Germline testing ‘should be considered’ for all patients with lung cancer, data suggest
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Key takeaways:
- Approximately 1 in 7 patients with lung cancer had a pathogenic germline variant.
- These variants often occurred in DNA damage-repair/homologous recombination-repair (DDR/HRR) genes.
- Identification of pathogenic germline variants through testing could have important implications for patients and their families.
About 15% of a large cohort of patients with lung cancer had pathogenic germline variants, nearly all of which could be clinically actionable, according to study results presented during an ASCO Plenary Series session.
Moreover, most patients with pathogenic germline variants, or PGVs, had them in DNA damage-repair/homologous recombination-repair (DDR/HRR) genes, including BRCA1 and BRCA2, making them potentially eligible for targeted treatment on a clinical trial.
“Given the current [National Comprehensive Cancer Network] 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 a pathogenic germline variant, our results suggest that all patients diagnosed with lung cancer should be considered for germline testing,” Renato G. Martins, MD, MPH, chair of hematology, oncology and palliative care at VCU Massey Cancer Center and of the department of internal medicine at VCU School of Medicine, said during the presentation.
Background and methods
Identification of PGVs is important to inform recommendations for cancer screening, surgery and other preventive measures, as well as cascade testing of family members at risk, Martins said. He noted that PGVs in TP53 and EGFR have been linked to a hereditary predisposition to lung cancer. However, few studies have investigated the prevalence and possible clinical implications of PGVs in patients with lung cancer.
To do so, Martins and colleagues retrospectively reviewed deidentified data of 7,788 patients with lung cancer (mean age at testing, 63 years; 71.1% women; 64.5% white) who underwent germline genetic testing between 2014 and 2022 at a commercial diagnostic lab. Most (71.1%) had a reported personal history of other cancers.
Researchers defined clinically actionable PGVs as those associated with NCCN or professional society clinical management guidance and/or clinical trial eligibility. The number of genes tested varied (median, 79) based on the preference of the ordering clinician.
Key findings
Overall testing results showed 14.9% of patients (n = 1,161) had a total of 1,503 PGVs in 81 genes known to be associated with cancer risk. Another 2.9% of patients were carriers, or heterozygous for an autosomal recessive cancer predisposition syndrome, Martins said. Genes in which PGVs occurred most often included BRCA2 (2.8%), CHEK2 (2.1%), ATM (1.9%), TP53 (1.3%), BRCA1 (1.2%), EGFR (1%), APC (0.9%) and PALB2 (0.5%). Among patients with lung cancer only, 16% tested positive for PGVs or likely PGVs in cancer risk genes, with higher proportions of PGVs in BRCA2 (3.4%), EGFR (2.1%) and ATM (2%).
Most patients in the full cohort with PGVs (61.3%) had a PGV in an DDR/HRR gene, and 95.1% (n = 1,104) had a PGV in a gene with potential management implications.
Martins noted a couple study limitations, including that genetic testing referral may reflect selection bias and that the referring health care provider chose which genes to test for each patient, resulting in a lack of uniformity.
Next steps
Martins cited a need for research on targeted treatment for patients with lung cancer and PGVs in HRR genes.
“The FDA and NCCN endorse targeted therapies for patients with breast, pancreatic, prostate and ovarian cancers who carry [HRR PGVs],” Martins said. “Targeted therapy use in lung cancer patients with [HRR PGVs] warrants investigation.”
Meanwhile, lung cancer oncologists should consider germline genetic testing for some but not necessarily all patients, Kara Maxwell, MD, PhD, assistant professor of medicine at Penn Medicine, said during a discussion after the presentation.
“Thinking of some low-hanging fruit for referrals for germline testing could be helpful,” she said. “Age of onset less than 46 [years], an EGFR mutation in a [tyrosine kinase inhibitor]-naive [patient], DNA repair mutations all may be really a good way to start, potentially even using somatic testing as a screening tool. And as always when we think about germline cancer risk susceptibility, take a family history.”
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Sorscher S, et al. Abstract 388570. Presented at: ASCO Plenary Series (virtual); Aug. 16, 2022.
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