Background & Aims

ERBB2-pathway activation, through amplification or activating mutations, represents a new target for colon cancer (CC) treatment. We compared molecular methods to the gold-standard for assessing ERBB2 status and determined the prognostic value of ERBB2 amplification, mutations, and expression using data from two phase III trials involving nearly 3,000 stage III CC patients.

Methods

In the PETACC8 trial, IHC/FISH, DNA, and RNA analysis were performed on 1813, 1719, and 1733 samples, respectively. In the IDEA-France trial, DNA and RNAseq were performed on 1129 and 1263 samples. The breast cancer SCAN-B cohort (n=3409) served as an external reference. A new molecular ERBB2-amplified status was defined using ERBB2 NGS-score, RNAseq expression, and clustering based on ERBB2 neighboring gene expression. Concordance between diagnostic techniques and the association between time-to-recurrence (TTR) and ERBB2-status were evaluated.

Results

The prevalence of the molecular ERBB2-amplified group was 1.85% in PETACC8 and 1.5% in IDEA-France, with a concordance of 0.81 (95% CI [0.70-0.92]) with the gold-standard IHC/FISH method in PETACC8. A non-linear relationship was observed between TTR and ERBB2-expression, with extreme groups showing a less favorable prognosis (P<.0001) in both colon and breast cancers. Patients with molecular ERBB2-amplified status or mutations had the poorest prognosis, followed by low-expression and intermediate-expression groups (3-year TTR 67.0%, 71.2%, and 77.9%, respectively). In multivariate analysis, the low-expression group had a significantly shorter TTR (HR=1.28; 95%CI [1.07-1.52]).

Conclusions

The molecular definition of ERBB2-status could represent a cost-effective alternative in stage III CC. ERBB2 alterations and low RNA expression significantly reduce TTR, highlighting the complex role of ERBB2.

中文翻译：

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III 期结肠癌的 ERBB2 综合分析和预后：PETACC8 和 IDEA-France 队列的结果

 背景和目标

通过扩增或激活突变激活 ERBB2 通路，代表了结肠癌 （CC） 治疗的新靶点。我们将分子方法与评估 ERBB2 状态的金标准进行了比较，并使用涉及近 3,000 名 III 期 CC 患者的两项 III 期试验的数据确定了 ERBB2 扩增、突变和表达的预后价值。

 方法

在 PETACC8 试验中，分别对 1813、1719 和 1733 个样本进行了 IHC/FISH、DNA 和 RNA 分析。在 IDEA-France 试验中，对 1129 和 1263 个样本进行了 DNA 和 RNAseq。乳腺癌 SCAN-B 队列 （n=3409） 作为外部参考。使用 ERBB2 NGS 评分、RNAseq 表达和基于 ERBB2 相邻基因表达的聚类定义了新的分子 ERBB2 扩增状态。评估诊断技术之间的一致性以及复发时间 （TTR） 和 ERBB2 状态之间的关联。

 结果

ERBB2 分子扩增组的患病率在 PETACC8 中为 1.85%，在 IDEA-France 中为 1.5%，与金标准 IHC/FISH 方法在 PETACC8中的一致性为 0.81 （95% CI [0.70-0.92]）。观察到 TTR 和 ERBB2 表达之间存在非线性关系，极端组在结肠癌和乳腺癌中均显示较差的预后 （P<.0001）。分子 ERBB2 扩增状态或突变的患者预后最差，其次是低表达和中表达组 （3 年 TTR 分别为 67.0% 、 71.2% 和 77.9%）。在多变量分析中，低表达组的 TTR 显著缩短 （HR=1.28;95%CI [1.07-1.52]）。

 结论

ERBB2 状态的分子定义可能代表 III 期 CC 的一种具有成本效益的替代方案。ERBB2 改变和低 RNA 表达显着降低 TTR，突出了 ERBB2 的复杂作用。