Growing number of patients with EGFR activating mutation (EGFR M+) treated with EGFR-TKIs (tyrosine kinase inhibitors) suffer from metastases to central nervous system (CNS). This is because the prognosis of patient with EGFR M+ has substantially prolonged by EGFR-TKIs, but efficacy of EGFR-TKIs in CNS lesion is relatively low. By using Matrix Assisted Laser Desorption/Ionization (MALDI) Mass Spectrometry imaging (MSI) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), we analyzed whether erlotinib is penetrating to CNS.
Autopsy specimens from a patient with EGFR M+ who was taking erlotinib for two months were analyzed. On suspicion of leptomeningeal metastasis, patient was taking erlotinib even after the radiological progression in thoracic lesion until 48 hours before death. iMScope (Shimadzu, Japan) was used for IMS, and the concentrations of erlotinib in specimens were validated using LC-MS/MS.
Autopsy survey found no leptomeningeal metastasis. MSI showed erlotinib distribution to normal tissue and tumor lesion but not to brain specimens. Concentration of erlotinib (ng/mm2) in normal lung tissue, pulmonary metastases with lymphangitis carcinomatosis, pleural dissemination, medulla oblongata, cerebellum, and cerebrum was 12.0, 11.8, 12.5, 2.8, 1.4 and 1.7, respectively. Concentration of cerebrospinal fluid was 96.4 ng/mL, which is slightly higher than the previous reports probably due to the trace contamination of blood during the procedure of collection.
Although erlotinib concentration in normal and cancer lesion was biologically enough, concentration to CNS lesion was fairly low. Penetration to cerebrospinal fluid did not correlate with distribution of erlotinib to brain parenchyma. These results may suggest that the efficacy of erlotinib to CNS metastasis is achieved by the destruction of blood brain barrier and penetration to the cancer lesion. Whether better control of CNS metastasis will be achieved by penetration to CNS parenchyma or only to the cancer lesion is an interesting debate for the future development of TKIs.
Clinical trial identification
Y. Goto: membership on an advisory board or board of directors Lilly, Boehringer Ingelheim, Taiho
A. Hamada: corporate-sponsored research from Chugai. Y. Ohe: membership on an advisory board or board of directors Chugai, AstraZeneca, Lilly, Boehringer Ingelheim, Novartis, ONO, BMS. All other authors have declared no conflicts of interest.