HER2-HER3 Heterodimer Quantification by FRET-FLIM and Patient Subclass Analysis of the COIN Colorectal Trial
HER2-HER3 Heterodimer Quantification by FRET-FLIM and Patient Subclass Analysis of the COIN Colorectal Trial
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DOI：
10.1093/jnci/djz231
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发表时间：
2020-09-01
影响因子：
10.3
通讯作者：
Ng, Tony
中科院分区：
文献类型：
--
作者：
Barber, Paul R.;Weitsman, Gregory;Ng, Tony
背景：III期MRC COIN试验显示，在奥沙利铂基础化疗的一线治疗中，添加egfr靶点西妥昔单抗没有统计学意义上的显著益处。这项研究利用了HER2-HER3二聚体的额外信息来实现患者分层，并揭示了以前隐藏的具有不同疾病进展和治疗反应的患者亚组。方法：用荧光寿命成像显微镜对550例接受奥沙利铂和氟嘧啶化疗（有或没有西妥昔单抗）的COIN试验患者的原发肿瘤样本进行HER2-HER3二聚体的定量分析。采用贝叶斯潜类分析和协变量还原分析HER2-HER3二聚体、RAS突变和西妥昔单抗对无进展生存期和总生存期（OS）的影响。所有统计检验均为双侧检验。结果：对398例患者的队列进行潜在分类分析，发现两个预后不同的患者亚类（中位生存期= 1624天[95%置信区间[CI] = 1466至1816天]vs 461天[95% CI = 431至504天]）：1类（15.6%）显示西图昔单抗在生存期获益（风险比= 0.43,95% CI = 0.25至0.76,P = 0.004）。2级显示HER2-HER3升高与较好的OS相关（风险比= 0.64,95% CI = 0.44 ~ 0.94, P = 0.02）。在一个独立的验证队列（n = 152）上形成了一个类别预测签名并进行了测试，验证了二聚体测定的预后效用。基于10个基线临床病理和遗传协变量，在完整的试验数据集中（n = 1630）也发现了类似的亚类。结论：我们的研究表明，联合使用HER二聚体成像和常规突变分析将能够识别出一小部分患者（bbb10 %），他们在化疗后预后更好。需要更大的前瞻性队列来证实其在预测抗egfr治疗结果方面的效用。
Background: The phase III MRC COIN trial showed no statistically significant benefit from adding the EGFR-target cetuximab to oxaliplatin-based chemotherapy in first-line treatment of advanced colorectal cancer. This study exploits additional information on HER2-HER3 dimerization to achieve patient stratification and reveal previously hidden subgroups of patients who had differing disease progression and treatment response. Methods: HER2-HER3 dimerization was quantified by fluorescence lifetime imaging microscopy in primary tumor samples from 550 COIN trial patients receiving oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab. Bayesian latent class analysis and covariate reduction was performed to analyze the effects of HER2-HER3 dimer, RAS mutation, and cetuximab on progression-free survival and overall survival (OS). All statistical tests were two-sided. Results: Latent class analysis on a cohort of 398 patients revealed two patient subclasses with differing prognoses (median OS = 1624 days [95% confidence interval [CI] = 1466 to 1816 days] vs 461 days [95% CI = 431 to 504 days]): Class 1 (15.6%) showed a benefit from cetuximab in OS (hazard ratio = 0.43, 95% CI = 0.25 to 0.76, P = .004). Class 2 showed an association of increased HER2-HER3 with better OS (hazard ratio = 0.64, 95% CI = 0.44 to 0.94, P = .02). A class prediction signature was formed and tested on an independent validation cohort (n = 152) validating the prognostic utility of the dimer assay. Similar subclasses were also discovered in full trial dataset (n = 1630) based on 10 baseline clinicopathological and genetic covariates. Conclusions: Our work suggests that the combined use of HER dimer imaging and conventional mutation analyses will be able to identify a small subclass of patients (>10%) who will have better prognosis following chemotherapy. A larger prospective cohort will be required to confirm its utility in predicting the outcome of anti-EGFR treatment.