Study Shows High Rate of Actionable Mutations in Lung Cancer

As many as 16% of patients with lung cancer had pathogenic germline variants (PGVs), most of which were potentially actionable with specific therapies, a review of almost 8,000 patients showed.

Overall, 14.9% of the patients had PGVs, 95% of which were potentially actionable. After excluding patients with other types of cancer, the proportion with PGVs increased to 16%. A majority of the PGVs occurred in DNA damage repair (DDR) or homologous recombination repair (HRR) genes.

The findings, combined with other evidence, make a compelling case for genetic testing of all patients with lung cancer, said Renato Martins, MD, of the VCU Massey Cancer Center in Richmond, Virginia, during an American Society of Clinical Oncology Virtual Plenary presentation.

"The FDA and NCCN [National Comprehensive Cancer Network] endorse targeted therapies for patients with breast, pancreatic, prostate, and ovarian cancers who carry HRR PGVs," said Martins. "Targeted therapy use in lung cancer patients with HRR PGVs warrants investigation."

Background of Genetic Testing

"Given the current NCCN recommendations for genetic testing patients diagnosed with other cancer types, the Moonshot Version 2.0 recommendations [favoring genetic testing for all patients with cancer], 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 genetic testing," Martins said.

Beginning with olaparib (Lynparza) for advanced BRCA-mutant ovarian cancer in 2014, the FDA has announced eight approvals for drugs targeting HRR-deficient cancers, said Andrew McKenzie, PhD, of the Sarah Cannon Research Institute in Nashville, Tennessee, during an introduction to Martins' talk. Most recently, the FDA extended olaparib's approval to include adjuvant treatment of BRCA-mutant, HER2-negative high-risk early breast cancer. The FDA's European counterpart has granted a similar number of approvals related to HRR-deficient tumors.

"These approvals are in specifically identified patient populations, where there is a high likelihood that homologous recombination deficiency, which is measured directly through genomic-scar assays like loss of heterozygosity [LOH] or through the detection of specific mutations in things like BRCA1 or BRCA2," said McKenzie.

"In the past few years, we've sort of seen an explosion in this space, where we're starting to understand the biology better and we're starting to understand which patients might benefit most from PARP inhibitors," he added. "Most of these are looking for patients that have some sort of BRCA status or HRD status or LOH status, as those are the patients we think are most likely to respond to PARP inhibitors."

By way of his own introduction to the data, Martins noted that the NCCN currently recommends germline testing for PGVs for all patients with pancreatic and ovarian cancer, patients younger than 50 with colorectal cancer and possibly those ≥50, and many patients with breast cancer. The American Society of Breast Surgeons recommends germline testing for all patients with newly diagnosed breast cancer. Echoing McKenzie's comments, he noted that the FDA has approved PARP inhibitors for multiple tumors associated with DDR/HRR genes.

PGVs of TP53 and EGFR are associated with a hereditary disposition to lung cancer. However, few studies have examined the spectrum and prevalence of other PGVs in patients with lung cancer, Martins continued. Identifying PGVs could help inform recommendations for early cancer detection, preventive measures, and cascade testing of at-risk family members.

Study Design, Results

To investigate the prevalence, spectrum, and clinical implications of PGVs in lung cancer, Martins and colleagues retrospectively reviewed data from patients with lung cancer and genetic testing results from a commercial diagnostic laboratory for 2014-2022. Personal and family history of cancer, as well as demographic information, were obtained from treating clinicians. The number of genes tested varied according to clinician preference.

Data analysis included 7,788 patients, who had a mean age of 63, and women accounted for 71.1% of the total cohort. The median number of genes tested was 79, and 71% of the patients had a personal history of some other type of cancer.

The overall results showed that 14.9% of the cohort tested positive for PGVs. The most common variants were 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%). About half of the patients (49.3%) tested negative, and 32.8% had uncertain results.

Limiting the analysis to patients with lung cancer only, the PGV-positive rate increased to 16%. BRCA2 still topped the list of the most common variants (3.4%), followed by EGFR (2.1%), ATM (2.0%), CHEK2 (1.9%), TP53 (1.3%), BRCA1 (1.2%), and APC (1.0%). The negative subgroup decreased to 47.0% and the uncertain group increased slightly to 33.6%.

For the overall cohort, 95% (1,104 of 1,160) of PGVs were clinically actionable. The data also showed that 61.3% of the PGVs involved DDR/HRR gene defects.

The key findings differed substantially from another recent investigation of PGVs in lung cancer, said invited discussant Kara Maxwell, MD, PhD, of Penn Medicine in Philadelphia. The single-center study showed that 4.3% of patients with lung cancer had PGVs.

Maxwell noted that 71% of patients in Martins' cohort had a history of other cancers as compared with 26% of the single-center study. Similar disparities existed with respect to the proportion of high-risk patients.

Martins' results have differences and similarities with other recent studies as well. More information is needed relative to why patients with certain mutations develop lung cancer, she continued.

Multiple unanswered questions remain regarding the goals, target populations, disease states for which genetic testing might be appropriate, and whether testing for somatic gene mutations might represent a screening tool to identify patients who should be tested for PGVs.

"Germline genetic testing of all lung cancer patients is probably a bit premature," said Maxwell. "Thinking about some 'low-hanging fruit' for genetic testing might be helpful -- age of onset less than 46, EGFR mutations, TKI [tyrosine kinase inhibitor] naive, DNA repair mutations, all might be a good way to start, potentially even using somatic testing as a screening tool. And as always, when we think about germline and cancer susceptibility, take a family history."

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