Brain Metastasis of Patients with Lung Adenocarcinoma: Epidermal Growth Factor Receptor Mutations and Response to Whole-Brain Radiation Therapy

Introduction

Approximately 1.2 million new cases of lung cancer occur worldwide every year ( ). Most patients with non-small cell lung cancer (NSCLC) are diagnosed at an advanced stage ( ). Brain metastases develop during the course of the disease in ≈30–50% of the NSCLC patients, especially in those with adenocarcinoma ( ). Brain metastasis results in significant morbidity and mortality in NSCLC patients, so the prognoses of these patients are very poor. The overall survival after brain metastasis has occurred is around 1–4 months ( ).

Whole brain radiotherapy (WBRT) plays an important role in the treatment of NSCLC patients with brain metastasis ( ). The recently used regimen for WBRT is usually 30 Gy delivered in 10 fractions over 2 weeks. The effect of WBRT includes improvement of neurologic symptoms, such as headache, nausea or other neurologic deficits, and quality of life ( ). NSCLC patients with brain metastasis who received WBRT had median overall survival ranging from 3 to 6 months ( ). It is uncommon for WBRT to produce complications, particularly acute toxicity. When acute toxicities occur, they are often self-limited. Dementia is the most common late-delayed complication, and it was noted 4–36 months after treatment in approximately 10–15% of the patients who received WBRT ( ).

Epidermal growth factor receptor (EGFR), a transmembrane glycoprotein of the ErbB receptor family, controls cell proliferation, differentiation, anti-apoptosis, angiogenesis, and invasion ( ). After ligand binding, dimerization develops between HER receptors, which triggers tyrosine phosphorylation. Then, several intracellular signaling cascades are activated by EGFR, including: Ras/Raf/MEK/ERK, phophotidylinositol 3-kinase (PI3K)/AKT, Src tyrosine kinases, PLCγ, PKC, and STAT activation and downstream signaling ( ). NSCLC patients with tumors harboring EGFR mutations have a dramatic treatment response to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), gefitinib and erlotinib ( ). EGFR mutations are frequently associated with lung adenocarcinoma, females, never smokers, and East-Asian ethnicity. L858R mutation and a deletion in exon-19 (del-19) account for 90% of the EGFR mutations ( ).

Because lung adenocarcinoma frequently metastasizes to the brain and has a high EGFR mutation rate, interaction between brain metastasis, radiotherapy and EGFR mutation has been reported in preclinical and clinical studies. This may provide a new clinical treatment concept and modality. The more we understand the issue, the better care we can provide for our patients.

Brain Metastasis and EGFR Mutation

The brain is a frequent metastatic site of lung cancer, especially adenocarcinoma ( ). However, the mechanism by which lung cancer metastasizes to the brain is still unknown. For breast cancer, ErbB2 overexpression is associated with brain metastases and poor prognosis, and ErbB2 amplification is an important risk factor for brain metastasis in breast cancer patients ( ). Overexpression of ErbB2, specifically in lung adenocarcinoma, is correlated with poor prognosis and intrinsic chemoresistance ( ). ErbB2 may phosphorylate downstream molecules and activate PI-3 kinase/AKT pathways. These pathways are also activated in NSCLC with EGFR mutations and inhibited by EGFR-TKIs ( ). report that EGFR mutations were detected in 12 of 19 metastatic lung adenocarcinomas to the brain (63%) and 10 patients had del-19. The authors concluded that EGFR mutations frequently present in brain metastases ( ). EGFR mutations may play an important role in brain metastasis of lung cancer.

Preclinical Study and Mechanism