Germ-line exon 21 EGFR mutations, V843I and P848L, in nonsmall cell lung cancer patients

To the Editor: Somatic epidermal growth factor receptor ( EGFR ) mutations are now routinely integrated in the molecular diagnosis of nonsmall cell lung cancers (NSCLC) [1, 2]. Thus, germ-line EGFR mutations are rarely mentioned or looked for in the context of patients with a family history of cancer, as their association with NSCLC familial cancer risk is not well established. Moreover, the predictive value of these mutations for response to EGFR tyrosine kinase inhibitors (TKIs) is not well known [3]. We report here two different heterozygous germ-line EGFR variants identified in two Caucasian NSCLC patients, who demonstrated different responses to EGFR-TKI. A 63-year-old Caucasian, male former smoker with no family history of cancer (fig. 1a), was admitted for dyspnoea in August 2011, leading to discovery of a lower left lobe lung tumour and pleural effusion. Trans-thoracic biopsy diagnosed an invasive, acinar-predominant adenocarcinoma, classified cT2a N3 M1a (stage IV). Molecular analyses of the tumour by direct sequencing identified two concomitant heterozygous EGFR exon 21 mutations, L858R and V843I, confirmed in two independent experiments (fig. 1b). The V843I variant, but not L858R, was also detected in DNA obtained from a blood sample, with written informed consent, confirming a germ-line mutation (fig. 1c). Following treatment with cisplatin and pemetrexed, the patient relapsed in December 2012 with vertebral metastasis. An EGFR-TKI (erlotinib) was initiated, resulting in a stable disease for 9 months. Figure 1. a–c) Case 1, with epidermal growth factor receptor ( EGFR ) exon 21 mutations (V843I and L858R). a) Pedigree chart. The black case corresponds to the index patient. b) DNA sequencing electrophoretograms for DNA obtained from lung tumour tissue identifying EGFR exon 21 mutations; both mutations are present. c) DNA sequencing electrophoretograms for DNA obtained from blood, identifying one EGFR exon 21 mutation, the V834I variant, is present and confirming …