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J.C. Heng

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    MO15 - Novel Genes and Pathways (ID 89)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO15.06 - A prospective internet-based study of patients with lung cancer harboring baseline EGFR T790M to identify germline carriers and characterize familial risk (ID 1667)

      16:15 - 17:45  |  Author(s): J.C. Heng

      • Abstract
      • Presentation
      • Slides

      The EGFR T790M mutation, commonly seen with acquired resistance to EGFR kinase inhibitors, has also been described rarely as a germline mutation in association with familial lung cancer. In a prior study (Oxnard et al, JTO, 2012), the presence of EGFR T790M at diagnosis was associated with a 50% chance of carrying an underlying germline T790M mutation. This suggests that by studying patients whose cancer was shown to carry T790M at diagnosis, it is possible to efficiently screen for a germline allele that otherwise is rare among patients with non-small cell lung cancer. We therefore initiated a prospective trial to identify patients and families carrying germline EGFR mutations in order to characterize phenotype and cancer risk.

      Subjects are eligible if they (1) have a cancer harboring EGFR T790M (excluding acquired T790M), (2) are a relative of a known germline carrier, or (3) are already known to carry a germline EGFR mutation on prior testing. Subjects may present at a participating cancer center or may enroll remotely using a study website ( Eligible subjects receive genetic counseling in person or over the phone, and then submit a saliva and/or blood specimen for central testing in a CLIA lab. Results are disclosed to the subject if they wish but do not enter the medical record. Those subjects carrying germline EGFR mutations are given the option of inviting relatives to participate. Chest CT scans are collected from germline carriers and analyzed centrally to study nodule prevalence and characteristics. Available tumor specimens are collected for central pathology review and advanced genomic analysis.

      The trial was registered to (NCT01754025) and began accrual in December 2012. To date, 7 subjects have been enrolled and 5 are actively being screened, including 4 kindreds. More than half of the subjects have participated remotely via the study website. Of 4 probands with lung cancer and germline T790M, 3 have a family history of lung cancer, 2 of whom have children with CT scans showing multiple sub-centimeter ground-glass nodules. The fourth proband has no family history of lung cancer, suggesting variable penetrance or a de novo germline event. All cancers in germline T790M carriers have also harbored secondary EGFR kinase domain mutations.

      Using a novel trial design, including remote accrual, genetic counseling by phone, and germline testing by mail, we have begun collecting a sizeable cohort of families affected by germline EGFR mutations. By leveraging referrals from commercial laboratories and contributing academic centers, we aim to study 100 patients over a three year period in order to better understand the natural history and risk associated with this unique familial cancer syndrome. Supported by grants from the Conquer Cancer Foundation of ASCO, the Bonnie J. Addario Lung Cancer Foundation, and the National Cancer Institute.

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