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Detection of Rare Mutations in CtDNA Using Next Generation Sequencing
Published on: August 24, 2017
Detection of Overlooked Rare EGFR Mutations in Non-small Cell Lung Cancer Using Multigene Testing
Naoki Shiraishi1, Takayuki Takahama1,2, Kazuko Sakai3
1Genome Medical Center, Kindai University Hospital, Osaka, Japan.
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.
Insights
The Oncomine Dx Target Test (ODxTT) missed 10 actionable EGFR mutations in non-small cell lung cancer (NSCLC) patients. Comprehensive genomic profiling is recommended for early detection of these critical mutations.
Area of Science:
- Oncology
- Genetics
- Molecular Diagnostics
Background:
- Precision oncology for non-small cell lung cancer (NSCLC) faces challenges in identifying rare driver mutations.
- The Oncomine Dx Target Test Multi-CDx System (ODxTT) is widely used in Japan for NSCLC genetic testing.
- This study investigates potential overlooked druggable epidermal growth factor receptor (EGFR) mutations by ODxTT.
Purpose of the Study:
- To evaluate if the ODxTT system misses actionable EGFR mutations in NSCLC patients.
- To identify the frequency and types of EGFR mutations overlooked by ODxTT.
- To assess the clinical significance of these missed mutations.
Main Methods:
- Retrospective analysis of 82 non-small cell lung cancer (NSCLC) adenocarcinoma cases initially reported as mutation-negative by ODxTT.
- Targeted sequencing of EGFR exons 18-21 using binary alignment map files.
- Pathological significance of identified mutations assessed using the ClinVar database.
Main Results:
- Ten actionable EGFR mutations (exons 19 and 18) were identified in 12.2% of initially negative cases.
- Detection rates varied among other common genetic tests: Cobas EGFR Mutation Test v2 (3/10), Lung Cancer Compact Panel (6/10), Amoy Dx (0/10).
- Five patients received EGFR tyrosine kinase inhibitor (TKI) therapy, showing partial response (3), stable disease (1), or progressive disease (1).
Conclusions:
- ODxTT failed to detect 10 actionable EGFR mutations in a significant proportion of NSCLC cases.
- Comprehensive genomic profiling is crucial for early and accurate identification of EGFR mutations in suspected cases.
- Timely detection of actionable mutations can guide targeted therapy selection in NSCLC treatment.
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