PO.CL01.03 · 临床研究

携带高基因组瘢痕评分（GSS）的早期与转移性非小细胞肺癌（NSCLC）患者的临床结局

Clinical outcome of patients with early stage and metastatic non-small cell lung cancer (NSCLCa) harboring high genomic scarring score (GSS)

编号 2431 展板 1 时间 4/20 09:00–12:00 区域 Section 40 主讲 Panteleimon Konstantoulakis, PhD

分会场 Biomarkers Predictive of Therapeutic Benefit 3

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作者与单位 Authors & Affiliations

Panteleimon Konstantoulakis¹, Georgia Christopoulou¹, Apostolos Klinakis², Katerina Tsilingiri², Ioannis Vatselas², Natalia Asimakopoulou³, Vassilis Georgoulias³, Ioannis Pateras⁴, Konstantinos Ntostoglou⁵, Georgios Christodoulopoulos⁶, Athanasios Kotsakis⁶, Vasiliki Anastasopoulou², Dora Hatzidaki⁵, Abdriani Harpidou⁷, Emilia Tsaroucha⁸, Gary Karponi⁹

¹GENOTYPOS Science Labs, Athens, Greece,²Biomedical Research Foundation Academy of Athens, Athens, Greece,³Medical Oncology, Metropolitan Hospital, Athens, Greece,⁴Pathology, Attikon University Hospital, Athens, Greece,⁵Hellenic Oncology Research Group, Athens, Greece,⁶Medical Oncology, University Hospital of University of Thessaly, Larissa, Greece,⁷Medical Oncology, Sotiria Hospital, Athens, Greece,⁸Pulmonary Diseases, Sotiria Hospital, Athens, Greece,⁹Pathology, Microdiagnostics Lab, Thessaloniki, Greece

摘要 Abstract

中文摘要

背景：DNA损伤与基因组不稳定是癌症的标志性特征。已有研究表明，双链断裂修复缺陷的肿瘤对铂类化合物、免疫检查点抑制剂（ICI）和PARP抑制剂有响应。我们此前曾报道，28%的早期非小细胞肺癌（NSCLC）患者呈现高基因组瘢痕评分（h-GSS），这是基因组不稳定的一个指标，而来自这些患者的患者来源异种移植（PDX）对奥拉帕利（olaparib）响应良好。本研究的目的是探究h-GSS早期与转移性NSCLC患者的免疫图谱，并评估其临床结局。材料与方法：本研究纳入了67例（I-III期，早期）和52例（IV期）无可靶向基因组改变的患者。使用一款商业化检测组合（AmoyDx® HRD Complete）评估其GSS，该检测组合还可鉴定20个同源重组修复（HRR）基因的突变。采用免疫组化评估PD-L1表达（肿瘤比例评分-TPS）以及早期和晚期耗竭（分别为TCF1+PD1+和TCF1-PD1+）的CD8+细胞。所有早期患者接受了以铂类为基础的辅助化疗，IV期患者接受了以免疫治疗为基础的方案。结果：在28/67（41.8%）I-III期NSCLC患者的肿瘤和16/52（30.8%）IV期患者的肿瘤中检出h-GSS。TP53突变（TP53mut）分别见于27/28（96.4%）和22/39（56.4%）的I-III期h-GSS和l-GSS肿瘤（p<0.001），以及12/16（75.0%）和15/34（44.1%）的IV期h-GSS和l-GSS肿瘤（p=0.067）。与野生型TP53肿瘤相比，早期而非IV期的TP53mut患者呈现更好的无病间期（DFI）和总生存（OS）（分别为p=0.002和0.026）。与l-GSS/TP53野生型对照相比，早期h-GSS/TP53mut和l-GSS/TP53mut患者的DFI更好（分别为p=0.012和p=0.002），而只有h-GSS/TP53mut状态与更好的OS相关（p=0.031）。在IV期肿瘤中，l-GSS而非h-GSS的PD-L1表达与显著更好的OS相关（HR=0.2，95%CI：0.1-0.6，p=0.009）。最后，在IV期疾病患者中，与l-GSS肿瘤相比，h-GSS肿瘤中PD1+TCF1+（0.067）和PD1+TCF1-（0.054）耗竭型肿瘤浸润淋巴细胞的密度均呈增高的统计学趋势。结论：本研究结果明确提示，以GSS评估的NSCLC基因组不稳定性有望成为在预后和治疗选择方面更好地对患者进行分层的重要工具。

