PO.CL01.02 · 临床研究

与局部晚期/转移性（LA/M）头颈部鳞状细胞癌（HNSCC）患者对免疫治疗（IO）应答或耐药相关的转录组和基因组特征

Transcriptomic and genomic signatures associated with response or resistance to immunotherapy(IO) in locally advanced/metastatic (LA/M) head and neck squamous cell carcinoma (HNSCC) patients

编号 1034 展板 2 时间 4/19 02:00–05:00 区域 Section 41 主讲 Christophe Le Tourneau, MD, PhD

分会场 Biomarkers Predictive of Therapeutic Benefit 2

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作者与单位 Authors & Affiliations

Elodie Girard¹, Sonia Canjura-Rodriguez², Bastien Cabarrou³, Constance Lamy¹, Anne Schnitzler¹, Frédérique Penault-Llorca⁴, Emmanuel Bouilhol⁵, Roger Sun⁶, Eric Deutsch⁷, François Legrand⁸, Séverine Tabone-Eglinger⁹, Valery Attignon², Caroline Even¹⁰, Christophe Le Tourneau¹, Ellen Van Obberghen-Schilling⁵, Marta Jimenez¹¹, Nicolas Servant¹, Thomas Filleron³, Edith Borcoman¹, Pierre Saintigny¹², Ivan Bièche¹³

¹Institut Curie, Paris, France,²Centre Léon Bérard, Lyon, France,³Oncopole Claudius Regaud - IUCT-O, Toulouse, France,⁴Centre Jean Perrin, Clermont Ferrand, France,⁵Institut de Biologie Valrose, Nice, France,⁶Radiotherapy, Institute Gustave Roussy, Villejuif, France,⁷Full Professor, Dept. of Radiation Onc., Institute Gustave Roussy, Villejuif, France,⁸R&D, Unicancer, Paris, France,⁹Cancer Research Center of Lyon, Lyon, France,¹⁰Gustave Roussy, Villejuif, France,¹¹Unicancer, Paris, France,¹²Ctr. Léon Bérard, Lyon, France,¹³Genetics Department, Inst. Curie, Paris, France

摘要 Abstract

中文摘要

背景：IO 在 LA/M HNSCC 患者中的疗效有限。识别耐药和应答的生物标志物对更好地分层患者至关重要。我们对未接受过 IO 治疗的 HNSCC 患者的基因组和转录组特征进行了刻画，以识别对 IO 应答的特异性基因组和转录组特征。方法：我们分析了来自 CHECK'UP（NCT03412058）和 TOPNIVO（NCT03226756）试验、接受 IO 治疗的 176 例 LA/M HNSCC 患者的基线 FFPE 样本，这些患者具有可用的基线 RNAseq 数据。采用带弹性网络（Elastic Net）程序的惩罚性 Cox 模型识别与 PFS 和 OS 相关的基因特征。使用重采样程序，为每个基因计算自助抽样选择稳定性（BSS）指数，仅将 BSS > 30% 的基因纳入最终模型，以确定 PFS 和 OS 的评分。此外，对 149 对配对的肿瘤和种系 DNA 进行了全外显子测序。在使用基因组改变进行生物统计学分析时，仅考虑变异等位基因频率（VAF）至少为 10% 的癌基因、抑癌基因中的变异（SNV、Indel、CNV）及改变的信号通路。结果：该队列（中位年龄 62.5 岁）以口咽（39.8%）和口腔（29.8%）肿瘤为主，77.8% 为男性，62.3% 有饮酒史，81.7% 有吸烟史，60.0% 为转移性。客观缓解率为 17.4%，中位 PFS 和 OS 分别为 1.9 个月（95%CI=[1.8-2.5]）和 8.1 个月（95%CI=[6.1-9.7]）（中位随访 33.3 个月，95%CI=[28.7-36.5]）。最常见的基因组改变影响 CCND1、CDKN2A、FAT1、TERT、TP53 基因以及 3q26-q28 的增益。在单变量分析中，存在 TERT 或 FAT1 改变与更差的 PFS 显著相关。在校正临床变量后，FAT1 改变的存在和 Hippo 信号通路的上调仍与更差的 PFS 相关。TERT 突变的存在也与更差的 OS 相关，而 PI3K/AKT/mTOR 通路在单变量和多变量分析中分别与改善的 OS 相关。在 500 个差异表达最显著的转录本中，分别筛选出 21 基因和 18 基因表达特征以评估其与 PFS 和 OS 的关联。PFS 和 OS 的 C 指数分别为 0.72 和 0.71（内部自助验证后为 0.58 和 0.57）。使用时间依赖性 ROC 曲线将评分二分（低 vs 高），校正临床因素后的 HR 分别为 PFS 3.62（95%CI = [2.42; 5.43]）和 OS 3.86（95%CI = [2.52; 5.91]；p<0.0001）。结论：我们识别出与 IO 耐药密切相关的稳健转录组特征和基因组改变，为患者分层提供了潜在的生物标志物。TERT 或 FAT1 改变与更差的预后相关。

