可靶向的 ERBB2 突变状态是雌激素受体阳性、ERBB2 非扩增原发性小叶乳腺癌不良预后的独立标志物：公共数据集的回顾性计算机分析。

Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: a retrospective in silico analysis of public datasets.

机构信息

Nottingham Breast Cancer Research Centre, Nottingham Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK.

Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma, Japan.

出版信息

Breast Cancer Res. 2020 Aug 11;22(1):85. doi: 10.1186/s13058-020-01324-4.

DOI:10.1186/s13058-020-01324-4

PMID:32782013

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7422515/

Abstract

BACKGROUND

Invasive lobular carcinoma (ILC) accounts for 10-15% of primary breast cancers and is typically estrogen receptor alpha positive (ER+) and ERBB2 non-amplified. Somatic mutations in ERBB2/3 are emerging as a tractable mechanism underlying enhanced human epidermal growth factor 2 (HER2) activity. We tested the hypothesis that therapeutically targetable ERBB2/3 mutations in primary ILC of the breast associate with poor survival outcome in large public datasets.

METHODS

We performed in silico comparison of ERBB2 non-amplified cases of ER+ stage I-III primary ILC (N = 279) and invasive ductal carcinoma (IDC, N = 1301) using METABRIC, TCGA, and MSK-IMPACT information. Activating mutations amenable to HER2-directed therapy with neratinib were identified using existing functional data from in vitro cell line and xenograft experiments. Multivariate analysis of 10-year overall survival (OS) with tumor size, grade, and lymph node status was performed using a Cox regression model. Differential gene expression analyses by ERBB2 mutation and amplification status was performed using weighted average differences and an in silico model of response to neratinib derived from breast cancer cell lines.

RESULTS

ILC tumors comprised 17.7% of all cases in the dataset but accounted for 47.1% of ERBB2-mutated cases. Mutations in ERBB2 were enriched in ILC vs. IDC cases (5.7%, N = 16 vs. 1.4%, N = 18, p < 0.0001) and clustered in the tyrosine kinase domain of HER2. ERBB3 mutations were not enriched in ILC (1.1%, N = 3 vs. 1.8%, N = 23; p = 0.604). Median OS for patients with ERBB2-mutant ILC tumors was 66 months vs. 211 months for ERBB2 wild-type (p = 0.0001), and 159 vs. 166 months (p = 0.733) for IDC tumors. Targetable ERBB2 mutational status was an independent prognostic marker of 10-year OS-but only in ILC (hazard ratio, HR = 3.7, 95% CI 1.2-11.0; p = 0.021). Findings were validated using a novel ERBB2 mutation gene enrichment score (HR for 10-year OS in ILC = 2.3, 95% CI 1.04-5.05; p = 0.040).

CONCLUSIONS

Targetable ERBB2 mutations are enriched in primary ILC and their detection represents an actionable strategy with the potential to improve patient outcomes. Biomarker-led clinical trials of adjuvant HER-targeted therapy are warranted for patients with ERBB2-mutated primary ILC.

摘要

背景

浸润性小叶癌（ILC）占原发性乳腺癌的 10-15%，通常雌激素受体 alpha 阳性（ER+）且 ERBB2 非扩增。ERBB2/3 中的体细胞突变正在成为增强人表皮生长因子 2（HER2）活性的一种可行机制。我们在大型公共数据集测试了假设，即在原发性乳腺癌的 ERBB2/3 可治疗性突变与不良生存结局相关。

方法

我们使用 METABRIC、TCGA 和 MSK-IMPACT 信息，对 ER+I 期-III 期原发性 ILC（N=279）和浸润性导管癌（IDC，N=1301）的非扩增 ERBB2 病例进行了基于计算的比较。使用现有的体外细胞系和异种移植实验的功能数据，确定了对 neratinib 有反应的激活突变。使用 Cox 回归模型对 10 年总生存率（OS）进行了多变量分析，包括肿瘤大小、分级和淋巴结状态。使用加权平均差异和源自乳腺癌细胞系的 neratinib 反应的计算模型，对 ERBB2 突变和扩增状态的差异基因表达进行了分析。

结果

ILC 肿瘤占数据集所有病例的 17.7%，但占 ERBB2 突变病例的 47.1%。与 IDC 病例相比，ERBB2 突变在 ILC 中更为丰富（5.7%，N=16 与 1.4%，N=18，p<0.0001），并且聚集在 HER2 的酪氨酸激酶结构域中。在 ILC 中，ERBB3 突变并不丰富（1.1%，N=3 与 1.8%，N=23；p=0.604）。ERBB2 突变 ILC 肿瘤患者的中位 OS 为 66 个月，而 ERBB2 野生型的中位 OS 为 211 个月（p=0.0001），而 IDC 肿瘤的中位 OS 为 159 个月和 166 个月（p=0.733）。可靶向的 ERBB2 突变状态是 10 年 OS 的独立预后标志物，但仅在 ILC 中（风险比，HR=3.7，95%CI 1.2-11.0；p=0.021）。使用新的 ERBB2 突变基因富集评分（ILC 中 10 年 OS 的 HR=2.3，95%CI 1.04-5.05；p=0.040）验证了发现。