PO.CL09.01 · 临床研究
真实世界临床基因组数据库揭示小细胞肺癌分子亚型的患病率及其独特的生物学程序
Prevalence and distinct biological programs of small cell lung cancer molecular subtypes revealed by real-world clinico-genomics database
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：小细胞肺癌（SCLC）的分子亚型凸显了患者的异质性，并持续具有作为预测性生物标志物的潜力。对免疫检查点抑制剂（ICI）的耐药以及真实世界（RW）治疗的影响仍是尚未解决的问题。我们旨在通过利用具有精心整理的结局和治疗模式的多模态真实世界数据（RWD），加深对SCLC亚型生物学及其治疗意义的理解。
方法：我们分析了来自Caris-ConcertAI关联临床基因组数据库的一个基于美国的SCLC队列（381份样本；376例患者）。我们对初治样本患者（n=230）的转录组数据进行了非负矩阵分解（NMF），并将其应用于经治样本（n=66）。后续治疗包括ICI+化疗（n=179）和单纯化疗（n=49）。PD-L1 IHC结果基于22c3检测，采用肿瘤阳性百分比1%的临界值。基因签名来自MSigDB。
发现：与既往文献一致，谱系定义性转录因子的表达在四种NMF亚型中各不相同。两组（NMF1-SCLC-A/N，初治33.5% vs. 经治33.3%；NMF2-SCLC-A-like，15.2% vs. 19.7%）富含神经内分泌（NE）特征；两组（NMF3-SCLC-I，28.7% vs. 21.2%；NMF4-SCLC-P-like，22.6% vs. 13.6%）表现出免疫特征，且其患病率在经治样本中仍然保持。NMF1表现出ASCL1/NEUROD1的激活转录程序、高增殖签名和低免疫浸润——与经典NE亚型一致。NMF2表现出ASCL1相关的活性，而其升高的代谢通路与典型的SCLC-A有所不同。NMF3类似于炎症型SCLC-I亚型，具有广泛的免疫签名，并由较高的PD-L1 IHC阳性率所证实。然而，同时增强的免疫抑制性TGF-beta/纤维化通路可能削弱ICI治疗的疗效前景。NMF3中的REST/NOTCH激活和低NE特征提示YAP1驱动的NE去分化，并伴随缺氧相关程序（血管生成、KRAS信号），这可能为靶向治疗提供参考。NMF4与典型的SCLC-P相匹配，具有POU2F3激活和MYC过表达。尽管不典型，但POU2F3与NEUROD1的共表达可能提示MYC驱动的亚型混合。初步分析显示NMF3-SCLC-I亚型预后最佳。生存结局在NMF亚型内因所接受的治疗而异，这需要对其预测价值进行进一步验证。
结论：来自该美国真实世界队列的SCLC分子亚型与全球临床试验队列的亚型相一致并有所拓展，揭示了富含代谢通路和亚型混合的独特聚类。当前的标准治疗（SoC）方案对亚型患病率的影响有限。对与亚型独特通路激活相关的真实世界结局的分析，将为新型治疗策略提供参考。
查看英文原文 English abstract
Background: Molecular subtypes of Small Cell Lung Cancer (SCLC) highlight patient heterogeneity and continue to carry potential as predictive biomarkers. Resistance to Immune Checkpoint inhibitor (ICI) and impact of RW treatments remain outstanding. We aim to enhance understanding of SCLC subtype biology and therapeutic implications by leveraging the multi-modal RWD with curated outcome and treatment pattern.
Methods: We analyzed a US-based SCLC cohort (381 samples; 376 patients) from Caris-ConcertAI linked clinico-genomic database. We performed Non-negative Matrix Factorization (NMF) on transcriptomic data from patients with treatment-naïve samples (n=230), and applied to treatment-experienced samples (n=66). Subsequent treatments included ICI+chemo (n=179) and chemo only (n=49). PD-L1 IHC results are based on the 22c3 assay using tumor percent cutoff of 1%. Gene signatures are obtained from MSigDB.
Findings: Consistent with previous literature, expression of lineage-defining transcription factors varied across four NMF subtypes. Two groups (NMF1-SCLC-A/N, 33.5% treatment-naïve vs. 33.3% experienced; NMF2-SCLC-A-like, 15.2% vs. 19.7%) were neuroendocrine (NE)-enriched; two (NMF3-SCLC-I, 28.7% vs. 21.2%; NMF4-SCLC-P-like, 22.6% vs. 13.6%) displayed immune features, with prevalence remained in post-treated samples. NMF1 showed activated transcriptional programs of ASCL1/NEUROD1, high proliferation signatures, and low immune infiltration-consistent with classical NE subtypes. NMF2 exhibited ASCL1-associated activity, while its elevated metabolic pathways differ from canonical SCLC-A. NMF3 resembled the inflamed SCLC-I subtype, with broad immune signatures, confirmed by higher prevalence of PD-L1 IHC positivity. Yet the promise of an efficacious ICI therapy could be dampened by concurrently heightened immunosuppressive TGF-beta/fibrosis pathways. REST/NOTCH activation and low NE features in NMF3 indicated YAP1-driven NE dedifferentiation, accompanied by hypoxia-related programs (angiogenesis, KRAS signaling) that may inform targeted therapy. NMF4 matched canonical SCLC-P with POU2F3 activation and MYC overexpression. Though atypical, the concurrent expression between POU2F3 and NEUROD1 may point to MYC-driven subtype mixing. Preliminary analysis revealed NMF3-SCLC-I subtype with the best prognosis. Survival outcomes vary by treatment received within NMF subtypes, warranting further validations on their predictive values.
Conclusion: SCLC molecular subtypes from this US RW cohort align and extend those from global clinical trial cohorts, revealing distinct clusters enriched with metabolic pathway and subtype mixing. Current SoC regimen has limited impact on the subtype prevalence. The analysis of RW outcome associated with subtypes' unique pathway activation will inform novel treatment strategies.
利益披露 Disclosure
Y. Luo,
AbbVie Employment.
L. Wang,
AbbVie Employment.
N. Jahchan,
AbbVie Employment.
P. Ansell,
AbbVie Employment.
X. Zhao,
AbbVie Employment.
W. Zhao,
AbbVie Employment.