Brain Metastasis in Patients with Non-Small Cell Lung Cancer: Immunohistochemical Markers

Introduction

Lung cancer is the leading cause of cancer death in the United States ( ) and NSCLC comprises approximately 85% of lung cancer cases. It is estimated that 25% of patients present with Stage I and II disease ( ) typically managed with surgery with or without adjuvant chemotherapy ( ; ). However, despite having early-stage disease, approximately 50% of these patients will relapse ( ). Advances in the management of brain metastases during the past few decades have provided patients with longer survival and better quality of life. Despite these advances, brain metastases continue to be a major challenge in neuro-oncology. NSCLC remains the leading cause of death from cancer in both men and women, with approximately 210,000 new cases of NSCLC diagnosed annually in the United States. Central nervous system metastasis is a common and devastating problem for patients with NSCLC, with reported incidences of up to 54%. Lung cancer is the malignancy that most commonly metastasizes to the brain; it is estimated that approximately 10% of patients already have brain metastases at the time of diagnosis and that approximately 40% of patients with lung cancer will develop brain metastases during the course of the disease. Among these patients, those with locally advanced disease who are treated with chemotherapy and chest radiotherapy with or without surgery have a high rate of developing brain metastases. It is anticipated that, with the advances of combined modality therapy that has led to improvements in intrathoracic local disease control and prolonged overall survival, there will be a concomitant increase in the number of patients with NSCLC metastatic to the brain.

To our knowledge to date, it remains unclear whether patients with early-stage NSCLC should be screened for brain metastases according to published clinical guidelines ( ; ; ). In its latest joint statement, the American Thoracic Society and the European Respiratory Society recommend no preoperative imaging of the brain in patients with NSCLC ( ). In fact, it is believed that the routine screening is cost-ineffective because of the low incidence of brain metastasis in asymptomatic patients (Yohena et al., 2005). Some reports argue that early detection of occult brain metastases will avoid increased morbidity either by allowing earlier treatment of the brain or by avoiding futile thoracotomies. It has been reported that performance status, extent of extracranial disease, control of primary cancer, and age are predictors of overall survival in patients with NSCLC. However, studies have produced contrasting results regarding the correlation between tumor histology and the risk of developing brain metastases. Therefore, there is a need to identify biologic markers that can identify patients with NSCLC who are at increased risk of developing brain metastases. Patients with NSCLC who develop brain metastases are most likely to benefit from therapy addressing the brain that would substantially improve their quality of life. An analysis of subgroups of patients with NSCLC demonstrated that certain populations are at particularly high risk of brain metastasis.

Several lines of studies have demonstrated that the metastatic cascade is rather complex and involves reciprocal interactions between tumor cells and host tissues, including alterations in tumor cell proliferation, insensitivity in growth inhibitory signals, evasion of programmed cell death, adhesion, proteolysis, invasion, and sustained angiogenesis. Herein, the discussion will be limited to those markers involved in one or more aspects of the aforementioned fundamental characteristics of tumorigenesis and development of metastases. These include epidermal growth factor receptor (EGFR), Ki-67, caspase-3, vascular endothelial growth factors A and C (VEGF-A and VEGF-C) and vascular endothelial growth factor receptor (VEGFR), and E-cadherin.

Markers with potential role in predicting NSCLC metastases to the brain Ki-67

Immunostaining with the Ki-67 antibody is a widely accepted method for evaluating proliferative activity in a variety of human tumors. Various methods have been used to evaluate the proliferative activity of a neoplasm, but the most widely used method is the estimate of the labeling index (LI), which consists of dividing the number of positive tumor cells by the total number of tumor cells in 10 hot spots. The latter is defined as the area of the tumor with the highest number of positive cells. The Ki-67 LI correlates well with the predicted growth fraction, although it consistently overestimates the proliferative activity of tumors and, thus, is not an exact reflection of tumor growth. Our group found a strong correlation between a high Ki-67 LI and the development of brain metastases ( ). We found that patients with a Ki-67 LI ≥30% not only had a bad prognosis in general but also had a 12 times increased risk of developing brain metastases compared with patients who had lower proliferative activity (adjusted odds ratio of 12.2) ( Figure 7.1 ).