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Marzanna Ciesielka



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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-14 - The Molecular Landscape of Lung Adenocarcinomas with Activating EGFR Gene Mutations Determined by Targeted-Sequencing (ID 12476)

      16:45 - 18:00  |  Author(s): Marzanna Ciesielka

      • Abstract
      • Slides

      Background

      The analysis of EGFR activating mutations and ALK rearrangement is a routine procedure in qualification of NSCLC patients for molecularly targeted therapy. Targeted sequencing, as a type of NGS, allows more comprehensive analysis of low-frequency variations in suppressors and oncogenes that are commonly mutated in solid tumors. In the following study we analyzed a molecular landscape of NSCLC patients harboring EGFR activating mutations who response for EGFR TKIs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The studied group included 19 Caucasian patients (7 male and 12 female, median age 65±12 years, 4 current smokers, 12 non-smokers and 3 former-smokers) with lung adenocarcinoma. 12 (63%) deletions in exon 19, 4 (21%) substitutions Leu858Arg in exon 21, 2 (11%) insertions A763_Y764 in exon 20 and 1 (5%) substitution Thr790Met in exon 20 of EGFR gene were detected using real-time PCR technique. Four non-smoking patients (median age 65±12 years) with lung adenocarcinoma and wild-type (wt) of EGFR gene were a control group. The DNA for the analysis was isolated from FFPE tissue or cellblocks and the mutational landscape was evaluated using Illumina’s TruSight Tumor 26 panel on miSeq platform (Illumina, USA).

      4c3880bb027f159e801041b1021e88e8 Result

      The targeted sequencing confirmed lack of EGFR gene mutations in control group and the presence of EGFR mutations in 84% (16/19) of patients with these mutations confirmed in routine diagnostics - all deletions in exon 19 and substitutions in exon 21 were confirmed. Targeted sequencing did not identify rare mutations in exon 20. NGS compared to real-time PCR technique achieved 86,95% accuracy with 84,21% of sensitivity and 100% of specificity or PPV and NPV values reached 100% and 57,10%, respectively. The targeted sequencing allowed to identify 166 variants in 25 out of 26 genes covered by the analysis. The most frequently mutated suppresors were TP53, MSH6 and APC (38%; 19% and 17% respectively) and oncogenes were MET, PDGFR and EGFR-AS1 (31%, 14% and 13% respectively). The frequency of particular variants was significantly higher in smokers than in non-smokers (p=0,0002; χ²=16,94). U-Man Whitney test showed that the median number of genetic alternations in EGFR mutated group was significantly higher than in wt EGFR group (p=0.0091; median: 17 vs 11 respectively).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The targeted sequencing allowed to detect the most common activating mutations in EGFR gene and numerous variants both in suppressors and oncogenes. NGS showed too low sensitivity for detection of rare EGFR mutations. The molecular landscape was more unpredictable and varied in smokers compare to non-smokers.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.13 - Targeted Therapy (Not CME Accredited Session) (ID 979)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.13-08 - Assessment of EGFR Gene Mutations In cf-DNA in Monitoring of Response to EGFR TKIs in Patients with Lung Adenocarcinoma (ID 12474)

      12:00 - 13:30  |  Author(s): Marzanna Ciesielka

      • Abstract
      • Slides

      Background

      Molecular analysis of cf-DNA in NSCLC patients enables detection and monitoring of EGFR mutations. It allows for detection of the acquired resistance for 1st and 2nd generation of EGFR-TKIs caused Thr790Met substitution. The third generation of EGFR-TKIs (osimertinib) could overcome the resistance in patients with Thr790Met mutation.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The studied group included 23 Caucasian patients (8 male and 15 female, median age 71±9) with diagnosed lung adenocarcinoma and with EGFR mutations detected in tumor samples. Blood samples were collected before administration of EGFR-TKIs in all patients, and re-collected repeatedly from 10 patients during therapy. EGFR mutations and content of mutated cf-DNA were analyzed using ctEGFR Mutation Analysis Kit (Entrogen, USA) in Rotor-Gene Real-Time PCR device (Qiagen, Germany).

      4c3880bb027f159e801041b1021e88e8 Result

      Analysis of EGFR activating mutations in cf-DNA showed 82.61% concordance/sensitivity (19/23) with tumor samples. The mean content of mutated cf-DNA was 7.44% and it was significantly lower (p<0.000035) than in tumor samples (34.54%). Concentration of mutated cf-DNA positively correlated with advanced stage of the disease. Monitoring of EGFR status in cf-DNA showed reduction and stabilization of mutant DNA content with the emergence of response to EGFR-TKIs treatment. Primary Thr790Met substitution was undetectable in cf-DNA and in tumor samples. Acquired resistance in Thr790Met mechanism during EGFR-TKIs treatment was detected only in one patient (1/10). This patient responded to osimertinib therapy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Analysis of EGFR mutations in cf-DNA shows lower sensitivity than in DNA isolated from tumor samples. Multiple evaluations of EGFR status may be useful in monitoring of therapy and allows for early detection of acquired resistance.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.