Germline testing may be warranted for all patients with lung cancer, according to research presented by Sorscher et al during the August ASCO Plenary Series Program (Abstract 388570). The retrospective review of nearly 8,000 patients with lung cancer undergoing germline testing found that 14.9% had pathogenic germline variants, and 95.1% of these variants were potentially clinically actionable. In addition, 61.3% of these pathogenic germline variants were on DNA damage repair or homologous recombination repair genes.
“Given the current National Comprehensive Cancer Network (NCCN) recommendations for germline testing for patients diagnosed with other cancer types, the Moonshot Version 2.0 recommendations, and the profound implications for both patients and their families that result from identifying pathogenic germline variants, our results suggest that all patients diagnosed with lung cancer should be considered for germline testing,” said study author Renato G. Martins, MD, MPH, Chair of Hematology/Oncology and Palliative Care at Virginia Commonwealth University Massey Cancer Center in Virginia.
As Dr. Martins reported, the NCCN currently recommends germline testing for cancer-causing pathogenic germline variants for all patients (aged < 50 years) diagnosed with pancreatic, ovarian, or colorectal cancer and is considered for those diagnosed at age 50 or more. The screening guidelines also recommend germline testing for a substantial portion of patients with breast cancer. The Moonshot Version 2.0 also recommends evaluation of germline testing for all patients diagnosed with cancer, said Dr. Martins, in part to mitigate existing health-care inequities in germline testing.
Although pathogenic germline variants in TP53 and EGFR—specifically, the T790 mutation—have been associated with hereditary predisposition to lung cancer, few studies have investigated the broader prevalence and spectrum of pathogenic germline variants in patients diagnosed with lung cancer.
“Identifying pathogenic variants informs recommendations for screening for early cancer detection, preventive measures such as surgery, and cascade testing of at-risk family members,” said Dr. Martins.
Actionable Mutations Common Among Lung Cancer Patients
For this study, Dr. Martins and colleagues aimed to investigate the prevalence, frequency, and clinical implications of pathogenic germline variants in patients with lung cancer. The retrospective review used de-identified data from a convenience cohort of individuals diagnosed with lung cancer undergoing germline genetic testing at a commercial diagnostic laboratory performed between 2014 and 2022. Personal and family history of cancer and demographic data were obtained from requisition forms completed by the clinicians.
According to Dr. Martins, this study included potentially the largest cohort of germline-tested patients with lung cancer. Overall genetic test results showed that 49.3% of patients tested negative, while 32.8% had variants of unknown significance. An additional 2.9% of patients tested were carriers of heterozygotes for autosomal recessive cancer predisposition syndrome. Finally, 14.9% of patients had a positive result for a pathogenic germline variant or a likely pathogenic germline variant.
The following pathogenic germline variants were detected: BRCA2 (2.8%), CHEK2 (2.1%), ATM (1.9%), TP53 (1.3%), BRCA1 (1.2%), EGFR (1.0%), APC (0.9%), and PALB2 (0.5%). When only patients with a diagnosis of lung cancer were included in the analysis, 16% had positive results for a pathogenic germline variant, which was higher than the overall population. Analysis of clinically actionable positive results in the overall study cohort showed that 61% of patients had a pathogenic germline variant on a DNA damage repair gene or a homologous combination repair gene, and 95% of pathogenic germline variants had potential management implications.
Disclosure: Dr. Martins reported a financial relationship with Roche/Genentech. In addition, his institution has received research funding from Eisai, Genentech, Lilly, Merck Sharp & Dohme, and Pfizer.
