Findings of Pathogenic Germline Variants in Lung Cancer Leads to Recommendation for Germline Testing for All Patients

Renato G. Martins, MD, MPH

In an analysis of cancer-causing pathogenic germline variants (PGVs) among 7788 patients with lung cancer, almost all PGVs identified among these patients were found to be potentially clinically actionable and almost two/thirds of these were in DNA damage repair (DDR)/homologous recombination repair (HRR) genes.

The investigators suggested that the implications of their study aligned with recommendations from the National Comprehensive Cancer Network (NCCN) and the Moonshot version 2.0 to consider ordering germline testing for all patients diagnosed with lung cancer.

“Our results suggest that all patients diagnosed with lung cancer should be considered for germline testing,” said Renato G. Martins, MD, MPH, the chair of hematology, oncology, and palliative care at VCU Massey Cancer Center and the Department of Internal Medicine at the VCU School of Medicine in Richmond, Virginia, when presenting the findings of the retrospective study during the August session of the American Society of Clinical Oncology Plenary Series.

Germline testing for cancer-causing PVGs are currently recommended for most patients with pancreatic, ovarian, colorectal, and breast cancer by NCCN guidelines as well as the American Society of Breast Surgeons. The Moonshot 2.0 recommends consideration for germline testing for all patients with cancer.

Few studies have investigated the broader prevalence of PGVs in patients with lung cancer, but these variants could inform recommendations for screening, surgery, and testing for at-risk family members.

Investigators, led by first study author Stephen Sorscher, MD, of the Wake Forest School of Medicine, conducted a retrospective review of patients diagnosed with lung cancer undergone germline genetic testing between 2014 and 2022. Patients with lung metastases from primary cancers not of the lung or from neuroendocrine tumors or sarcomas were excluded from the cohort. PGVs classified as clinically actionable were defined in association with NCCN and other recommendations.

A total of 7788 patients were included, which is likely the largest cohort of germline testing in patients with lung cancer, according to Martins. The mean age of patients was 63 years (standard derivation, 15.2) and 71.1% of patients were female. The majority of patients were White (64.5%) followed by other (10.3%) and Black (5.4%). The median number of genes tested was 79. A total of 71.1% of patients had a personal history of other cancer.

Overall, PGVs or likely variants were identified in 14.9% of patients, variants of unknown significance were reported in 32.8%, 2.9% were considered carriers, and 49.3% of patients were negative for variants. Of identified PGVs, BRCA2 was tested for in 7282 patients and found in 2.8%, CHEK2 was tested for in 7111 and found in 2.1%, ATM was tested for in 7102 and found in 1.9%, TP53 was tested for in 7327 and found in 1.3%, BRCA1 was tested for in 7241 and found in 1.2%, EGFR was tested for in 4349 and found in 1.0%, APC was tested for in 6554 and found in 0.9%, and PALB2 was tested for in 7121 and found in 0.5%.

“It is possible that doctors would be more likely to be ordering germline testing in patients that have a history of multiple cancers and hence would be more likely to have a pathogenic germline variant as the cause behind these cancers,” Martins said.

When excluding the 71.1% with other cancers, the remaining patients had PGVs or likely variants in 16%, 33.6% had variants of unknown significance, 3.4% were considered carriers, and 47.0% were negative for PGVs. In this group, BRCA2 was tested for in 2040 patients and BRCA2 PGVs were found in 3.4%, EGFR was tested for in 1589 and found in 2.1%, ATM was tested for in 1975 and found in 2.0%, CHEK2 was tested for in 1974 and found in 1.9%, TP53 was tested for in 2025 and found in 1.3%, BRCA1 was tested for in 2021 and found in 1.2%, APC was tested for in 1915 and found in 1.0%, PALB2 was tested for in 1979 and found in 0.9%, BAP1 was tested for in 1507 and found in 0.7%, MSH6 was tested for in 1978 and found in 0.5%, and PMS2 was tested for in 1978 and found in 0.5%.

Martins noted that there was no clear increase in prevalence found when the test results were analyzed by ancestry and ethnicity as well as by history of other cancers.

Among the PGVs or likely variants found in the overall population, 61.3% of variants were in DDR/HRR genes and 95.1% were in genes with potential management implications.

Martins reminded that PARP inhibitors are approved to treat patients with DDR/HRR genes in patients with breast, pancreatic, ovarian, and prostate cancers, but are not yet approved in lung cancer. “The FDA and NCCN endorse targeted therapies for patients with breast, pancreatic, prostate, and ovarian cancers who carry HRR PGVs. Targeted therapy use in [patients with] lung cancer with HRR PGVs warrants investigation,” he said.

He noted that the study was limited by possible selection bias due to personal medical history or family history and that the genes tested for were not the same in all patients as testing was at the discretion of each provider.

_Reference

_{Sorscher S, LoPiccolo J, Chen E, et al. Landscape of pathogenic germline variants in patients with lung cancer. J Clin Oncol. 2022;40(suppl 26):388570. doi:10.1200/JCO.2022.40.36_suppl.388570}