Inherited germline T790M mutation and somatic epidermal growth factor receptor mutations in non-small cell lung cancer patients.

Five cases of non-small cell lung cancer, associated with germline transmission of epidermal growth factor receptor (EGFR)-T790M mutation, have been reported1; these patients had family histories of lung cancer. The activity of gefitinib was tested in only two patients, who were both refractory to this drug.2 Herein, we describe a family of European descent in which two family members had non-small cell lung cancer associated with germline transmission of T790M mutation and who were treated with gefitinib (Figure 1A). The proband was a 72-year-old female, never-smoker, who was diagnosed with an adenocarcinoma of the lung with bilateral pulmonary lesions. This patient was initially treated with chemotherapy for four courses, resulting in stable disease for 6 months, as determined by radiological examination. When the disease progressed, treatment with oral gefitinib at the dose of 250 mg/d was initiated, resulting in a partial response lasting for 9 months; subsequently, the patient developed pleural and cerebral progression of disease and died within 5 months. A 74-year-old never-smoker sister of the proband was diagnosed with a poor differentiated locally advanced (stage IIIB for pleural effusion) carcinoma of the lung and was treated with a first-line chemotherapy, resulting in a partial response lasting for 12 months, after which new bone metastases were observed. As second-line treatment, oral gefitinib 250 mg/d was started, and a partial response was obtained that is lasting from 45 months; the patient is still alive and on treatment with gefitinib. No other members of this family developed lung cancer. DNA was isolated from peripheral blood mononuclear cells or paraffin-embedded tumor samples, using the microDNA-kit (Qiagen, Hilden, Germany). Nested polymerase chain reaction to amplify EGFR (exons 18–21) and K-RAS (exon 1) and sequencing of polymerase chain reaction products on a ABI-3100 Genetic Analyzer was performed. The EGFR-T790M mutation was found in the germline DNA of both patients (Figure 1B), whereas no mutations were detected in the EGFR exons 18, 19, and 21. In contrast, no EGFR mutations were observed in the two daughters of proband and in the two sons of individual II. In the tumor tissue of individual I, we identified the deletion of EGFR E746-A750 in exon 19 but no EGFR mutations in the exons 18, 20, and 21 (Figure 1C). In the tissue of individual II, no EGFR mutations in the exons 18, 19, and 21 were found, whereas the exon 20 could not be studied because no sufficient tumor tissue was present. No mutations were observed in codons 12 and 13 of K-RAS exon 1 in the tissues of both patients. Our data support the hypothesis that an inherited T790M mutation confers an enhanced susceptibility to develop lung tumors3; moreover, the presence of a T790M germline mutation does not necessarily predict for resistance to EGFR-tyrosine kinase inhibitors. The responses to gefitinib could possibly be due to the absence of T790M and K-RAS mutations and the occurrence of EGFR-activating mutations in the tumor tissues. However, other mechanisms, such as increased gene copy number,4 may be responsible for response to gefitinib in the case of individual II.