Study shows leptomeningeal metastases more prevalent in NSCLC patients with EGFR mutations

Leptomeningeal metastases (LM), a devastating complication and predictor of poor survival in lung cancer patients, was found to be more prevalent in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. Patients receiving tyrosine kinase inhibitors (TKIs) targeting EGFR mutations had a longer overall survival (OS) than those who did not receive TKIs, demonstrating the effectiveness of TKIs for LM therapy.

The leptomeninges are the membranes that surround the brain, including the arachnoid mater and pia mater, and ensue when cancer cells metastasize to intracranial structures and the cerebrospinal fluid (CSF). LM occurs in 10-26% of lung cancer and the presence of LM is a devastating complication for patients and often associated with poor survival. Treatment strategies for LM include epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), chemotherapy, whole brain radiotherapy (WBRT), intrathecal chemotherapy (ITC), surgery, and ventriculoperitoneal (VP) shunt operations. However, therapeutic options for treating LM are challenging with no standard treatment. The use of EGFR-TKIs markedly prolong survival in patients with EGFR mutations and frequent EGFR mutations.

A group of Chinese investigators retrospectively screened 5,387 NSCLC patients at Guangdong Lung Cancer Institute, Guangdong General Hospital, from January 2011 to June 2015 to examine the prevalence of EGFR mutations in NSCLC patients with LM as well as treatments and clinical outcomes. Medical records of patients were reviewed for demographics, tumor-related features, and major treatments. Patients with known EGFR status were screened for LM by cerebrospinal fluid (CSF) cytology test or gadolinium-enhanced brain magnetic resonance imaging (MRI). OS was determined from the period of LM diagnosis to death or last follow-up. OS was estimated using the Kaplan-Meier method and presented as a median value with a two-sided 95% confidence interval (CI).

The results of the study published in the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer (IASLC), showed that of the 5,387 patients examined only 3,775 patients were tested for EGFR gene status. Of those tested for EGFR status, 1,258 patients had confirmed EGRF mutations and 2,517 had wild-type EGFR (no identified mutations). The incidence of LM in all 5,387 patients was 3.4% (184/5,387). However, the incidence of patients with LM harboring EGFR mutations (9.4%, 118/1258) were significantly more than those with a wild-type EGFR status (1.7%, 42/2,517; χ2 = 122.9, p <0.001). Of the 118 patients harboring EGFR mutations, 109 patients had the most common EGFR mutations, 53 had exon 19 deletions (del 19) and 56 had Leu858Arg mutations (L858R).

Patients that were given TKIs for treatment of LM had longer OS than patients that did not take TKIs (10 months, 95% CI=8.9-11.1 vs. 3.3 months, 95% CI = 0.5-6.1; p <0.001). Patients that had not taken TKIs prior to LM demonstrated a longer OS than those who failed on initial TKIs (12.2 months, 95% CI=9.7-14.8 vs. 9.2 months, 95% CI=7.8-10.5; p=0.016). Patients that underwent WBRT for LM did not show longer OS than those without WBRT (9.3 months, 95% CI=8.4-10.3 vs. 8.1 months, 95% CI=4.8-11.4; p=0.448) and patients treated with both WBRT and TKIs did not have longer OS than those who only received TKIs (9.7 months, 95% CI=8.7-10.8 vs. 10.1 months, 95% CI=7.1-13.1; p=0.778). Chemotherapy after LM was associated with prolonged survival when compared to those not receiving chemotherapy (21.0 months, 95% CI=14.8-27.1 vs. 8.7 months, 95% CI=6.8-10.6; p=0.001). Overall, the two factors that significantly affected prolonged survival after LM were TKIs (p<0.001, HR=0.218, 95% CI=0.116-0.411) and chemotherapy (p<0.001, HR=0.206, 95% CI=0.092-0.460).

The authors comment that, "This study had some limitations, however, we showed that OS after LM was longer than that in previous reports, and LM were much more frequent in NSCLC patients harboring EGFR mutations. EGFR-TKIs were the optimal strategy for LM with EGFR mutations, especially TKI treatment-naÏve patients. Nevertheless, active treatment with WBRT, with or without EGFR-TKIs, was not supported by our study."