Brain Metastasis in Patients with Non-Small Cell Lung Cancer: Response to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Introduction

The development of brain metastases occurs in up to 44% of patients with advanced non-small cell lung cancer (NSCLC), particularly in patients with adenocarcinoma ( ). Brain metastases are associated with a poor prognosis, with a median overall survival of 4–11 weeks in untreated patients and 4–15 months in treated patients ( ; ). Treatment of brain metastases remains a challenge. The blood–brain barrier is a physiologic obstruction to the delivery of systemic therapy to the central nervous system (CNS). Whole-brain radiation therapy (WBRT) represents the standard of care for multiple NSCLC brain metastases ( ). However, metastatic brain malignancy compromises this barrier and lets access of chemotherapy or targeted therapy to the tumor.

Recently, targeted therapies have shown efficacy in CNS metastases of epidermal growth factor receptor (EGFR)-mutated lung cancer. EGFR mutations are associated with responsiveness to EGFR-tyrosine kinase inhibitors (TKIs). This article will focus on the interest of EGFR-TKIs in CNS metastases of NSCLC.

EGFR mutation in NSCLC

EGFR is a cell membrane tyrosine kinase receptor. Somatic EGFR mutations are associated with the development of NSCLC. According to the U.S. Food and Drug Administration and the European Medicines Agency, treatment by EGFR-TKI, erlotinib, gefitinib, or afatinib is limited to patients with an EGFR-mutated NSCLC in first line setting. Erlotinib can be given regardless of the EGFR status as second- or third-line therapy. Second-generation TKIs, such as dacomitinib, are under development ( ).

Sequencing is the recommended technique to detect the mutations. Other more sensitive techniques are under evaluation ( ). Mutations are mainly detected in exons 18–21 of the EGFR gene encoding for the TK domain, and particularly the binding sites of EGFR-TKI ( Figure 4.1 ) ( ; ; ). In more than 85% of cases, EGFR mutations are exon 19 deletions or the L858R point mutation in exon 21 ( ; ; ). These mutations are almost exclusively found in nonsquamous NSCLCs, particularly papillary and lepidic adenocarcinoma ( ). In NSCLC, EGFR mutations are considered mutually exclusive from other molecular alterations, such as K-Ras and HER2 mutations or ALK gene rearrangements ( ). In NSCLC, EGFR mutations were reported in 5–10% of whites, in 30% of white nonsmokers, and more than 60% of Asian nonsmokers. EGFR mutations were more common in women (20–62%) than men (1–19%) ( ; ).

Figure 4.1, EGFR oncogenic mutations in lung cancer.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here