查看英文原文 English abstract

Background: DNA damage and genomic instability represent hallmarks of cancer. Tumors with defects in repairing double strand breaks have been shown to respond to platinum compounds, immune checkpoint inhibitors (ICI) and PARP inhibitors. We have previously reported that 28% of early-stage Non-Small Cell Lung Cancer (NSCLC) patients present high Genomic Scarring Score (h-GSS), an indicator of genomic instability, while patient-derived xenografts from those patients respond favorably to olaparib. The aim of this study was to investigate the immune landscape of h-GSS early-stage and metastatic NSCLC patients, and to assess their clinical outcome. Material and Methods: Sixty-seven (early stage I-III) and 52 (stage IV) patients with no actionable genomic alteration were enrolled in the study. Their GSS was assessed using a commercial panel (AmoyDx® HRD Complete), which also identifies mutations in 20 homologous recombination repair (HRR) genes. PD-L1 expression (tumor proportion score-TPS) and early and late exhausted (TCF1 + PD1 + and TCF1 - PD1+, respectively) CD8 + cells were assessed using immunohistochemistry. All patients with early-stage disease received platinum-based adjuvant chemotherapy while stage IV patients received immunotherapy-based regimens. Results: h-GSS was detected in tumors from 28/67 (41.8%) patients with stage I-III NSCLC and in 16/52 (30.8%) with stage IV. TP53 mutations ( TP53mut) were observed in 27/28 (96.4%) and 22/39 (56.4%) of stage I-III h-GSS and l-GSS tumors, respectively (p<0.001), and in 12/16 (75.0%) and 15/34 (44.1%) of h-GSS and l-GSS tumors stage IV tumors, respectively (p=0.067). Early-stage but not stage IV TP53 mut patients presented a better DFI and OS, compared to wild-type TP53 tumors (p=0.002 and 0.026, respectively). Early-stage h-GSS/TP53mut and l-GSS/TP53mut patients had better DFI (p=0.012 and p=0.002, respectively) compared to l-GSS/ TP53 wt counterparts, whereas only the h-GSS/ TP53 mut status was associated with a better OS (p=0.031). PD-L1 expression in l-GSS but not in h-GSS stage IV tumors was associated with a significantly better OS (HR=0.2, 95%CI: 0.1-0.6, p=0.009). Finally, there was a statistical trend towards an increased density of both PD1+TCF1+ (0.067) and PD1+TCF1- (0.054) exhausted tumor-infiltrating lymphocytes in h-GSS compared to l-GSS tumors in patients with stage IV disease. Conclusions: The findings of this study clearly suggest that genomic instability in NSCLC, as assessed by GSS, could become an important tool for better stratification of patients regarding prognosis and treatment choice.

利益披露 Disclosure

P. Konstantoulakis, AstraZeneca ). Amoy Diagnostics ), Travel. Pillar Biosciences Travel. G. Christopoulou, None.. K. Tsilingiri, None.. I. Vatselas, None.. N. Asimakopoulou, None.. V. Georgoulias, None.. I. Pateras, None.. K. Ntostoglou, None.. G. Christodoulopoulos, None. A. Kotsakis, AstraZeneca ), Travel. ROCHE ), Travel. BMS ), Travel. MSD ), Travel. ASTELLAS ), Travel. V. Anastasopoulou, None.. D. Hatzidaki, None. A. Harpidou, AstraZeneca ), Travel. BMS ), Travel. JANSSEN ), Travel. MSD ), Travel. E. Tsaroucha, None.. G. Karponi, None.

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