1. Fuerst, Mark L.

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All patients diagnosed with lung cancer should be considered for germline testing, according to a new study on the prevalence and spectrum of pathogenic germline variants (PGVs) in patients diagnosed with lung cancer. Among a cohort of 7,788 patients with lung cancer, 14.9 percent had PGVs, 95 percent had PGVs that were potentially clinically actionable, and 61 percent had PGVs in DNA damage repair (DDR) or homologous recombinant repair (HRR) genes.

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"PGVs 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 PGVs in patients diagnosed with lung cancer, and identifying PGVs informs recommendations for screening for early cancer detection, preventive measurements such as surgery, and cascade testing of at-risk family members," said Renato Martins, MD, MPH, Chair of Hematology, Oncology, and Palliative Care at VCU Massey Cancer Center and the Department of Internal Medicine at the VCU School of Medicine, during the presentation of the August 2022 ASCO Plenary Series (Abstract 388570).


Study Details

PARP inhibitors are already FDA-approved for patients with breast, pancreatic, ovarian, and prostate cancers who have PGVs in DDR or HRR genes. For example, BRCA1 and 2 are being studied in patients with DDR/HRR genes in those with other tumor types, Martins noted.


He presented information from a retrospective review of de-identified data from a convenience cohort of 7,788 patients diagnosed with lung cancer undergoing germline genetic testing at a commercial diagnostic laboratory performed between 2014 and 2022. "This is likely the largest cohort of germline testing patients with lung cancer," Martins said.


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


The number of genes tested varied per ordering clinician preference, based on different panels that were available, and clinically actionable PGVs were defined as those associated with National Comprehensive Center Network (NCCN) or professional society clinical management recommendations and/or clinical trial eligibility.


The patients, mean age 63 years, were predominantly female (71%), with Black patients underrepresented (5.4%). The median number of genes tested based on the panel selection was 79, and 71 percent of patients had a reported personal history of other cancers. The overall genetic testing results show 14.9 percent of patients had a PGV or likely PGV. The breakdown per PGV shows BRCA2 presence in 2.8 percent, CHEK2 in 2.1 percent, ATM in 1.9 percent, TP53 in 1.3 percent, BRCA1 in 1.2 percent, EGFR in 1 percent, APC is 0.9 percent, and PALB2 in 0.5 percent.


Restricting data to patients who had a diagnosis of lung cancer shows 16 percent had a PGV. "It is possible that the doctors would be more likely to order germline testing in patients that had a history of multiple cancers, and hence would be more likely to have a PGV as the cause behind these cancers," Martins explained.


In the overall population, 1 percent had a prevalence of EGFR mutations, whereas twice as many had EGFR mutations when restricted to lung cancer only. There was no clear increase in prevalence among different groups of ancestry and ethnicity. Ashkenazi Jewish ancestry did not lead to a higher rate of PGVs. When distributed by other malignant diagnosis, there was not a clear association with higher rates, he said. An analysis of clinically actionable positive results shows 61 percent have a PGV on a DDR or HRR gene. Overall, 95 percent of these PGVs had a potential management implication.


A main limitation of the study is "the referral for genetic testing may reflect a selection bias due to personal medical history or family history of cancer, making this cohort not representative of all patients with lung cancer in the general population," said Martins. Which genes were tested in each patient was left to the discretion of the referring health care provider and was therefore not uniform.


Martins concluded: "The FDA and NCCN endorse targeted therapies for patients with breast, pancreatic, prostate, and ovarian cancer who carry homologous recombinant PGVs, and targeted therapy used in lung cancer patients with homologous recombinant repair PGVs warrants investigation. 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 a PGV, our results suggest that all patients diagnosed with lung cancer should be considered for germline testing."


ASCO Discussant Kara Maxwell, MD, Assistant Professor of Medicine and Genetics at the University of Pennsylvania, commented: "What should a lung cancer oncologist do? I think that, while there may be some consideration here, germline genetic testing of all lung cancer patients is probably a bit premature. Thinking of some low-hanging fruit for referrals for germline testing I think could be helpful. Age of onset less than 46 and EGFR mutation in TKI-naive, DNA repair mutations all might 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, always take a family history."


Mark L. Fuerst is a contributing writer.