratumor heterogeneity (ITH), somatic copy number alteration (SCNA) ITH and clonal neoantigen load in patients. Validations in public cohorts further supported the generality of our findings.
CONCLUSIONS
We reported for the first time the association between HRD event and enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multifaceted public cohorts. We propose that HR pathway gene status could serve as novel and additional indicators guiding immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients.
背景
新辅助免疫疗法作为一种新型有效的干预手段在肺癌中不断涌现，但探索能够反映其治疗效果的有效替代指标的研究仍十分有限。本研究旨在通过对新辅助免疫治疗后不同疗效的非小细胞肺癌（NSCLC）患者的基因变化进行分析，寻找具有潜在预测价值的生物标志物。
方法
本研究纳入 3 例腺癌和 11 例鳞癌 NSCLC 患者，采用不同方案的新辅助免疫治疗后行手术切除。对治疗前的 FFPE 或新鲜组织及血液样本进行全外显子组测序（WES）。比较不同疗效患者的基因改变。在多个公共队列中进一步验证研究结果。
结果
在疗效较好的患者（即主要病理缓解（MPR）组）中，DNA 损伤修复（DDR）相关的插入缺失（InDel）特征和 DDR 相关基因突变富集。此外，MPR 患者表现出诱发的基因组不稳定性和独特的同源重组缺陷（HRD）事件。进一步检查同源依赖性重组（HR）通路基因的改变状态，发现克隆性改变仅在 MPR 组中富集。此外，还发现 HR 基因改变、肿瘤活细胞比例与 HRD 事件之间存在相关性，这些相关性共同调节肿瘤突变负荷（TMB）、肿瘤内突变异质性（ITH）、体细胞拷贝数改变（SCNA）ITH 和克隆性新生抗原负荷。在公共队列中的验证结果进一步支持了本研究结果的普遍性。
结论
本研究首次报道了 HRD 事件与肺癌新辅助免疫治疗疗效增强之间的关联。HRD 事件在多组公共队列中对患者治疗分层的作用仍然存在。我们提出 HR 通路基因状态可作为 NSCLC 患者免疫新辅助和免疫治疗决策的新的、额外的指标。
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