查看英文原文 English abstract

Background: IO efficacy in LA/M HNSCC patients is limited. Identifying biomarkers of resistance and response is crucial to better stratify patients. We characterized the genomic and transcriptomic landscape of IO-naive HNSCC patients to identify specific genomic and transcriptomic signatures of response to IO. Methods: We analyzed baseline FFPE samples of 176 LA/M HNSCC patients treated with IO from CHECK'UP (NCT03412058) and TOPNIVO (NCT03226756) trials, for whom baseline RNAseq data were available. A penalized Cox model with Elastic Net procedure was used to identify gene signatures associated with PFS and OS. Using a resampling procedure, a bootstrap selection stability (BSS) index was computed for each gene and only those with a BSS > 30% were included in the final model to determine a score for both PFS and OS. In addition, 149 paired tumor and germline DNA were sequenced using whole exome. For biostatistics analysis using genomic alterations, only variants (SNVs, Indels, CNVs) in oncogenes, tumor suppressor genes with a variant allele frequency (VAF) of at least 10% and altered signaling pathways were considered. Results: The cohort (median age 62.5 yo) included a majority of oropharynx (39.8%) and oral cavity (29.8%) tumors, 77.8% males, 62.3% with alcohol and 81.7% with tobacco use history and 60.0% of them were metastatic. Objective response rate was 17.4%, median PFS and OS were 1.9 months (mo) (95%CI=[1.8-2.5]) and 8.1 mo (95%CI=[6.1-9.7]), respectively (median follow-up of 33.3 mo, 95%CI=[28.7-36.5]). The most frequent genomic alterations affected CCND1 , CDKN2A , FAT1 , TERT , TP53 genes and a gain of 3q26-q28. In univariable analyses, the presence of TERT or FAT1 alteration were significantly associated with worse PFS. After adjustment for clinical variable, the presence of FAT1 alteration and the upregulation of Hippo signalling pathway remained associated with worse PFS. The presence of TERT mutation was also associated with worse OS whereas the PI3K/AKT/mTOR pathway was associated with improved OS in univariable and multivariable analysis, respectively. Among the 500 most differentially expressed transcripts, 21- and 18-gene expression signatures were selected to assess their association with PFS and OS, respectively. C-Index was 0.72 and 0.71 (0.58 and 0.57 after internal bootstrap validation) for PFS and OS, respectively. Scores were dichotomized using time-dependent ROC Curve (Low vs High) and HR adjusted for clinical factors were 3.62 (95%CI = [2.42; 5.43]) and 3.86 (95%CI = [2.52; 5.91]; p<0.0001) for PFS and OS, respectively. Conclusions: We identified robust transcriptomic signatures and genomic alterations strongly associated with IO resistance, offering potential biomarkers for patient stratification. TERT or FAT1 alteration were associated with worse prognosis.

利益披露 Disclosure

E. Girard, None.. S. Canjura-Rodriguez, None.. B. Cabarrou, None.. C. Lamy, None.. A. Schnitzler, None.. F. Penault-Llorca, None.. E. Bouilhol, None.. V. Attignon, None.. C. Even, None.. C. Le Tourneau, None.. E. Van Obberghen-Schilling, None.. M. Jimenez, None.. N. Servant, None.. T. Filleron, None.. E. Borcoman, None.

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