UNASSIGNED: A total of 355 treatment-naïve NSCLC patients were retrospectively enrolled. HRD status was assessed using the AmoyDx Genomic Scar Score (GSS), with a score of ≥50 considered HRD-positive. Genomic, transcriptomic, tumor microenvironmental characteristics and prognosis between HRD-positive and HRD-negative patients were analyzed.
UNASSIGNED: Of the patients, 25.1% (89/355) were HRD-positive. Compared to HRD-negative patients, HRD-positive patients had more somatic pathogenic homologous recombination repair (HRR) mutations, higher tumor mutation burden (TMB) (P<0.001), and fewer driver gene mutations (P<0.001). Furthermore, HRD-positive NSCLC had more amplifications in PI3K pathway and cell cycle genes, MET and MYC in epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutant NSCLC, and more PIK3CA and AURKA in EGFR/ALK wild-type NSCLC. HRD-positive NSCLC displayed higher tumor proliferation and immunosuppression activity. HRD-negative NSCLC showed activated signatures of major histocompatibility complex (MHC)-II, interferon (IFN)-γ and effector memory CD8+ T cells. HRD-positive patients had a worse prognosis and shorter progression-free survival (PFS) to targeted therapy (first- and third-generation EGFR-TKIs) (P=0.042). Additionally, HRD-positive, EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy regimens.
UNASSIGNED: Unique genomic and transcriptional characteristics were found in HRD-positive NSCLC. Poor prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive NSCLC. This study highlights potential actionable alterations in HRD-positive NSCLC, suggesting possible combinational therapeutic strategies for these patients.
■回顾性纳入355例未接受治疗的非小细胞肺癌患者。使用AmoyDx基因组疤痕评分(GSS)评估HRD状态,评分≥50分,认为HRD阳性。基因组,转录组,分析HRD阳性和HRD阴性患者的肿瘤微环境特征及预后。
■患者,HRD阳性占25.1%(89/355)。与HRD阴性患者相比,HRD阳性患者的体细胞致病性同源重组修复(HRR)突变较多,较高的肿瘤突变负荷(TMB)(P<0.001),驱动基因突变较少(P<0.001)。此外,HRD阳性非小细胞肺癌在PI3K通路和细胞周期基因中有更多的扩增,表皮生长因子受体(EGFR)/间变性淋巴瘤激酶(ALK)突变NSCLC的MET和MYC,EGFR/ALK野生型NSCLC中的PIK3CA和AURKA更多。HRD阳性NSCLC表现出更高的肿瘤增殖和免疫抑制活性。HRD阴性NSCLC显示主要组织相容性复合体(MHC)-II的激活特征,干扰素(IFN)-γ和效应记忆CD8+T细胞。HRD阳性患者的预后较差,靶向治疗(第一代和第三代EGFR-TKIs)的无进展生存期(PFS)较短(P=0.042)。此外,HRD阳性,EGFR/ALK野生型患者对无铂免疫治疗方案的反应在数值上较低。
■在HRD阳性NSCLC中发现了独特的基因组和转录特征。在HRD阳性NSCLC中观察到对EGFR-TKIs和免疫治疗的不良预后和不良反应。这项研究强调了HRD阳性NSCLC的潜在可行改变,提示这些患者可能的组合治疗策略。