CHEK2 Pathogenic Germline Variants in Patients With NSCLC

To the Editor:

Zhang et al.¹ recently reported that among 70 patients with NSCLC who carried CHEK2 pathogenic germline variants (PGVs), 29 (41.4%) had tumor “potentially actionable driver alterations,” and that KRAS mutations constituted 51.7% of those identified driver alterations. Their report raises several key questions, including universal germline testing of patients with NSCLC, the implications of identifying CHEK2 PGV carriers, and the potential clinical significance of the dual biomarker, somatic KRAS/CHEK2 PGV.¹

As the authors noted, CHEK2 PGVs in patients with NSCLC are rare (<1%), and, therefore, universal germline testing of patients with NSCLC to identify CHEK2 PGV carriers is problematic.¹ However, germline testing is recommended for all patients with tumors exhibiting probable incidental CHEK2 PGVs; the current routine next-generation sequencing of NSCLCs will—when CHEK2 is interrogated—identify probable incidental CHEK2 PGVs, and, therefore, a group that particularly should consider undergoing germline testing.²

The authors propose further studies to determine whether CHEK2 PGVs are NSCLC-predisposing.¹ In the meantime, it is important to recognize that CHEK2 PGVs are considered “actionable,” regardless of whether these PGVs are eventually proven to be NSCLC-predisposing. For example, the National Comprehensive Cancer Network recommends that patients identified with CHEK2 PGVs consider annual breast magnetic resonance imaging (because of their 20%–40% lifetime risk of breast cancer) and more aggressive screening for colorectal cancer, particularly when there is a family history of colorectal cancer.^2,3 In addition, there are therapeutic clinical trials for patients diagnosed with a variety of cancer types for patients with CHEK2 PGVs, and cascade germline testing is recommended for family members of patients carrying CHEK2 PGVs.^2,4

Zhang et al.¹ also reported that NSCLCs of patients carrying CHEK2 PGVs frequently had actionable RAS mutations. Studies are also needed to determine whether the response rate and other clinical benefits of KRAS inhibitors are different in patients who carry CHEK2 PGVs compared with those patients who do not carry CHEK2 PGVs. As a related example, Jung et al.⁵ recently found that dual TP53/EGFR tumor mutations predicted a poorer recurrence-free survival with treatment compared with that of patients with EGFR-mutated NSCLCs whose tumors have no TP53 mutation.

It is hoped that the report by Zhang et al.¹ will prompt future studies to establish with more certainty whether CHEK2 PGVs are NSCLC-predisposing, which patients with NSCLC should undergo germline testing for CHEK2 PGVs and studies aimed to assess the clinical significance and therapeutic implications of dual somatic KRAS/CHEK2 PGVs in patients with NSCLC.

CRediT Authorship Contribution Statement

Steven Sorscher: Conceptualization, Methodology, Investigation, Writing-original draft, Writing-review & editing, Supervision, Funding acquisition.

Data Availability

All data/statements in this perspective is either referenced in the text or the opinion of the author (Dr. Sorscher). The data that supports the findings/statements in this perspective is openly available in the references provided.