High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types.
High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types.
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DOI：
10.1016/j.annonc.2021.02.006
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发表时间：
2021-05
期刊：
影响因子：
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通讯作者：
Lin SY
中科院分区：
文献类型：
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作者：
McGrail DJ;Pilié PG;Rashid NU;Voorwerk L;Slagter M;Kok M;Jonasch E;Khasraw M;Heimberger AB;Lim B;Ueno NT;Litton JK;Ferrarotto R;Chang JT;Moulder SL;Lin SY
高肿瘤突变负荷（TMB-H）已被提议作为免疫检查点封锁（ICB）反应的预测生物标志物，这主要是由于肿瘤突变可能产生免疫原性新抗原。尽管最近泛癌症批准了 ICB 治疗任何 TMB-H 肿瘤（通过针对 9 种肿瘤类型的 Foundation One CDx 检测进行评估），但这种生物标志物的效用尚未在所有癌症中得到充分证明。癌症基因组图谱中包含的 10,000 多个患者肿瘤的数据被用来比较确定 TMB 的方法，并确定预测的新抗原负荷与 CD8 T 细胞之间的相关性。通过客观缓解率（ORR，N=1551）和总生存期（OS，N=1936）分析 TMB 与 ICB 治疗结果的关联。在 CD8 T 细胞水平与新抗原负载呈正相关的癌症类型中，如黑色素瘤、肺癌和膀胱癌，TMB-H 肿瘤对 ICB 的 ORR 为 39.8% (95% CI 34.9–44.8)，显着高于低 TMB (TMB-L) 肿瘤中观察到的结果（比值比 (OR) = 4.1，95% CI 2.9–5.8，P < 2×10−16）。在 CD8 T 细胞水平与新抗原负载之间没有关系的癌症类型中，例如乳腺癌、前列腺癌和神经胶质瘤，TMB-H 肿瘤未能达到 20% ORR（ORR = 15.3%，95% CI 9.2–23.4，P = 0.95），并且相对于 TMB-L 肿瘤也表现出显着较低的 ORR（OR = 0.46，95% CI） 0.24–0.88，P = 0.02）。对于评估的患者队列，两类肿瘤之间的整体 ORR 没有显着差异 (P = 0.10)。通过分析 OS 并将 TMB 视为连续变量，获得了等效结果。我们的分析未能支持 TMB-H 作为 ICB 治疗所有实体癌类型的生物标志物的应用。需要进一步的肿瘤类型特异性研究。
High tumor mutation burden (TMB-H) has been proposed as a predictive biomarker for response to immune checkpoint blockade (ICB), largely due to potential for tumor mutations to generate immunogenic neoantigens. Despite recent pan-cancer approval of ICB treatment for any TMB-H tumor, as assessed by the targeted Foundation One CDx assay in 9 tumor types, the utility of this biomarker has not been fully demonstrated across all cancers. Data from over 10,000 patient tumors included in The Cancer Genome Atlas were used to compare approaches to determine TMB and identify the correlation between predicted neoantigen load and CD8 T cells. Association of TMB with ICB treatment outcomes was analyzed by both objective response rates (ORRs, N=1551) and overall survival (OS, N=1936). In cancer types where CD8 T cell levels positively correlated with neoantigen load, such as melanoma, lung, and bladder cancers, TMB-H tumors exhibited a 39.8% ORR to ICB (95% CI 34.9–44.8), which was significantly higher than that observed in low TMB (TMB-L) tumors (odds ratio (OR) = 4.1, 95% CI 2.9–5.8, P < 2×10−16). In cancer types that showed no relationship between CD8 T cell levels and neoantigen load, such as breast cancer, prostate cancer, and glioma, TMB-H tumors failed to achieve a 20% ORR (ORR = 15.3%, 95% CI 9.2–23.4, P = 0.95), and also exhibited a significantly lower ORR relative to TMB-L tumors (OR = 0.46, 95% CI 0.24–0.88, P = 0.02). Bulk ORRs were not significantly different between the two categories of tumors (P = 0.10) for patient cohorts assessed. Equivalent results were obtained by analyzing OS and by treating TMB as a continuous variable. Our analysis failed to support application of TMB-H as a biomarker for treatment with ICB in all solid cancer types. Further tumor type specific studies are warranted.
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DOI：
10.4049/jimmunol.1700893
发表时间：
2017-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
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作者：
Jurtz V;Paul S;Andreatta M;Marcatili P;Peters B;Nielsen M
通讯作者：
Nielsen M
影响因子：
16.6
作者：
Gromeier M;Brown MC;Zhang G;Lin X;Chen Y;Wei Z;Beaubier N;Yan H;He Y;Desjardins A;Herndon JE 2nd;Varn FS;Verhaak RG;Zhao J;Bolognesi DP;Friedman AH;Friedman HS;McSherry F;Muscat AM;Lipp ES;Nair SK;Khasraw M;Peters KB;Randazzo D;Sampson JH;McLendon RE;Bigner DD;Ashley DM
通讯作者：
Ashley DM
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
15.9
作者：
Khasraw, Mustafa;Walsh, Kyle M.;Ashley, David M.
通讯作者：
Ashley, David M.
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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