Panda Anshuman, Betigeri Anil, Subramanian Kalyanasundaram, Ross Jeffrey S, Pavlick Dean C, Ali Siraj, Markowski Paul, Silk Ann, Kaufman Howard L, Lattime Edmund, Mehnert Janice M, Sullivan Ryan, Lovly Christine M, Sosman Jeffrey, Johnson Douglas B, Bhanot Gyan, Ganesan Shridar
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
Department of Physics and Astronomy, Rutgers University, Piscataway, NJ.
JCO Precis Oncol. 2017;2017. doi: 10.1200/PO.17.00146. Epub 2017 Dec 7.
An association between mutational burden and response to immune checkpoint therapy has been documented in several cancer types. The potential for such a mutational burden threshold to predict response to immune checkpoint therapy was evaluated in several clinical datasets, where mutational burden was measured either by whole-exome sequencing (WXS) or using commercially available sequencing panels.
WXS and RNA-seq data of 33 solid cancer types from TCGA were analyzed to determine whether a robust immune checkpoint activating mutation (iCAM) burden threshold associated with evidence of immune checkpoint activation exists in these cancers that may serve as a biomarker for response to immune checkpoint blockade therapy.
We find that a robust iCAM threshold, associated with signatures of immune checkpoint activation, exists in 8 of 33 solid cancers: melanoma, lung adenocarcinoma, colon adenocarcinoma, endometrial cancer, stomach adenocarcinoma, cervical cancer, ER+HER2- breast cancer, and bladder-urothelial cancer. Tumors with mutational burden higher than the threshold (iCAM+) also had clear histologic evidence of lymphocytic infiltration. In published datasets of melanoma, lung adenocarcinoma and colon cancer, patients with iCAM+ tumors had significantly better response to immune checkpoint therapy compared to those with iCAM- tumors. ROC analysis using TCGA predictions as gold standard showed that iCAM+ tumors are accurately identifiable using clinical sequencing assays, such as FoundationOne or StrandAdvantage. Using the FoundationOne derived threshold, analysis of 113 melanoma tumors, showed that iCAM+ patients have significantly better response to immune checkpoint therapy. iCAM+ and iCAM- tumors have distinct mutation patterns and different immune microenvironments.
In 8 solid cancers, a mutational burden threshold exists that may predict response to immune checkpoint blockade. This threshold is identifiable using available clinical sequencing assays.
在多种癌症类型中，已证实突变负荷与免疫检查点治疗反应之间存在关联。在多个临床数据集中评估了这种突变负荷阈值预测免疫检查点治疗反应的潜力，其中突变负荷通过全外显子测序（WXS）或使用市售测序面板进行测量。
分析了来自TCGA的33种实体癌类型的WXS和RNA测序数据，以确定在这些癌症中是否存在与免疫检查点激活证据相关的强大免疫检查点激活突变（iCAM）负荷阈值，该阈值可作为免疫检查点阻断治疗反应的生物标志物。
我们发现，在33种实体癌中的8种癌症中存在与免疫检查点激活特征相关的强大iCAM阈值：黑色素瘤、肺腺癌、结肠腺癌、子宫内膜癌、胃腺癌、宫颈癌、雌激素受体阳性人表皮生长因子受体2阴性乳腺癌和膀胱尿路上皮癌。突变负荷高于阈值的肿瘤（iCAM+）也有明显的淋巴细胞浸润组织学证据。在已发表的黑色素瘤、肺腺癌和结肠癌数据集中，与iCAM-肿瘤患者相比，iCAM+肿瘤患者对免疫检查点治疗的反应明显更好。使用TCGA预测作为金标准的ROC分析表明，使用FoundationOne或StrandAdvantage等临床测序检测方法可以准确识别iCAM+肿瘤。使用FoundationOne得出的阈值分析113例黑色素瘤肿瘤，结果表明iCAM+患者对免疫检查点治疗的反应明显更好。iCAM+和iCAM-肿瘤具有不同的突变模式和不同的免疫微环境。
在8种实体癌中，存在一个可能预测免疫检查点阻断反应的突变负荷阈值。使用现有的临床测序检测方法可以识别该阈值。
