Gibbs Cancer Center & Research Institute, Spartanburg, South Carolina.
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center & Research Institute, Tampa, Florida.
Cancer Epidemiol Biomarkers Prev. 2019 Jul;28(7):1141-1152. doi: 10.1158/1055-9965.EPI-18-1383. Epub 2019 Apr 23.
EGFR is a major therapeutic target for colorectal cancer. Currently, extended testing identifies only nonresponders to EGFR inhibitors (EGFRi). We aimed to develop a mutation signature that further refines drug-sensitive subpopulations to improve EGFRi outcomes.
A prespecified, 203-gene expression signature score measuring cetuximab sensitivity (CTX-S) was validated with two independent clinical trial datasets of cetuximab-treated patients with colorectal cancer ( = 44 and = 80) as well as an dataset of 147 cell lines. The CTX-S score was then used to decipher mutated genes that predict EGFRi sensitivity. The predictive value of the identified mutation signature was further validated by additional independent datasets.
Here, we report the discovery of a 2-gene (+) mutation signature that was useful in identifying EGFRi-sensitive colorectal cancer subpopulations. Mutant + tumors were more predominant in left- versus right-sided colorectal cancers (52% vs. 21%, = 0.0004), in microsatellite stable (MSS) versus microsatellite instable (MSI) cases (47% vs. 2%, < 0.0001), and in the consensus molecular subtype 2 versus others (75% vs. 37%, < 0.0001). Moreover, mutant + tumors had favorable outcomes in two cetuximab-treated patient-derived tumor xenograft (PDX) datasets ( = 0.0277, = 52; = 0.0008, = 98).
Our findings suggest that the and combination mutation may account for the laterality of EGFRi sensitivity and provide a rationale for refining treated populations. The results also suggest addition of + sequencing to extended testing that may directly increase the response rates of EGFRi therapy in selected patients.
These findings, if further validated through clinical trials, could also expand the utility of EGFRi therapies that are currently underutilized.
EGFR 是结直肠癌的主要治疗靶点。目前，扩展检测仅识别出对 EGFR 抑制剂（EGFRi）无反应的患者。我们旨在开发一种突变特征，进一步细化对药物敏感的亚群，以改善 EGFRi 的治疗效果。
我们验证了一个预先指定的 203 个基因表达特征评分，用于衡量西妥昔单抗的敏感性（CTX-S），该评分使用了两个独立的接受西妥昔单抗治疗的结直肠癌患者临床试验数据集（= 44 和 = 80）和一个包含 147 个细胞系的数据集。然后，CTX-S 评分用于破译预测 EGFRi 敏感性的突变基因。通过额外的独立数据集进一步验证了所鉴定的突变特征的预测价值。
在这里，我们报告了发现一种 2 个基因（+）突变特征，该特征可用于识别 EGFRi 敏感的结直肠癌亚群。突变+肿瘤在左-右结直肠癌中更为常见（52%比 21%，= 0.0004），在微卫星稳定（MSS）与微卫星不稳定（MSI）病例中更为常见（47%比 2%，< 0.0001），在共识分子亚型 2 与其他亚型中更为常见（75%比 37%，< 0.0001）。此外，在两个接受西妥昔单抗治疗的患者来源肿瘤异种移植（PDX）数据集中，突变+肿瘤的结局较好（= 0.0277，= 52；= 0.0008，= 98）。
我们的研究结果表明，和组合突变可能解释了 EGFRi 敏感性的偏侧性，并为细化治疗人群提供了依据。这些结果还表明，在扩展检测中增加+测序可能会直接提高选定患者 EGFRi 治疗的反应率。
如果通过临床试验进一步验证这些发现，也可能扩大目前未充分利用的 EGFRi 治疗的应用范围。
