HRD可預測NSCLC患者免疫新輔助治療的療效

我們研究了對新輔助免疫治療有不同反應的非小細胞肺癌(NSCLC)患者之間的遺傳變異,併發現了對療效有高度提示作用的潛在生物標誌物。

Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients

(J HEMATOL ONCOL, IF:17.38)

  • Zhou Z, Ding Z, Yuan J, et al. Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients. Journal of Hematology & Oncology 2022;15.

  • Correspondence: Lu Shun, Department of Medical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;

Background: 背景

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.

新輔助免疫治療是一種新興有效的肺癌干預手段,但發掘提示其療效標誌物的研究很有限。我們研究了對新輔助免疫治療有不同反應的非小細胞肺癌(NSCLC)患者之間的遺傳變異,併發現了對療效有高度提示作用的潛在生物標誌物。

Methods: 方法

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.

在本研究中,3例腺癌和11例鱗癌NSCLC患者接受了不同方案的新輔助免疫治療,隨後進行了手術切除。對未經治療的FFPE(Formalin-fixed paraffin-embedding)或新鮮組織和血液樣本進行全外顯子組測序(WES)。然後對有不同治療反應的患者之間的遺傳變異進行對比。研究結果在多個公共隊列數據中進一步得到驗證。

Results: 結果

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.

DNA損傷修復(DDR)相關InDel標記和DDR相關基因突變在治療反應較好的患者,即主要病理反應(MPR)組中富集。此外,MPR患者還表現出誘發基因組不穩定和獨特的同源重組缺陷(HRD)事件。通過進一步檢測同源性依賴重組(HR)通路基因的變異狀態,克隆變異在MPR組中富集。此外,確定了HR基因變異、存活腫瘤細胞百分比和HRD事件之間的關聯,這些關聯綜合反映在患者的腫瘤突變負荷(TMB)、腫瘤內突變異質性(ITH)、體細胞拷貝數改變(SCNA) ITH和克隆腫瘤抗原負荷中。公共隊列的驗證進一步支援了我們發現的普遍性。

Conclusions: 結論

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.

我們首次報道了肺癌中HRD事件與提高的新輔助免疫治療反應之間的關聯。HRD事件在患者不同治療分層中的作用在多方面的公共隊列中持續存在。我們提出,HR通路基因狀態可以作為指導NSCLC患者免疫新輔助治療和免疫治療決策的新的額外指標。

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