The following is a summary of “Germline EGFR Mutations and Familial Lung Cancer,” published in the December 2023 issue of Oncology by Oxnard, et al.

For a prospective study, researchers sought to characterize the clinical phenotype of patients and families harboring germline EGFR pathogenic variants (PVs) to enhance understanding of inherited lung cancer risk.

The Investigating Hereditary Risk from the T790M study enrolled lung cancer patients with potential germline EGFR PVs and their relatives through in-person or remote participation. Participants underwent germline testing and follow-up.

Over 5 years, 141 participants were enrolled, with 71% participating remotely. Of 116 participants tested for EGFR T790M, Mendelian inheritance patterns with variable lung cancer penetrance were observed in 59 kindreds. In confirmed or obligate carriers from 39 kindreds, 55% were affected by lung cancer, with 52% diagnosed by age 60. Somatic testing of lung cancers in carriers revealed that 95% had an EGFR driver commutation. Among 36 germline carriers without a cancer diagnosis, 15 had computed tomography (CT) imaging, and nine showed lung nodules, including a 28-year-old with >10 nodules. Geographic enrichment of germline EGFR T790M in the southeast United States led to genome-wide haplotyping, identifying a 4.1-Mb haplotype shared by 89%, estimated to originate 223-279 years ago.

It was the first prospective description of familial EGFR-mutant lung cancer, highlighting 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 efforts to identify affected individuals and family members for CT-based screening in high-risk populations.

Source: ascopubs.org/doi/full/10.1200/JCO.23.01372