Brain Metastasis from Non-Small Cell Lung Cancer: Use of Epidermal Growth Factor Receptor and HER2 Status for Targeted Therapy

Introduction

The most common origins of brain metastases in adults are lung (50–60%) and breast cancers (15–20%) ( ). Lung cancers are divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma subtypes. Because SCLCs have a high tendency of brain metastases at first diagnosis, central nervous system (CNS) prophylaxis is the classic standard treatment protocol ( ).

The prognosis of NSCLC varies according to stage, whereas presence of metastases (Stage IV) results in poor prognosis (5-year survival less than 5%) with median survival of less than 1 year ( ). In NSCLC, the brain metastasis occurs in 20–30% of patients during the course of their disease ( ). Because brain metastasis is a main cause of morbidity and mortality ( ), the prognosis of NSCLC with brain metastases is very poor, with a median survival of 4–11 weeks in untreated patients and 3–6 months in whole-brain radiation therapy (WBRT) ( ).

The standard treatment options for brain metastasis include symptomatic therapy with corticosteroids and WBRT ( ). The poor outcomes and relapses following WBRT alone indicate a need for new therapeutic options. However, treatment with systemic chemotherapy is controversial because chemotherapeutic agents may not cross the blood–brain barrier (BBB) and therefore are less effective against CNS disease ( ). The incidence of brain metastasis in NSCLC patients has been increasing over the last few years ( ), probably because of improved therapy, diagnostic modalities, and early detection screening programs. For example, in patients with HER2-positive breast cancer, improved targeted therapy might increase the incidence of brain metastases ( ).

Targeted therapy of NSCLC

The standard treatment options for resectable NSLCLs are surgery with or without adjuvant therapies depending on pathologic stage. If it is not resectable, systemic chemotherapy is recommended (e.g., Stage IIIb and IV) ( ). In addition, targeted therapy is used as first-line therapy in advanced NSCLC. For example, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib or erlotinib are recommended as first-line therapy for patients harboring EGFR mutations ( ). EGFR-TKIs significantly improve progression-free survival compared with standard chemotherapy in these patients ( ).