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N. Bosselut



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    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO10.03 - Decreased KRAS and Increased HER2 or PI3K mutations prevalence in the French emigrant population from African continent in lung adenocarcinoma metastatic cancer (ID 3106)

      16:25 - 16:30  |  Author(s): N. Bosselut

      • Abstract
      • Presentation
      • Slides

      Background
      Approximately 1.2 million people are diagnosed with lung cancer every year. The identification of genomic alteration can impact therapeutics. EGFR mutation status predicts how patients can respond to EGFR tyrosine kinase drugs (EGFR-TKI). EGFR positive patients have an improved response rate to erlotinib or gefitinib; KRAS mutated tumors are not sensitive to EGFR-TKI. Recently, it has been published that patients with mutations inHER2 have a high response rate to trastuzumab. The prevalence of EGFR and KRAS mutations are well known to be associated with sex, histological type of tumor, smoking status and also ethnic origin. HER2, BRAF and PI3K are relevant gene candidates to emerging therapies. Mutation prevalence of the latter genes has not yet been investigated in large populations.

      Methods
      We have analyzed 1375 consecutive patients with metastatic lung adenocarcinomas having the screening of EGFR, KRAS, BRAF, PI3K and HER2 gene mutational status in the Paul Brousse platform between November 2011 and April 2013. The DNA mutation screening was performed using the HRM technology and their identification were analyzed by allelic discrimination and/or sequencing. Our database included all mutations results as well as anonymous diagnosis and socio-demographic data. The birth location has been self-reported.

      Results
      Of the 1375 tumors, the frequencies of EGFR, KRAS, BRAF or HER2 mutations were those usually reported in Caucasian population. Mean age was 65.2 years (SD = 11.2), 821 were male and 519 female. Among our population, 140 patients reported of African birth location, 1220 of European birth location and 15 of Asian birth location.

      TABLE 1. Mutation prévalance and birth location
      European birth location African birth location Asia birth location Total
      EGFR (n/%) 129 (10.6) 13 (9.3) 5 (33.3) 147/1375 (10.7)
      KRAS (n/%) 318 (26.3) 21 (15.0) * 340/1366 (24.9)
      BRAF (n/%) 23 (1,9) 1 (0,75) * 24/1345 (1.8)
      HER2 (n/%) 13 (1.1) 4 (2.9) * 19/1327 (1.7)
      PIK3CA (n/%) 20 (2.0) 5 (4,2) * 25/1159 (2.2)
      *Low effective
      The percentage of EGFR mutations was higher in Asiatic patients, as previously reported. Interestingly the KRAS mutation rate was significantly lower in the African patients (15.0%, CI: 10.0 – 21.9) than in the European patients (26.3%; I: 23.9 – 28.8; p = 0.004). HER2 and PI3K mutation prevalences were more than doubled in African population compared to European population (Fisher's Exact Test, respectively p = 0.10; p = 0.17).

      Conclusion
      Our data show different EGFR, KRAS, and HER2 mutation rates according to the geographical birth location of patients. Interestingly, we noted a significant decreased Kras and higher HER2 and PI3K mutations prevalence in African birth location mutation rates compared to the other populations studied. The incidence of these mutations had not been extensively studied in the population of African birth location. That could suggest, especially in this population, the importance of systematic HER2 and PI3K screening to investigate specific targeted therapy.

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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-016 - High throughput somatic mutation profiling in paraffin embedded Non-Small Cell Lung Cancer biopsies using the LungCarta™ Panel in clinical routine practice (ID 2792)

      09:30 - 09:30  |  Author(s): N. Bosselut

      • Abstract

      Background
      The identification of EGFR mutations as a driver for oncogenic proliferation in Non-Small Cell Lung Adenocarcinoma (NSCLC), in parallel with the development of the tyrosine kinase inhibitors has opened the way to “theranostics”. However, as more targets are identified and more targeted inhibitors are marketed, the medical community now needs to interrogate multiple genes to generate an accurate molecular profile for each individual tumor and determine matching targeted therapeutics. The development of the Next Generation Sequencing (NGS) has opened a new area offering for more comprehensive screening of somatic mutations across 10s to 100s of genes. However, its application in routine clinical practice within the individual therapeutic setting remains impractical due to the large data sets produced, as well as the high potential for generating false positive mutations Therefore atargeted approach seems more appropriate when screening for actionable somatic mutations. MALDI-TOF mass spectrometry (MassARRAY® System) is a flexible high-throughput solution that can easily adapt to newly discovered mutations as well as detect minority alleles of mutated DNAof large sample sets.

      Methods
      We have evaluated the LungCarta™ Panel, a panel targeting 213 somatic mutations in 26 genes. The method relies on multiplex PCR followed by single base extension and analysis using MALDI-TOF Mass Spectrometry.Genes such as EGFR, KRAS, BRAF, ERBB2 or PI3KCA,MAP2K1, EPHA3, NTRKs, STK11, TP53 and DDR2are well-represented.

      Results
      For verification of this panel we have screened a set of 37 lung metastatic adenocarcinoma DNA isolated from formalin fixed paraffin embedded (FFPE) biopsies.These samples were previously characterized for EGFR, KRAS, ERBB2, PIK3CA and BRAF. We identified a total of 26 mutations in 23 of the 37 samples (62%) localized in 10 genes. 100% of the previously known mutations were verified and an additional 12 mutations were identified, 10 of these mutations were located in genes not previously screened. We were able to significantly reduce the DNA amount to as little as 24ng. To further validate the LungCarta panelresults we selected 15 of the samples to be analyzed using NGSand theTruSeqAmplicon - Cancer Paneland11 of the samples generated high quality libraries that could be sequenced. Using this NGS approach we validated the hits obtained by LungCarta. When comparing the two methods, NGS has a quite complicated workflow and we identified more than 50 positive hits for each sample requiring a large bioinformatics effort in order to separate true positives hits from false positive hits. This problem was not seen using the LungCarta where the standard turnaround time for each sample batch was less than 24 hours and the panel showed excellent robustness using DNA obtained from FFPE.

      Conclusion
      We have now applied the LungCarta™ panel to more than 400 patients with NSCLC and were able to not only treat patients promptly, but also enter some others in clinical trials We have identified targets that could be very interesting in the future. Compared to the NGS approach,LungCarta offers a relatively simple workflow with quick turnaround time and minimal sample input requirements.