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The jump-started a $1.8 billion investment in funding for cancer research in many areas, including studies on cancer disparities. One tool that's been proposed for cutting those disparities is (GT). A 2022 commentary heralded GT as contributing "to clinical utility by building on comprehensive and curated genomic databases and deriving evidence to inform testing protocols, therapeutic options, and related clinical decision support."

The National Comprehensive Cancer Network () recommends GT for patients diagnosed with various solid tumors, but not for lung cancer -- at least not yet. A recent study took a closer look at the prevalence and spectrum of pathogenic germline variants (PGVs) in patients diagnosed with lung cancer.

"Given the growing opportunities for precision therapies based on PGVs in DNA damage-repair (DDR)/homologous recombination-repair (HRR) genes and the importance of identifying PGVs to inform future cancer screening and cascade testing, we investigated the prevalence and potential clinical implications of PGVs in individuals with lung cancer," explained Steven Sorscher, of Wake Forest School of Medicine in Winston-Salem, North Carolina, and colleagues in an abstract presented at a 2022 .

The team retrospectively reviewed data for 7,788 people (71.1% were female; 64.5% were white), with a personal history of more than one cancer, diagnosed with lung cancer, who underwent germline DNA sequencing and exon-level copy number analysis between 2014 and 2022 at a commercial diagnostic laboratory. The researchers defined clinically actionable PGVs as "those associated with clinical management recommendations or trial eligibility per current, standard of care guidelines."

Sorscher's group reported that a median of 79 genes were tested, and 1,503 PGVs in 81 known cancer-risk genes in 14.9% of the patients. Also, 2.9% carried a single PGV in a gene associated with autosomal recessive inheritance. PGV rates stratified by self-reported ancestry came in at 11.8% for Black/African American, 11.8% for Asian or Pacific Islander, 14.5% for Hispanic, and 15.4% for white.

And among genes with more than 1,000 individuals tested, PGVs were most common in:

• BRCA2: 2.8%

• CHEK2: 2.1%

• ATM: 1.9%

• TP53: 1.3%

• BRCA1: 1.2%

• EGFR: 1.0%

Finally, among 1,161 individuals, 61.3% had a PGV in a DDR/HRR gene, which made them potentially eligible for a clinical treatment trial, and 95.1% had a PGV that was "potentially clinically actionable," the researchers said.

At the ASCO Plenary Series, study co-author Renato Martins, MD, MPH, of VCU Massey Cancer Center in Richmond, shared results from the study, while ASCO invited discussant Kara Maxwell, MD, of the University of Pennsylvania in Philadelphia, put the findings into perspective:

What was the impetus for the study "Landscape of pathogenic germline variants in patients with lung cancer"?

Martins: The NCCN recommends germline testing for cancer-causing PGVs for all patients diagnosed with pancreatic, ovarian, and colorectal cancer for those diagnosed below age 50 and to be considered in those diagnosed above age 50 ... recommends the evaluation of GT for all patients diagnosed with cancer, in part to mitigate existing inequities in GT.

In lung cancer, PGVs in TP53 and EGFR -- specifically T790M -- have been associated with a hereditary predisposition to lung cancer. Few studies have examined the broader prevalence and spectrum of PGVs in patients diagnosed with lung cancer. Identifying PGVs informs recommendations for screening for early cancer detection, preventive measures such as surgery, and cascade testing of at-risk family members. The study aimed to investigate the prevalence, frequency, and clinical implications of PGVs in lung cancer patients.

What is the take-home message from the study?

Martins: Targeted therapy use in lung cancer patients with HHR PGVs warrants investigation. Given the current NCCN recommendations for GT patients with other cancer types who carry HRR PGVs, 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 also be considered for GT.

What are some of your general impressions of the study?

Maxwell: We know that lung cancer is part of at least two inheritable risk syndromes -- namely Li-Fraumeni syndrome [TP53] and EGFR susceptibility syndrome. Lung cancer has been proposed to be associated with ATM and BRCA2 mutations as well.

This was an important study to conduct. My major take-home point is that this is a study of 7,788 patients from a commercial genetic testing lab ... there are a few consideration when we think about the study, and we'll think about them when we compare [the results] to another study.

What is that comparison study?

Maxwell: I chose a study recently reported that had mutation rates at a much lower end of the spectrum compared to this current one ... [Semanti Mukherjee, PhD] and colleagues reported data from the study, and in this [MSKCC IMPACT] series, only approximately 4.3% of patients with lung cancer had mutations.

So what are the differences? In the current study ... these are likely high-risk patients, those with positive family histories or younger age of onset. They are relatively more likely to have another cancer -- for example, 71% of the patients had another cancer history compared with only 26% in the Mukherjee study. Only 3% in the Mukherjee study were considered to be high risk. The probably lies somewhere in between [the two studies].

What do the current study results mean for known mutations in lung cancer?

Maxwell: For EGFR ... 1% of the overall patients, and 2% of the lung cancer-only patients, were found to have EGFR germline mutations, and this is significantly higher than has been reported prior, where about 0.3% to 0.9% of lung cancer patients are considered to be due to be germline EGFR mutations. That said, the EGFR mutation susceptibility syndrome is certainly a known entity [for] very early age of onset, and we have data suggesting that the EGFR mutation is responsible for causing these cancers.

In some good news, carriers seem to have more indolent cancers and there does not appear to be other cancer risks.

Similarly, the Li-Fraumeni syndrome ... mutations rates in the study were certainly higher than those reported in other studies, with about 1.3% of their lung cancer patients having TP53 mutations. This doesn't seem to be largely due to -- only 22 of the 95 carriers were mosaic; in the literature, about half a percent of lung cancer has been considered to be part of Li-Fraumeni. Again, that said, we do know that lung cancer is part of the Li-Fraumeni spectrum due to these germline TP53 mutations.

We know that lung cancer occurs in approximately 5%, and probably increasing as patients survive longer, and that the standardized incidence ratio is quite high compared to the general population [SIR 12.3%, 95% CI 7.8-18.5]. So both of these are important associations to remember, and to consider in patients with lung cancer.

Let's talk a little bit more about BRCA2 and ATM. The BRCA2 mutation rate in this study compared to some other studies ... in prostate and ovarian [cancers] ... is certainly lower, but they're higher than what we even see in breast cancer. It seems that BRCA2 carriers have an earlier age of onset, more likely to be young adenocarcinoma patients, likely non-smokers, and have absence of other drivers, so these are probably clinically significant lung cancers.

On the other hand, in a recent analysis of , the overall relative risk of lung cancer in BRCA1 and [BRCA2] was not significant at [RR] 1.13. That said, female BRCA2 carriers in the CIMBA study did have a significant risk of lung cancer, at [RR] 2.84.

The literature in ATM mutations is also a little mixed, although [there are] suggestions of importance. There is a likelihood that ATM mutations might contribute to lung cancer; however, that mechanism, and what it means clinically, still needs to be figured out.

What is the take-home message in terms of clinical implications?

Maxwell: In general, what this study really brings up is should germline genetic testing be recommended for all patients with lung cancer? Typically, we've used 5% mutation positivity rate as a cutoff; that has come down to 2.5% in many indications, and so by all indications, it seems that based on the results of this study, we should be testing all lung cancer patients.

That said, just like in metastatic prostate cancer, that's a large number of patients, so implementation really needs to be thought about. Should we think about maybe stratifying these recommendations by some factors like age of onset, family history, other personal cancer history, or even histology to help with implementation?

Read the Plenary Series commentary here.