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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Presentations: 1
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
P2.13-31 - p.(Leu747Pro) Mutation Leads to Misdiagnosis in EGFR Mutation Assessment – Analysis in a Cohort of 1841 Polish NSCLC Patients (ID 14123)
16:45 - 18:00 | Author(s): Paulina Skrońska
Epidermal growth factor receptor (EGFR) mutation assessment is essential for targeted therapy of non-small cell lung cancer (NSCLC) as predictive biomarker of the response to EGFR tyrosine kinase inhibitors (EGFR-TKI).
There is a number of well-known actionable mutations in EGFR gene such as a deletions in exon 19 or p.(Leu858Arg), still some others, infrequent or complex are also observed.
Missense substitution p.(Leu747Pro) (c.2239_2240TT>CC) is one of the rare mutations that might be misdiagnosed if EGFR mutation analysis is performed with commercial real-time PCR based kits. The eventual clinical consequences are considerable. While p.(Leu747Pro) substitution is reported as an most likely inhibiting mutation, it might be confused with an activating deletion in exon 19 of EGFR gene.
Up to date, majority of published reports providing data on p.(Leu747Pro) role in resistance towards EGFR-TKI came from Asia.
The frequency of p.(Leu747Pro) in the European population has not been evaluated yet. It was detected accidentally in large NSCLC patients cohorts using varied molecular methods.
The aim of the study was to assess the frequency of p.(Leu747Pro) in a group of 1841 NSCLC patients referred for EGFR mutation analysis between 2015 and 2017 to the National Institute of Tuberculosis and Lung Diseases.a9ded1e5ce5d75814730bb4caaf49419 Method
EGFR mutation analysis was performed with CE-IVD real-time PCR kit using complementary primer pairs and oligonucleotide probes.
The frequency of EGFR gene mutations was 8,4% (n=155), including deletions in exon 19 (n=84), p.Leu858Arg (n=56), insertions in exon 20 (n=9), p.Glu719X (n=1), p.Glu719X and p.Ser768Ile(n=5).
All samples with a deletion in exon 19 were reanalyzed by PNA-LNA PCR clamp to confirm the test result.
In case of a discrepancy between the outcomes, direct Sanger sequencing was performed.4c3880bb027f159e801041b1021e88e8 Result
Upon reanalysis, 4 (4,8%) lung adenocarcinoma patients (3 female, 1 male) with initially identified deletion in exon 19 proved to be misdiagnosed. Instead, in all p.(Leu747Pro) substitution was decisively confirmed with direct sequencing.
One patient with p.(Leu747Pro) mutation in EGFR gene gained clinical benefit from EGFR-TKI therapy. She achieved partial response according to RECIST while treated with erlotynib for 7 months.8eea62084ca7e541d918e823422bd82e Conclusion
Diagnostic laboratories as well as clinicians should be aware of the commercial real-time PCR based test limitations, despite their IVD certification.
New methods such as next generation sequencing may solve misdiagnosis problem with the exon 19 deletion of EGFR gene.
Data concerning rare variants in EGFR gene are limited and results are varied, the mechanism of the p.(Leu747Pro) variant response to EGFR-TKIs needs further investigation.6f8b794f3246b0c1e1780bb4d4d5dc53
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