Germline testing may be warranted for all patients with lung cancer, according to research presented during the August 2022 ASCO Plenary Series by Renato G. Martins, MD, MPH, Chair of Hematology Oncology and Palliative Care at Virginia Commonwealth University Massey Cancer Center, Richmond.¹ 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 in DNA damage repair or homologous recombination repair genes.

Renato G. Martins, MD, MPH

“Given the current 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 Dr. Martins.

As Dr. Martins reported, the National Comprehensive Cancer Network (NCCN) currently recommends germline testing for cancer-causing pathogenic germline variants for all patients (aged < 50) diagnosed with pancreatic, ovarian, and colorectal cancers and is considered for those diagnosed at age 50 or older. 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 T790M 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 measurements such as surgery, and cascade testing of at-risk family members,” said Dr. Martins.

Study Methods

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.

The researchers obtained personal and family histories of cancer and demographic data from requisition forms completed by clinicians. A lung cancer diagnosis was based on ICD-10 codes or language suggesting a primary lung cancer diagnosis on the test requisition. Individuals with lung metastases from primaries other than lung cancer, neuroendocrine tumors, or sarcomas as the basis for testing were excluded from the analysis.

Dr. Martins and colleagues defined clinically actionable pathogenic germline variants as those associated with the NCCN or professional society clinical management recommendations and/or clinical trial eligibility.

Genetic Test Results

As Dr. Martins reported, this study included 7,788 patients, which is potentially the largest cohort of germline-tested patients with lung cancer. The mean age of study participants was 63 years, 71% of patients were females, and 71% of patients had a reported personal history of other cancers. The median number of genes tested based on the panel selection was 79.

Overall genetic test results showed that 49.3% of patients tested negative, whereas 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 patients with a diagnosis of lung cancer alone (29%) were included in the analysis, 16% had positive results for a pathogenic germline variant, which was higher than the overall population. Not surprisingly, said Dr. Martins, the prevalence of EGFR mutations was twice as high among patients with lung cancer than the overall study population.

When patients were stratified by self-reported ancestry/ethnicity, subgroup analysis showed no clear increase in the prevalence pathologic germline variants among different groups. “It was somewhat surprising that Ashkenazi Jewish ancestry was not associated with a higher rate of pathogenic germline variants,” said Dr. Martins.

Finally, analysis of clinically actionable positive results in the overall study cohort showed that 61% of patients had a pathogenic germline variant in a DNA damage repair gene or a homologous combination repair gene, and 95% of pathogenic germline variants had potential management implications.

Study Limitations and Clinical Significance

Dr. Martins acknowledged several limitations to the study. Referral for genetic testing may reflect a selection bias due to personal medical history or family history of cancer, which would make this cohort not representative of all patients with lung cancer in the general population, he explained. In addition, the specific genes tested in each patient was left to the discretion of the referring health-care provider and was therefore not uniform.

Despite these limitations, the study authors underscored the clinical significance of identifying pathogenic germline variants in patients with lung cancer and, thus, the importance of germline testing. “Use of targeted therapy in patients with lung cancer who have homologous recombination repair pathogenic germline variants warrants investigation,” Dr. -Martins concluded. 

DISCLOSURE: Dr. Martins reported a financial relationship with Roche/-Genentech. His institution has received research funding from Eisai, Genentech, Lilly, Merck Sharp & Dohme, and Pfizer.

REFERENCE

1. Sorscher S, LoPiccolo J, Chen E, et al: Landscape of pathogenic germline variants in patients with lung cancer. ASCO Plenary Series. Abstract 388570. Presented August 16, 2022.