In the INHERIT study—reported in the Journal of Clinical Oncology—Geoffrey R. Oxnard, MD, FASCO, and colleagues identified associations between germline EGFR mutations and familial lung cancer.
As stated by the investigators, “The genomic underpinnings of inherited lung cancer risk are poorly understood. This prospective study characterized the clinical phenotype of patients and families with germline EGFR pathogenic variants.”
Geoffrey R. Oxnard, MD, FASCO
Study Details
The Investigating Hereditary Risk from T790M study (INHERIT) enrolled both patients with lung cancer who had tumor profiling indicating the presence of possible germline EGFR pathogenic variants and their relatives, either in person or remotely. The study was coordinated by the Addario Lung Cancer Medical Institute (ALCMI), with institutional review board approval at three ALCMI sites: Dana-Farber Cancer Institute, Vanderbilt-Ingram Cancer Center, and James Cancer Center at The Ohio State University. Participants underwent germline testing and follow-up. Computed tomography (CT) was recommended—but not required—for germline EGFR pathogenic variant carriers without lung cancer.
Study Details
A total of 141 participants were enrolled over a 5-year period, with 100 (71%) enrolled remotely. All participants were from the United States, except two from Australia and one from Brazil.
Based on previous somatic or germline genotyping, 116 participants from 59 kindreds were tested for germline EGFR T790M mutations; testing showed a pattern of “Mendelian inheritance with variable lung cancer penetrance.” In addition, 14 participants from one kindred were tested for germline EGFR R776H mutations, and 1 participant was tested for germline EGFR G724S mutations.
Among 91 confirmed or obligate carriers of a germline EGFR pathogenic variant from 39 different kindreds, 50 (55%) were affected with lung cancer, with 15 (21%) of 70 diagnosed by age 50 years and 34 (52%) of 65 diagnosed by age 60 years.
Somatic testing of lung cancers in germline pathogenic variant carriers showed that 35 (95%) of 37 had an EGFR driver co-mutation.
Among 36 germline pathogenic variant carriers without a cancer diagnosis, 15 underwent CT and 9 were found to have lung nodules, including a 28-year-old participant with more than 10 lung nodules.
Enrichment of germline EGFR T790M was identified in the Southeast United States. Genome-wide haplotyping of 46 germline carriers identified a 4.1-Mb haplotype shared by 41 (89%) carriers. According to the investigators, this founder mutation was estimated to have originated between 223 and 279 years ago.
The investigators concluded, “To our knowledge, this is the first prospective description of familial EGFR-mutant lung cancer, identifying a recent founder germline EGFR T790M variant enriched in the Southeast United States. The high prevalence of EGFR-driver lung adenocarcinomas and lung nodules in germline carriers supports effort to identify affected patients and family members for investigation of CT-based screening for these high-risk individuals.”
Dr. Oxnard, of Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the Conquer Cancer Foundation of ASCO, Bonnie J. Addario Lung Cancer Foundation, National Cancer Institute, and others. For full disclosures of the study authors, visit ascopubs.org.
