2017ASCO:中国1000例肿瘤患者CWES分析免疫治疗潜在生物标志物

2017-05-22 编辑:礼泉 来源:艾兰博曼医学网 作者:鱼会飞


免疫治疗成为越来越广为接受的肿瘤疗法,关键是确定患者能否从治疗中获益。本研究通过外显子分析数据对中国患者潜在的PD1/PD-L1治疗的生物标志物进行分析。相关研究结果发表在6月2-6日在美国芝加哥举行的第53届美国临床肿瘤学会年会(ASCO)上。

研究中共纳入中国20个省70个医院的1000多名肿瘤患者,并对每位患者的肿瘤/正常样本进行了分析,研究了四种潜在的生物标志物肿瘤突变负荷(TMB)、错配修复缺陷(MMR)、微卫星不稳定性(MSI)、PD-L1 (CD274)扩增(PD-L1 AMP)。分析的结果与白种人的TCGA数据库队列进行对比。

临床全外显子测序分析发现,与TCGA队列一致,40.8%的中国肿瘤患者人群当中至少出现过以上所述生物标志物中的一种。排名前三的TMB分别为肺癌、食管癌和结直肠癌。中国的肝细胞癌(HCC)患者比TCGA研究队列显示出更高的TMB(106 vs 65)。经过PD1/PD-L1 抑制剂治疗的5例晚期癌症患者(3例肺癌,1例黑色素瘤和1例胆囊癌)持续在临床治疗中获益(SD≥6个月/PR/CR)。与TCGA队列相比 ,中国结直肠癌组(252例)MSI高或者MMR相对较低 (8.33% vs. 12.5%, 3.97% vs. 10.0% )。PD-L1 AMP最常发生在肺鳞状细胞癌(14.3%VS 9.8%TCGA),HER2阳性乳腺癌(8.8%VS 6.8%TCGA,HER2状态未知)和肉瘤(6.0%VS 9.4%TCGA)。1例中国肾癌患者PD-L1 AMP接受PD-1抗体治疗,持续PFS为7个月。

通过以上的CWES分析和有限的临床随访发现,约40%的中国癌症患者至少有4种潜在的免疫治疗预测性生物标志物突变中的一种。 需要长期跟踪来验证这些标记的有效性。

原文摘要

摘要编号:#11605

Author(s): Qiang Xu, Guan Wang, Chun Dai, Xiaoman Xu, Jinwang Wei, Jiayue Xu, Angela Wu, Jiping Wang; GenomiCare, Shanghai, China; Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, MA

Comprehensive analysis of potential immunotherapy genomic biomarkers by profiling paired tumor/normal exome of 1,000 Chinese cancer patients.

Background: With the broadening landscape of immunotherapy use, it is important to identify patients who are likely to benefit from the therapy. We reported the comprehensive analyses of potential predictive biomarkers for PD1/PD-L1 inhibitors based on Chinese patients’ exome profiling data. Methods: Over 1,000 cancer patients from 70 hospitals across 20 provinces in China were recruited and the whole exome of tumor/normal samples of each patient were sequenced. Four potential genomic biomarkers: tumor mutation burden (TMB), mismatch repair deficiency (MMR), microsatellite instability (MSI), and PD-L1 (CD274) amplification (PD-L1 AMP) were analyzed in this Chinese cohort and compared with the mainly Caucasian cohort in TCGA database. Results: At least one of the four preselected genomic biomarkers was identified in 40.8% of this Chinese cancer patient cohort by clinical whole exome sequencing (CWES) analysis. Similar to TCGA cohort, the top 3 high TMB tumor types are lung, esophagus and colorectal cancer. Chinese hepatocellular carcinoma (HCC) patients showed higher TMB than the TCGA cohort (Median: 106 vs. 65 non-synonymous mutations per tumor NMT), which might be due to different etiologies. Five late stage cancer patients (3 lung, 1 melanoma and 1 gallbladder) using PD1/PD-L1 blockade with high TMB showed durable clinical benefit (SD≥6months/PR/CR). Comparing with TCGA data, Chinese colorectal cancer cohort (252 patients) had relative lower MSI-high or MMR related mutations (8.33% vs. 12.5%, and 3.97% vs. 10.0% respectively). PD-L1 AMP most frequently occurred in lung squamous (14.3% VS 9.8% TCGA), HER2-positive breast cancer (8.8% VS 6.8% TCGA with unknown HER2 status) and sarcoma (6.0% VS 9.4%TCGA). One Chinese renal cell carcinoma patient with PD-L1 AMP received anti-PD-1 treatment and on-going PFS is 7 months by far. Conclusions: Our CWES analysis and limited clinical follow-up observations suggested that about 40% Chinese cancer patients had at least one of the 4 potential immunotherapy predictive biomarker mutations. Long-term follow-up is needed to verify the validity of those markers.







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