EGFR mutation and striking response to gefitinib in a patient with leptomeningeal carcinomatosis and erlotinib-refractory adenocarcinoma lung cancer

Proc Amer Assoc Cancer Res, Volume 47, 2006 4029 Although various mutations of the epidermal growth factor receptor (EGFR) gene have been identified to confer sensitivity towards the EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, it is not known if there are mutations that may result in differential activities of the two inhibitors. We describe a 70 year-old Japanese-American never-smoker woman with advanced adenocarcinoma of the lung who developed symptomatic brain metastases while on erlotinib. She failed further chemotherapies, including temozolomide and irinotecan, and subsequently developed extensive symptomatic leptomeningeal carcinomatosis. The patient then demonstrated prompt striking clinical response as early as three weeks of starting monotherapy gefitinib (150mg p.o. daily), which was subsequently confirmed radiographically by repeat CT and MRI. Using laser microdissection (LMD) and EGFR gene sequencing, we identified two heterozygous somatic EGFR mutations, L858R and E884K, in her pretreatment tumor biopsy specimen and tumor cells isolated from her cerebrospinal fluid. In vitro transfection and biochemical studies demonstrated that the novel E884K mutation confers opposite effects in sensitivity to the two EGFR inhibitors. EGFRE884K and EGFRL858R+E884K enhanced the sensitivity of the mutated receptor to gefitinib inhibition. Conversely, the E884K mutation resulted in decreased responsiveness of the receptor to erlotinib, and it significantly abrogated the drug sensitivity conferred by L858R (EGFRL858R+E884K). This study demonstrates that it is possible to have EGFR mutation mediating differential responses to gefitinib and erlotinib. This also represents the first case to describe a striking response to single-agent gefitinib in a patient with leptomeningeal metastases and erlotinib-refractory lung adenocarcinoma.