23P - Germline testing in a selected cohort of non-small cell lung cancer (NSCLC) patients: Final results from the INHERITY LC study

Background

Inherited predisposition has not traditionally been considered a risk factor for lung cancer (LC), and genetic testing is not routinely established. Preliminary data estimate the prevalence of pathogenic germline variants (PGVs) in NSCLC between 2.3% and 14.9%. INHERITY LC is a prospective multicenter study aiming to explore germline mutations in a selected cohort of patients (pts) with NSCLC and elucidate the role of genetics in LC.

Methods

From May 2021 to April 2023 145 pts with NSCLC who fulfilled at least one of the following selection criteria were enrolled: 1) family history of NSCLC: one first-degree relative, or two or more second-degree relatives with NSCLC regardless of age 2) age and negative or low tobacco exposure: diagnosis ≤ 45 years or ≤ 60 years with a pack-years ≤ 15 3) presence of somatic actionable mutations in tumor biopsy. Germline genetic testing was performed by next-generation sequencing (NGS) using a 74-gene panel (SOPHiA GENETICS®).

Results

We found 15 carriers harboring PGVs including pathogenic/likely pathogenic (P/LP) variants with a prevalence of 10.3%. Most of them were involved in DNA damage repair pathway (DDR) genes: BRCA2 (1), CHEK2 (2), ATM (2), PALB2 (1), BARD1 (1), XRCC2 (1), MRE11(1) and NBN (3), FAN1 (1), MLH1 (1), TP53 (1). PGVs carriers were predominantly female (67%), adenocarcinoma subtype (73%), and had negative or low tobacco exposure with a median of 9 pack-years. A prevalence of 10.7% of carriers with PGVs was found among those pts with a known familiar history of LC. A prevalence of 9.8% was described among pts selected by age and tobacco exposure criterion, and also among those selected according to the presence of a somatic mutation. 65 (45%) pts met more than one selection criterion, and a higher prevalence of PGVs of 22% was observed in those pts (9) who met all three selection criteria.

Conclusions

The INHERITY LC study found a PGV prevalence of 10%, with most of the genes involved in the DDR pathway. Specific criteria may be useful in selecting NSCLC pts for genetic testing in clinical practice. The identification of PGV in NSCLC may have implications for prevention, early detection, and identification of individuals at risk.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Asociación para la Investigación del Cáncer de Pulmón en Mujeres (ICAPEM).

Funding

Asociación para la Investigación del Cáncer de Pulmón en Mujeres (ICAPEM).

Disclosure

All authors have declared no conflicts of interest.