Detection of Overlooked Rare EGFR Mutations in Non-small Cell Lung Cancer Using Multigene Testing

Abstract

Background: Recognizing rare molecular variants of driver mutations poses a challenge in precision oncology, particularly for treatment of non-small cell lung cancer (NSCLC). In this study, we aimed to determine whether Oncomine Dx Target Test Multi-CDx System (ODxTT), the most widely used genetic test for NSCLC in Japan, potentially overlooks druggable EGFR mutations.

Materials and methods: Among 418 patients who underwent molecular testing using ODxTT at our hospital, 267 were diagnosed with adenocarcinoma. No mutations were reported in 82 of these cases. For these 82 cases, we searched for EGFR mutations in exons 18-21 by examining the binary alignment map file. Once a mutation was identified, its pathological significance was evaluated using the ClinVar database to determine whether ODxTT had overlooked any actionable EGFR mutations.

Results: Mutations in EGFR exons 19 and 18 were identified in six and four cases, respectively. Three, six, and none of these variants were detectable using the Cobas EGFR Mutation Test v2, Lung Cancer Compact Panel, and Amoy Dx, respectively. Of the 10 patients, five were subsequently treated with EGFR TKI; three showed partial response, one had stable disease, and one had progressive disease.

Conclusions: ODxTT failed to identify 10 actionable EGFR mutations, accounting for 12.2% (10/82) of the cases initially reported as not carrying actionable mutations. Therefore, comprehensive genomic profiling should be actively performed early in cases with high clinical suspicion of EGFR mutations.

Keywords: EGFR mutation; Oncomine Dx Target Test; next‐generation sequencing; non‐small cell lung cancer.

FIGURE 1

Driver mutations in EGFR detected using ODxTT in adenocarcinoma (n = 264).

FIGURE 2

BAM data for EGFR exon 19 deletion (p.E746_S752delinsV) displayed in IGV. The chr7:55242400–55 242 500 region in case 9 was visualized using IGV. Although the patient tested negative, a deletion was observed.

FIGURE 3

Chest computed tomography images before and after administering osimertinib in case 5. (A) Chest CT scan before osimertinib treatment. (B) Chest CT scan 1 year after treatment. Tumor shrinkage and decreased pleural effusion were observed.