A long-term responding epidermal growth factor receptor mutated non-small cell lung cancer patient with extremely high mutation allele frequency

Abstract

License (http://creativecommons.org/licenses/by-nc-sa/4.0/) Epidermal growth factor receptor (EGFR) mutation is the most frequent oncogenic driver in non-small cell lung cancer (NSCLC) [1, 2]. Among EGFR mutations, exon 19 deletion and exon 21 L858R are two of the most common mutations; hence they are referred to as common mutations [1]. In addition to them, there are many types of EGFR mutation other than common mutations. They are treated as uncommon mutations [3, 4]. Recent advances in analysis technology using next-generation sequencing (NGS) have made great progress also in the area of EGFR mutation [5–8]. By this analytic method, it has become clear that there is heterogeneity among patients with common mutations. Among these possible heterogeneities, mutation allele frequency (MAF) has drawn attention [9–13]. MAF is defined as the number of times a mutated base is observed, divided by the total number of times any base is observed at the locus. It corresponds to the percentage of sequencing reads that contain the mutation, and the proportion of alleles is affected by the proportion of tumor cells in the sample and the presence of copy number alterations [9–13]. Here we report a case of a patient with EGFR mutation with very high MAF, who responded to EGFR-tyrosine kinases for a long time. An 82-year-old woman was referred to our hospital for the treatment of EGFR mutated adenocarcinoma of the lung. Her performance status (ECOG) was 0, and clinical stage was stage IVA. She was diagnosed as having EGFR mutated (exon 21 L858R) adenocarcinoma of the lung. Gefitinib was effective for 28 months. Since the adenocarcinoma recurred, afatinib was administered and it responded for 24 months. Due to the gradual progression of dementia during this course of treatment, afatinib treatment was terminated. The content ratio of tumor cells in the tissue sample and MAF were examined using NOIR-SS (DNA Chip Research Inc. Tokyo, Japan) [6]. In brief, DNA was extracted from slices of FFPE tissue block of the patient using a Maxwell RSC DNA FFPE kit (Promega, Madison, USA). 50 ng of DNAs were fragmented by a Covaris Focusedultrasonicator (Woburn, MA, USA) and a molecular barLetter to Editor