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J. Morere



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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): J. Morere

      • 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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    O06 - Cancer Control and Epidemiology I (ID 135)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      O06.01 - Lung cancer risks, beliefs, and healthcare access among the underprivileged (ID 2113)

      10:40 - 10:50  |  Author(s): J. Morere

      • Abstract
      • Presentation
      • Slides

      Background
      One goal of the current French National Cancer Plan is to reduce health inequities in cancer control. In this study, an underprivileged population was investigated to analyze exposure to lung cancer risk factors and health care access in order to highlight ways to improve lung cancer control in that population.

      Methods
      Within the nationwide observational study EDIFICE 3, conducted by phone interviews among a representative sample of 1603 subjects aged between 40 and 75 years old, we used the “EPICES” validated questionnaire to examine the association of underserved status with lung cancer risk factors, beliefs, and health care access.

      Results
      Based on the EPICES score, underserved subjects represented 33% of the sample. These subjects subjectively perceived a higher risk of cancer compared to subjects in the served population (21% vs. 14% respectively, p<0.01). Among people with cancer, underserved subjects have a higher rate of lung cancer (10% of cancers vs. 1%, p<0.05). They also have more cancer risk factors: a high BMI (26.0 vs. 24.8, p<0.01), are active smokers (38% vs. 23%, p<0.01) with a higher consumption of cigarettes (16.0 cigarettes/day vs. 10.1, p<0.01) and for a longer period (29.4 years vs. 26.3, p<0.01), and also practice less sport (42% vs. 77%, p<0.01). They have more comorbidities: on average (2.2 vs. 1.8, p<0.01), at least one (76% vs. 65%, p<0.01), hypertension (24% vs. 19%, p<0.05), cardiovascular disease (13% vs. 9%, p<0.05) and respiratory disease (13% vs. 7%, p<0.01). Access to healthcare is not an issue (consultations with a general practitioner are more frequent for the underserved group: 5.4 vs. 3.7 per year, p<0.01). They trust the national health system less (an average score from 1 to 10; 6.0 vs. 6.3, p <0.05). However, 85% of underserved subjects think that lung cancer can be efficiently screened vs. 78% of the served population (p<0.01).

      Conclusion
      In order to reduce inequities in lung cancer control, the effort of upstream interventions should be focused on prevention, as healthcare access does not discriminate. Underserved subjects have a high level of trust in lung cancer screening but a riskier behavior in terms of smoking. This constitutes new targets for specific communication campaigns and Health authorities’ interventions.

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    P1.24 - Poster Session 1 - Clinical Care (ID 146)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P1.24-046 - How are treated French patients with metastatic lung adenocarcinoma with "uncommon" EGFR mutations? How could we do better? (ID 3109)

      09:30 - 09:30  |  Author(s): J. Morere

      • Abstract

      Background
      The progression-free survival and response rate of patients with EGFR-mutant tumors treated with an EGFR TKI has been reported to be superior to standard chemotherapeutic regimens. These mutations, concentrated in the exons 18 to 21 encoding the tyrosine kinase domain of the receptor. However, TKI sensitivity depends upon the nature and location of the mutations. Eighty to 90% of all lung adenocarcinoma-associated EGFR mutations are short, in-frame deletions in exon 19 and the exon 21 point mutation L858R; 70% of tumors with the latter mutations respond to treatment with the EGFR TKIs. The remaining 10 to 20 % of EGFR mutations include several additional point mutations that can be considered as "uncommon mutations". Their identification is problematic for therapeutic decision. Indeed, it remains unclear whether these mutations have benefit upon progression-free or overall survival. Therefore a comprehensive strategy is required to prioritize treatment decisions by physicians in the routine clinical practice.

      Methods
      By retrospectively analyzing mutational data of 3,200 consecutive patients with metastatic lung adenocarcinomas diagnosed for EGFR mutational status, we have identified those whose tumors had uncommon mutations (mutations that were neither base pair deletion in exon 19 nor the L858R in exon 21). We have contacted the physicians in charge of these patients and asked them the individual therapeutic decision. We have also questioned them about the level of their knowledge on the sensitivity of uncommon mutations to TKIs and how to improve this knowledge.

      Results
      Out of 3,200 metastatic lung adenocarcinomas, 351 tumors (11%) exhibited abnormalities in the exons 18 to 21. Of these 351 EGFR mutated tumors, 171 (48.7%) were base pair deletions in the exon 19: and 129 (36.7%) were the L868R in the exon 21. The 14.5 % remaining tumors showed "uncommon" mutations. There were G719 to A, C, or S mutations in 18 patients (5%), the L861Q mutation in 14 patients (3%) and only 1 Ins 18 pb in the exon 19. In exon 20, the T790M mutations were found in 4 tumors and in-frame insertions of varying lengths that confer resistance to TKI in 2 patients. Ten additional mutations, most of them being double mutations, were observed in 12 patients (3.4%). Of the 51 patients with uncommon mutations, 15 (29%) have received gefitinib or erlotinib whereas at least 32 patients should have received anti-EGFR therapies. Reasons for this difference were 1) the lack of knowledge of the sensitivity of rare mutations, and mostly double mutations, 2) the difficulty of finding the answer, either on the record or in the scientific literature, 3) the possibility of introducing a platinum-based chemotherapy, 4) the lack of experience of the theranostic which includes many gene mutations.

      Conclusion
      Opportunities for improvement could be: 1) better information on the medical report when there is scientific evidence suggesting sensitivity or resistance of the rare mutation. 2) in parallel, a more accurate information on the lack of knowledge on the sensitivity or resistance, 3) a website for quick access to this type of information and changes along with the knowledge evolution.

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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): J. Morere

      • 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.