High EGFR Gene Copy Number Predicts Poor Outcome in Triple-negative Breast Cancer

Heae Surng Park; Min Hye Jang; Eun Joo Kim; Hyun Jeong Kim; Hee Jin Lee; Yu Jung Kim; Jee Hyun Kim; Eunyoung Kang; Sung-Won Kim; In Ah Kim; So Yeon Park

Disclosures

Mod Pathol. 2014;27(9):1212-1222. 

In This Article

Abstract and Introduction

Abstract

Epidermal growth factor receptor (EGFR) is frequently overexpressed in triple-negative breast cancer and is emerging as a therapeutic target. EGFR gene copy number alteration and mutation are highly variable and scientists have been challenged to define their prognostic significance in triple-negative breast cancer. We examined EGFR protein expression, EGFR gene copy number alteration and mutation of exon 18 to 21 in 151 cases of triple-negative breast cancer and correlated these findings with clinical outcomes. In addition, intratumoral agreement of EGFR protein overexpression and gene copy number alteration was evaluated. EGFR overexpression was found in 97 of 151 cases (64%) and high EGFR gene copy number was detected in 50 cases (33%), including 3 gene amplification (2%) and 47 high polysomy (31%). Five EGFR mutations were detected in 4 of 151 cases (3%) and included G719A in exon 18 (n=1), V786M in exon 20 (n=1), and L858R in exon 21 (n=3). One case had two mutations (G719A and L858R). High EGFR copy number, but not EGFR mutation, correlated with EGFR protein overexpression. Intratumoral heterogeneity of EGFR protein overexpression and EGFR copy number alteration was not significant. In survival analyses, high EGFR copy number was found to be an independent prognostic factor for poor disease-free survival in patients with triple-negative breast cancer. Our findings showed that EGFR mutation was a rare event, but high EGFR copy number was relatively frequent and correlated with EGFR overexpression in triple-negative breast cancer. Moreover, high EGFR copy number was associated with poor clinical outcome in triple-negative breast cancer, suggesting that evaluation of EGFR copy number may be useful for predicting outcomes in patients with triple-negative breast cancer and for selecting patients for anti-EGFR-targeted therapy.

Introduction

Triple-negative breast cancer is a subtype of breast cancer characterized by the absence of expression of estrogen and progesterone receptors and human epidermal growth factor receptor 2 (HER2), accounting for 10–20% of all breast cancers.[1–3] Histopathologically, the majority of triple-negative breast cancers are high-grade invasive carcinomas of no special type, metaplastic carcinomas, and medullary carcinomas.[3] Triple-negative breast cancer carries a poorer prognosis than other subtypes of invasive breast cancer.[1] It is relatively sensitive to chemotherapy, but early relapse and visceral metastases are common and overall survival remains poor.[4,5] In addition, current systemic therapeutic options for triple-negative breast cancer are limited to conventional cytotoxic chemotherapy, whereas non-triple-negative breast cancer, that is, hormone receptor-positive, or HER2-positive breast cancer may have benefit from anti-hormonal or HER2-targeted therapy. The search for specific molecular targets in triple-negative breast cancer and the development of therapeutics for these targets are ongoing.

Epidermal growth factor receptor (EGFR) alterations have been implicated in the pathogenesis and progression of many malignancies including non-small cell lung cancer[6,7] and glioblastoma.[8] EGFR is a well-established treatment target for colorectal cancer, non-small cell lung cancer, and squamous cell carcinoma of the head and neck. In breast cancer, EGFR overexpression has been reported in up to 78% of triple-negative breast cancers,[9–20] more than in non-triple-negative breast cancers,[12,15] suggesting that EGFR is a potential therapeutic target for triple-negative breast cancer. EGFR tyrosine kinase inhibitors have yielded insignificant response rates in breast cancer,[21–23] possibly due to the lack of patient selection in these studies; they were not restricted to breast cancers with EGFR overexpression or triple-negative breast cancers. Recently, however, EGFR-targeting monoclonal antibody, cetuximab, has improved outcomes in triple-negative breast cancers.[24]

EGFR gene amplification, one of the mechanisms of EGFR overexpression, is highly variable and found in up to 24% of triple-negative breast cancer.[10,11,13,14,19,25]EGFR gene mutation, another mechanism of EGFR overexpression, has been reported to be rare,[11,17,19,25,26] although a recent study reported that it was present in 11% of triple-negative breast cancers.[16] EGFR immunoreactivity has been presented as an independent indicator of poor prognosis in patients with triple-negative breast cancer.[18,20] However, there have been no reports on the prognostic impact of EGFR copy number alteration or mutation in triple-negative breast cancer. Intratumoral heterogeneity of EGFR protein overexpression and copy number alteration has also not been studied in triple-negative breast cancer, although it may be associated with responsiveness to EGFR-targeted therapy.

The primary goals of this study were to (1) evaluate the rates and prognostic significance of EGFR copy number alteration and mutation in triple-negative breast cancers and (2) assess intratumoral heterogeneity of EGFR protein overexpression and copy number alteration.

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