2017ASCO:ctDNA TMB与DNA修复突变及NSCLC患者PD-1/PD-L1免疫治疗反应相关

2017-05-22 编辑:礼泉 来源:艾兰博曼医学网 作者:鱼会飞


探寻PD-1/PD-L1抗体药物靶向治疗效果的生物标志物对治疗NSCLC格外重要。肿瘤突变负荷(TMB)是激活状态效用T细胞基因组不稳定性和新抗原结合位点的潜在生物标志物。来自西北大学医学发展治疗研究所(NMDTI)和西北Memorial医院的科学家开创了一种新的ctDNA TMB的检测方法,通过检测TMB与临床变量之间的关系,对免疫阻断反应得效果进行评估。

采用回顾性分析的方式对136例NSCLC患者进行二代测序(NGS)检测。由于Guardant360进行的ctDNA检测目前暂未被TMB证实。本研究采用碱基替换和删除的方式来确定和排除潜在的变体,但是把重排、融合和拷贝数变异相关变体排除在外。另外,获得了17位PD-1/PD-L1免疫治疗的患者的生存数据,并且在一线治疗开始前或治疗开始90田后获得其ctDNA。

研究结果表明,ctDNA TMB与参与直接或者间接DNA修复基因的突变数量相关(t检验,p <0.05)。在一些功能性突变中,吸烟也与较高的TMB相关(卡方检验,p=0.034)。驱动基因突变 (EGFR, KRAS) 和先前的放射性治疗与TMB无关。较低的ctDNA TMB(低于中位数,15个突变/ MBp)与PFS、OS较长相关(Kaplan-Meier对数秩检验,p <0.05)。

研究结论认为,ctDNA TMB与DNA修复基因突变的数量存在着显著的相关性。吸烟会导致更高的TMB评分。然而,在一小部分患者,ctDNA TMB预测值较低预示着检查点阻断。潜在的原因包括小样本量,ctDNA反映肿瘤负荷的可能性,以及DNA测序长度有限(约78,000-138,000bp)。 需要较大的前瞻性研究来验证这些成果。

摘要原文:

摘要编号:11537

Association of circulating tumor DNA (ctDNA) tumor mutational burden (TMB) with DNA repair mutations and response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer (NSCLC).

Author(s): Andrew A. Davis, Young Kwang Chae, Sarita Agte, Alan Pan, Wade Thomas Iams, Marcelo Rocha De Sousa Cruz, Nisha Anjali Mohindra, Victoria Meucci Villaflor, Francis J. Giles; Northwestern University, Chicago, IL; Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL; Northwestern Memorial Hospital, Chicago, IL

Identifying optimal biomarkers for response to anti-PD-1/PD-L1 therapies in NSCLC is critical. TMB is a potential biomarker of genomic instability and neoantigen binding sites to activated effector T cells. The goal of this study was to derive a measure of ctDNA TMB and to examine the association between TMB and clinical variables, DNA repair mutations, and response to checkpoint blockade. Methods: We retrospectively examined 136 patients with NSCLC who had undergone ctDNA next-generation sequencing (NGS) in our institution. The ctDNA testing, performed by Guardant360, is not currently clinically indicated for TMB. We derived ctDNA TMB using coding base substitutions and indel alterations both including and excluding potentially functional variants, but excluded rearrangements, fusions, and copy number variants. In addition, survival data were obtained for 17 patients who were treated with anti-PD-1/PD-L1 therapy and had ctDNA before first line therapy or within 90 days of therapy initiation. Results: ctDNA TMB was associated with the number of direct and indirect DNA repair gene mutations (t-test, p < 0.05). Smoking was also associated with higher TMB when including functional variants (chi-square test, p = 0.034). Driver mutations (EGFR, KRAS) and prior radiation therapy were not correlated with TMB. Lower ctDNA TMB (below the median, 15 mutations/MBp) was associated with longer PFS and OS (Kaplan-Meier log-rank test, p < 0.05). Conclusions: ctDNA TMB was derived and was significantly associated with greater number of DNA repair mutations. Smoking predicted higher TMB score. However, in a small subset of patients, lower ctDNA TMB predicted response to checkpoint blockade. Potential reasons include the small sample size, the possibility of ctDNA reflecting tumor burden, and the limited length of DNA sequenced (~78,000-138,000 bp). Larger, prospective studies are necessary to validate these findings.



 





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