Beyond microsatellite testing: assessment of tumor mutational burden identifies subsets of colorectal cancer who may respond to immune checkpoint inhibition
Beyond microsatellite testing: assessment of tumor mutational burden identifies subsets of colorectal cancer who may respond to immune checkpoint inhibition
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DOI：
10.21037/jgo.2018.05.06
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发表时间：
2018-08-01
影响因子：
2.1
通讯作者：
Klempner, Samuel J.
中科院分区：
文献类型：
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作者：
Fabrizio, David A.;George, Thomas J., Jr.;Klempner, Samuel J.
背景：PD1/PD-L1靶向检查点抑制剂在结直肠癌（CRC）中的临床应用主要集中在微卫星不稳定（msi -高）患者的亚群上。然而，所提出的使这些患者对免疫治疗敏感的基因型并不仅仅由MSI状态捕获。在转移性黑色素瘤、尿路上皮性膀胱癌和非小细胞肺癌中，通过综合基因组谱估计肿瘤突变负担（TMB）与全外显子组测序相关联，并与检查点反应相关联。我们试图探索具有高TMB的微卫星稳定型（MSS） CRC患者的子集，并确定与该表型相关的特定基因组特征。此外，我们探索了量化TMB作为CRC中PD1/PD-L1治疗的潜在预测性生物标志物的能力。方法：对6004例结直肠癌用福尔马林固定、石蜡包埋的组织切片，采用clia批准的CGP法进行测序。MSI和TMB状态使用经过验证的方法计算确定。根据所有MSI-High患者的TMB分布，根据满足90%概率区间的下界值定义TMB-high的截止值。结果：604例患者中，5702例（95.0%）出现MSS肿瘤，302例（5.0%）出现MSI-H肿瘤。除1例（99.7%）MSI-H为tmb高（范围6.3-746.9 mut/Mb）外，5702例（97.0%）MSS中有5538例（范围0.0-10.8 mut/Mb）为tmb低（范围6.3-746.9 mut/Mb）。因此，5702例MSS病例中有164例（2.9%）被确认为tmb高（范围，11.7-707.2 mut/Mb），这表明可能对检查点抑制剂治疗有反应的目标人群增加了54%（分别为466例和302例）。在MSS/ tmb高的病例中，PD-1抑制剂被证实有效。结论：同步TMB评估准确地将MSI肿瘤分类为TMB-高，同时将近3%或CRC识别为MSS/TMB-高。这一亚群可能扩大CRC患者群体，他们可能受益于基于免疫检查点抑制剂的治疗方法。
Background: The clinical application of PD1/PD-L1 targeting checkpoint inhibitors in colorectal cancer (CRC) has largely focused on a subset of microsatellite instable (MSI-high) patients. However, the proposed genotype that sensitizes these patients to immunotherapy is not captured by MSI status alone. Estimation of tumor mutational burden (TMB) from comprehensive genomic profiling is validated against whole exome sequencing and linked to checkpoint response in metastatic melanoma, urothelial bladder cancer and non-small cell lung carcinoma. We sought to explore the subset of microsatellite stable (MSS) CRC patients with high TMB, and identify the specific genomic signatures associated with this phenotype. Furthermore, we explore the ability to quantify TMB as a potential predictive biomarker of PD1/PD-L1 therapy in CRC.Methods: Formalin-fixed, paraffin embedded tissue sections from 6,004 cases of CRC were sequenced with a CLIA-approved CGP assay. MSI and TMB statuses were computationally determined using validated methods. The cutoff for TMB-high was defined according to the lower bound value that satisfied the 90% probability interval based on the TMB distribution across all MSI-High patients.Results: MSS tumors were observed in 5,702 of 6,004 (95.0%) cases and MSI-H tumors were observed in 302 (5.0%) cases. All but one (99.7%) MSI-H cases were TMB-high (range, 6.3-746.9 mut/Mb) and 5,538 of 5,702 (97.0%) MSS cases were TMB-low (range, 0.0-10.8 mut/Mb). Consequently, 164 of 5,702 (2.9%) MSS cases were confirmed as TMB-high (range, 11.7-707.2 mut/Mb), representing an increase in the target population that may respond to checkpoint inhibitor therapy by 54% (466 vs. 302, respectively). Response to PD-1 inhibitor is demonstrated in MSS/TMB-high cases.Conclusions: Concurrent TMB assessment accurately classifies MSI tumors as TMB-high and simultaneously identifies nearly 3% or CRC as MSS/TMB-high. This subgroup may expand the population of CRC who may benefit from immune checkpoint inhibitor based therapeutic approaches.