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Katarzyna Duk
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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.13-14 - The Clinical Usefulness of Liquid Biopsy for Detection and Dynamic Monitoring of EGFR T790M in NSCLC Patients on EGFR-TKI Therapy (ID 14135)
16:45 - 18:00 | Author(s): Katarzyna Duk
- Abstract
Background
The greatest limitation of the I & II generation EGFR TKIs’ efficacy is the resistance acquired by most treated patients through the T790M mutation present in exon 20 of EGFR gene. Non-invasive access to the tumor DNA circulating in the blood of NSCLC patients, so called liquid biopsy, enables the real-time monitoring of status and level of mutated EGFR gene DNA (mEGFR) during EGFR TKI treatment instead of retrospective evaluation of tumor tissue specimens. In the present study we evaluated the feasibility and the diagnostic usefulness of quantitative EGFR mutations analysis in liquid biopsy collected from NSCLC patients during EGFR TKI treatment.
a9ded1e5ce5d75814730bb4caaf49419 Method
The study group consists of 40 patients with advanced NSCLC treated with EGFR TKI (erlotinib, gefitinib or afatinib) in the first line. Peripheral blood is prospectively collected at the time of diagnosis (baseline) and then every month during treatment. In 10 patients (7 patients with deletion in exon 19 and 3 patients with L858R mutation in exon 21 of EGFR gene) sampling was followed until clinical progression. The mutated EGFR DNA was analyzed quantitively in plasma using cobas EGFR Mutation Test v2 (Roche, Germany).
4c3880bb027f159e801041b1021e88e8 Result
The mEGFR in plasma of NSCLC patients demonstrated notable dynamics during EGFR TKI treatment. In 8 out of 10 (80%) patients followed until progression, who responded well to EGFR TKIs, the complete clearence of mEGFR in plasma in first 2 months of treatment was observed, regardless the type of activating EGFR mutation. The levels of mEGFR remained undetectable in plasma for several months of treatment in those patients. In 6 (60%) patients a rapid raise to or above mEGFR baseline preceded clinical progression in time, in 4 patients by at least four weeks. In 4 patients, the raising level of mEGFR in plasma was accompanied by the increasing T790M mutation level. In 2 patients, the plasma level of mEGFR was undetectable at diagnosis and during treatment.
8eea62084ca7e541d918e823422bd82e Conclusion
The dynamic changes in levels of mutated EGFR gene DNA in plasma of NSCLC patients reflect their response to EGFR TKI treatment. The monitoring of T790M mutation levels in plasma by allele-specific qPCR assay allows to observe disease progression on EGFR TKIs much earlier than conventional imaging techniques. The study is ongoing: at least 80 patients are to be recruited and clinical data correlated with results of molecular tests. This study is financed by the investigator initiated research grant from AstraZeneca.
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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): Katarzyna Duk
- Abstract
Background
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
