PDF(Pubmed)
Abstract：
UNASSIGNED: The clinical significance of homologous recombination deficiency (HRD) in breast cancer, ovarian cancer, and prostate cancer has been established, but the value of HRD in non-small cell lung cancer (NSCLC) has not been fully investigated. This study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical care.
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.
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.
摘要：
■同源重组缺陷（HRD）在乳腺癌中的临床意义，卵巢癌,前列腺癌已经被证实，但HRD在非小细胞肺癌(NSCLC)中的价值尚未得到充分研究.本研究旨在系统分析未经治疗的非小细胞肺癌患者的HRD状态及其与患者预后的关系,以进一步指导临床护理。
■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。
■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。
