In a prospective cohort study, entitled Investigating HEreditary RIsk from T790M (INHERIT) and published on 14 August 2023 in the JCO, Prof. Geoffrey R. Oxnard of the Dana-Farber Cancer Institute in Boston, MA, US, and colleagues report on 77 individuals from 39 kindreds carrying pathogenic germline variants in EGFR. The data confirms the existence of an underappreciated syndrome of familial EGFR-mutated lung cancer predisposition which is characterised by development of lung adenocarcinomas harbouring an atypical spectrum of somatic EGFR mutations and high prevalence of lung nodules in germline carriers without a lung cancer diagnosis.
The study team found that in individuals with familial EGFR-mutated lung cancer, lung nodules can be found as early as the third decade of life and can be stable for many years, potentially consistent with adenocarcinoma in situ. This syndrome is one of few inherited cancer syndromes in which the pathogenic germline variant is in an oncogene, not a tumour suppressor gene.
The authors wrote in the background that cancer genomics has transformed understanding and treatment of non-small cell lung cancer (NSCLC). In contrast, understanding of the germline genetics associated with lung cancer risk has evolved little. Somatic genotyping of genes like EGFR, ALK, ROS1, among others, is now routine in the care of advanced NSCLC because mutations in these genes can indicate sensitivity to oral targeted therapies. Such targetable mutations are detected more commonly in NSCLC occurring in patients with no history of cigarette smoking. However, understanding of lung cancer risk, particularly inherited risk, is inadequate to explain the widespread prevalence of lung cancer in never smokers.
While familial contributions to lung cancer risk have long been recognised, few high-risk germline variants have been identified. In 2005, Bell et al. first described the germline EGFR T790M variant in a family of European descent with multiple members who developed lung adenocarcinoma. There have since been several case reports describing kindreds harbouring this and other germline pathogenic variants in EGFR (including R776H, V769M, V834L).
In 2012, the researchers reported that the widespread use of somatic genotyping of NSCLC could offer an opportunity to identify lung cancer patients at risk of carrying germline EGFR T790M pathogenic variants. Because the somatic EGFR T790M mutation is usually detected only after acquired drug resistance to targeted therapy, its presence at initial diagnosis suggests the possibility of a germline allele. They launched the INHERIT to prospectively evaluate the prevalence of germline EGFR T790M in patients harbouring this variant on tumour genotyping at diagnosis, as well as to describe this rare hereditary syndrome.
With the expectation that these families would be difficult to identify, the study offered remote enrolment, counseling, and testing to increase the referral base. The study was coordinated by the Addario Lung Cancer Medical Institute. The INHERIT study enroled lung cancer patients whose tumour profiling harboured possible germline EGFR pathogenic variants and their relatives, either in-person or remotely, providing germline testing and follow-up.
A total, 141 participants were enroled over a 5-year period, 100 (71%) remotely. Based upon prior genotyping, 116 participants from 59 kindreds were tested for EGFR T790M, consistent with a pattern of Mendelian inheritance with variable lung cancer penetrance. In confirmed or obligate carriers of a germline EGFR pathogenic variant from 39 different kindreds, 50 of 91 (55%) were affected with lung cancer with 34 of 65 (52%) diagnosed by age 60. Somatic testing of lung cancers in carriers revealed that 35 of 37 (95%) had an EGFR driver co-mutation.
Among 36 germline carriers without a cancer diagnosis, 15 had CT imaging and 9 had lung nodules, including a 28-year-old with >10 lung nodules. Given geographic enrichment of germline EGFR T790M in the US Southeast, 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.
The authors commented that while prior reports of germline EGFR pathogenic variants have been largely limited to individual select kindreds, this is the first prospective study of multiple unrelated kindreds with pathogenic germline variants in EGFR, allowing to better understand the characteristics of these patients and their families. In this first prospective description of familial EGFR-mutated lung cancer, the study team identified a recent founder germline EGFR T790M variant enriched in the US Southeast. 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.
Overall, more than half of germline carriers of EGFR T790M were diagnosed with lung cancer by the age of 60, and lung nodules were common in those without a cancer diagnosis. Lung cancers in germline carriers commonly carried a somatic driver EGFR mutation and had favourable outcomes on osimertinib. Genome-wide haplotyping identified a large and recent haplotype shared by most germline carriers.
While this study illustrates the risk of lung cancer in individuals with germline EGFR pathogenic variants, the optimal management of such families is not yet established, though the authors proposed several management principles. First, the identification of certain EGFR mutations at diagnosis (e.g. T790M, R776H) on cancer genomic profiling, with or without a second EGFR driver mutation, should lead to the consideration of germline EGFR testing, particularly with an elevated variant allele frequency consistent with a possible germline variant. Patients with germline EGFR pathogenic variants may have multiple primary lung adenocarcinomas and may benefit from a personalised approach including local management of a dominant primary. For those with high risk or advanced cancers they recommend osimertinib which can be tolerated with durable effect.
Carriers of germline EGFR variants will need more precise estimates of penetrance to plan their care. Optimal surveillance for lung cancer has not been defined for carriers of pathogenic germline EGFR variants. Their risk of lung nodules is high, as is their risk of developing EGFR-mutated lung cancer. There have not yet been definitive estimates of the penetrance of germline EGFR pathogenic/likely pathogenic variants. The study team favour an initial low-dose screening CT in adult carriers to document lung nodules, with monitoring scans as appropriate if nodules are detected. In individuals with a negative screening CT scan, it is difficult to identify the optimal window for repeat CT imaging, though the risk of nodules appears to increase with age. Further study of CT screening in this population is needed to enable more detailed consensus guidelines on management of this unique population.
The opportunity to study EGFR-targeting agents like osimertinib for cancer interception (risk reduction) in this population should also be examined.
This work was supported in part by the Conquer Cancer Foundation of ASCO, the Bonnie J. Addario Lung Cancer Foundation, the Team Mitch Fund of the Dana-Farber Cancer Institute, Research Incentive Fund of Hospital de Clinicas de Porto Alegre, the Ingram Cancer Professorship at Vanderbilt Ingram Cancer Center, and the National Cancer Institute of the US NIH.
Oxnard GR, Chen R, Pharr JC, et al. Germline EGFR mutations and familial lung cancer. JCO; Published online 14 August 2023. DOI: 10.1200/JCO.23.01372