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

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.

Invasive lobular carcinoma of the breast: the increasing importance of this special subtype

“…The acquisition of ERBB2 and ERBB3 mutations in ILC has been shown to be associated with an increased risk of relapse and poorer outcomes, likely representing an escape mechanism to endocrine therapy [ 44 ]. Indeed, a recent, large meta-analysis showed that ILCs account for 47% of all ERBB2 mutated (not amplified) cases, and that targetable ERBB2 mutations are an independent prognostic marker of poorer 10-year overall survival [ 80 ]. This team then postulated that mutation of ERBB2/3 may initiate alternate downstream activity (as opposed to ERBB2/3 amplification) and derived a gene expression signature to measure this.…”

Invasive Lobular Carcinoma of the Breast: Ongoing Trials, Challenges, and Future Directions

“…Additionally, Ecadherin loss appears to result in activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt signaling pathway, irrespective of oncogenic mutations in PIK3CA [12]. Somatic mutations in ILC differ from those in IDC, with increased prevalence of mutations in FOXA1, AKT1, PTEN, HER2, HER3, and FGFR4 seen in HR-positive, HER2negative ILC compared to HR-positive, HER2-negative IDC [8,13,14]. Within ILC, specific gene expression signatures have recently been described, providing evidence for heterogeneity within this tumor type and potential predictors of response to therapy [7,15,16] Upon clinical presentation, patients with ILC face unique challenges starting with delays in diagnosis and imprecision of clinical staging.…”

“…Recent studies have shown enrichment of activating HER2 mutations in ILC compared to IDC, with 5.7% of early stage ILC cases having such mutations compared to 1.4% of IDC cases [13]. Rates of HER2 mutations appear to be even more prevalent in certain subtypes of ILC, with up to 26% of pleomorphic ILC tumors harboring such mutations [51].…”

HER2 splice variants in breast cancer: investigating their impact on diagnosis and treatment outcomes

“…Lower incidences of central nervous system metastases may indicate this inhibitor should be used for patients at high risk of this metastatic pattern [66]. There is some evidence this inhibitor may be used to target mutations in the tyrosine kinase domain of the HER2 receptor, even in HER2-tumours [67].…”