Germline EGFR Mutations and Familial Lung Cancer

Abstract

Purpose: 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 (PVs).

Methods: The Investigating Hereditary Risk from T790M study (ClinicalTrials.gov identifier: NCT01754025) enrolled patients with lung cancer whose tumor profiling harbored possible germline EGFR PVs and their relatives, either in person or remotely, providing germline testing and follow-up.

Results: A total of 141 participants were enrolled over a 5-year period, 100 (71%) remotely. Based upon previous genotyping, 116 participants from 59 kindreds were tested for EGFR T790M, demonstrating a pattern of Mendelian inheritance with variable lung cancer penetrance. In confirmed or obligate carriers of a germline EGFR PV from 39 different kindreds, 50/91 (55%) were affected with lung cancer with 34/65 (52%) diagnosed by age 60 years. Somatic testing of lung cancers in carriers revealed that 35 of 37 (95%) had an EGFR driver comutation. Among 36 germline carriers without a cancer diagnosis, 15 had computed tomography (CT) imaging and nine had lung nodules, including a 28-year-old with >10 lung nodules. Given geographic enrichment of germline EGFR T790M in the southeast United States, genome-wide haplotyping of 46 germline carriers was performed and identified a 4.1-Mb haplotype shared by 41 (89%), estimated to originate 223-279 years ago.

Conclusion: 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.

Figure 1.. Schema of INHERIT EGFR study.

Participants were eligible based on prior cancer genotyping results [positive for EGFR T790M (pre-treatment) or another EGFR mutation previously described as a pathogenic germline variant (e.g.R776H)], or if they or a relative were a known germline carrier. Eligible participants were enrolled and offered germline testing following genetic counseling and were followed for 2 years. Those found to be germline positive could invite their relatives to be considered for study enrollment. Participation could be remote or in person at a study site.

Fig 2.

Pedigrees of affected families exhibit variable penetrance across generations. Current age or age at death/diagnosis are provided, as well as those who tested positive (+), negative (−), or obligate carriers (*). (A) Lung cancer can occur with or without smoking history, and (B) although it can be diagnosed early in life, some carriers remain without lung cancer late in life. BR, breast cancer; CATYPE, cancer (type unknown); CO, colon cancer; LG, lung cancer; LK, leukemia; PR, prostate cancer.

Fig 2.

Pedigrees of affected families exhibit variable penetrance across generations. Current age or age at death/diagnosis are provided, as well as those who tested positive (+), negative (−), or obligate carriers (*). (A) Lung cancer can occur with or without smoking history, and (B) although it can be diagnosed early in life, some carriers remain without lung cancer late in life. BR, breast cancer; CATYPE, cancer (type unknown); CO, colon cancer; LG, lung cancer; LK, leukemia; PR, prostate cancer.

Fig 3.

Enrichment of germline carriers in the Southeast United States. (A) Although the majority of probands (index carriers from involved kindreds) were enrolled from the Southeast or bordering states, (B) participants with lung cancer but without germline mutations were enrolled from across the United States.

Fig 3.

Enrichment of germline carriers in the Southeast United States. (A) Although the majority of probands (index carriers from involved kindreds) were enrolled from the Southeast or bordering states, (B) participants with lung cancer but without germline mutations were enrolled from across the United States.

Fig 4.

Lung cancer outcomes in germline carriers. Kaplan-Meier curves showing (A) survival from date of diagnosis for 22 patients with germline T790M and stage IV lung cancer and (B) survival from date of diagnosis for 38 patients with germline T790M regardless of lung cancer stage. (C) In germline carriers receiving osimertinib, duration of therapy was prolonged without unexpected toxicity.

Fig 4.

Lung cancer outcomes in germline carriers. Kaplan-Meier curves showing (A) survival from date of diagnosis for 22 patients with germline T790M and stage IV lung cancer and (B) survival from date of diagnosis for 38 patients with germline T790M regardless of lung cancer stage. (C) In germline carriers receiving osimertinib, duration of therapy was prolonged without unexpected toxicity.

Fig 4.

Lung cancer outcomes in germline carriers. Kaplan-Meier curves showing (A) survival from date of diagnosis for 22 patients with germline T790M and stage IV lung cancer and (B) survival from date of diagnosis for 38 patients with germline T790M regardless of lung cancer stage. (C) In germline carriers receiving osimertinib, duration of therapy was prolonged without unexpected toxicity.