Broad Molecular Testing in Lung Cancer: The Struggle to Translate Recommendations to Clinical Practice

By Kara Nyberg, PhD
Posted: June 24, 2020

Over the past decade, lung cancer has emerged as a shining example of how precision medicine can dramatically improve patient outcomes. Up to 85% of patients with lung cancer harbor potentially actionable driver mutations, and matching targeted therapy to druggable alterations in the first-line setting prolongs survival two to three times over compared with cytotoxic chemotherapy.1-3

To capitalize on the power of precision medicine for patients, several major medical societies have long recommended routine testing for genomic alterations in driver oncogenes to guide the selection of first-line treatment for patients with NSCLC. Initial guidance in 2013 focused solely on EGFR and ALK mutational analysis for patients with advanced-stage adenocarcinoma,4 but many additional biomarkers have since been added to the diagnostic landscape, both for adenocarcinoma and other disease histologies. Current guidelines now recommend numerous biomarkers for upfront testing at the time of NSCLC diagnosis—EGFR, ALK, ROS1, BRAF, KRAS, NTRK, MET, RET, and HER2—underscoring the wide breadth of targets and corresponding therapies that can be leveraged for disease management.4-6

The speed at which the field is moving has made it difficult to stay abreast of current testing standards for some oncology facilities, particularly community hospitals that outsource pathology tests or where shortcomings in interdepartmental communication occur. Even when molecular testing involved just a handful of biomarkers, community-based testing lagged behind the benchmarks set in academic practice. An analysis of genomic tests ordered by community oncologists throughout New Jersey and Maryland published in 2017 showed that only 59% of patients underwent EGFR and ALK biomarker testing, and only 8% were tested for all seven mutations recommended by the National Comprehensive Cancer Network guidelines as of 2014.3 The lead author of the study, Martin E. Gutierrez, MD, co-chair of Thoracic Oncology, John Theurer Cancer Center, Hackensack Meridian Health, thinks that testing rates have increased since his study was published, “but there is still a gap that needs to be improved,” he said.

Eric S. Nadler, MD, MPP, who serves as medical director of U.S. Oncology Health Informatics and Internet Technology at Baylor University Medical Center, confirmed that the rates of genomic biomarker testing are improving but that testing of new markers consistently falls behind that of the familiar ones such as EGFR, ALK, and ROS1. “Instead of testing [becoming] more streamlined over the past few years, with clear guidelines and guidance, the exposure of testing and manners of testing have made the testing patterns more heterogenous and the practice of ordering specific tests more confusing for the clinical oncologist,” Dr. Nadler said.

“Instead of testing [becoming] more streamlined over the past few years, with clear guidelines and guidance, the exposure of testing and manners of testing have made the testing patterns more heterogenous and the practice of ordering specific tests more confusing for the clinical oncologist.” –Eric S. Nadler, MD, MPP

Testing deficiencies do not necessarily stem from a lack of awareness. “I think the recognition that testing has to happen is an understood proposition in the community. There are not a lot of patients with adenocarcinoma who are not getting tested these days,” Dr. Nadler said.

“The problem has to do with logistics more than lack of awareness,” Dr. Gutierrez said. Several retrospective analyses of biomarker testing in real world clinical practice underscore a variety of clinical and logistical challenges for community-based oncologists. Common setbacks include insufficient tissue for testing, lack of infrastructure in obtaining and sending biopsy samples for testing, unacceptably long turnaround times for results, and uncertainty regarding reimbursement. As time ticks away in getting all the pieces to fall into place, the pressure to treat patients reaches a tipping point, so sometimes testing is just not done or oncologists resort to chemotherapy before genomic test results are available.

Given the burgeoning number of recommended molecular tests for lung cancer, multigene panel testing using next-generation sequencing (NGS) offers an attractive diagnostic alternative that can keep pace with the dynamics of precision medicine. In a single push, NGS enables identification of all the point mutations, insertions, deletions, copy number alterations, fusion genes, and microsatellite instability information needed to guide the potential use of targeted therapy. NGS can also identify genomic alterations that open the door to clinical trials of investigational therapies.

“NGS should absolutely be the standard of care at this point, especially now that payers are starting to cover it,” said Nathan A. Pennell, MD, PhD, of the Taussig Cancer Institute, Cleveland Clinic Foundation. Three tissue-based NGS tests have been approved by the U.S. Food and Drug Administration for patients with lung cancer: FoundationOne CDx, the Oncomine Dx Target Test, and the MSKIMPACT assay. Moreover, in 2017, the U.S. Centers for Medicare and Medicaid Services (CMS) approved coverage of NGS testing under the Parallel Review Program, and private payers have started to follow suit.

“There are too many biomarkers to do individual gene tests anymore; you just can’t get them all done. And it costs a lot more to do multiple tests and bill for each individually than it does to do one NGS test,” Dr. Pennell said. Dr. Pennell and his colleagues recently devised a mathematical model that showed that upfront tissue-based NGS testing was both faster—with a 2-week turnaround time—and less costly than testing sequentially for alterations in EGFR, ALK, ROS1, BRAF, MET, HER2, RET, and NTRK1 using single-gene tests or testing simultaneously for alterations in EGFR, ALK, ROS1, and BRAF using hotspot panels followed by single-gene tests for the remaining biomarkers.7

Although NGS offers an obvious solution for hospitals that lack testing capabilities, NGS uptake in community settings remains anemic due to many of the same clinical and logistical problems that plague single-gene tests. Obtaining adequate tissue still tops the list of challenges. “Frequently in the community, tissue is obtained by bronchoscopy, so bronchoalveolar lavage or fine needle aspiration cytology is all that is available,” Dr. Gutierrez said. “The lack of tissue when you want to do tissue-based NGS can be a nightmare,” which has prompted Dr. Gutierrez to order plasma-based cell-free circulating tumor DNA NGS testing up front in appropriate settings—for example, if a patient is referred to him with only a fine needle aspiration specimen.

Although NGS offers an obvious solution for hospitals that lack testing capabilities, NGS uptake in community settings remains anemic due to many of the same clinical and logistical problems that plague single-gene tests. Obtaining adequate tissue still tops the list of challenges.

Accumulating data support the use of plasma NGS as a worthy tool for genomic biomarker testing, especially in situations where tissue is scarce.8,9 Although one must take negative liquid biopsy results with a grain of salt due to variable amounts of tumor DNA shed into circulation and lower sensitivity levels compared with tissue-based testing, positive results are clinically actionable. Thus, plasma NGS offers a means to enhance testing rates and improve widespread delivery of molecularly guided therapy.

Aside from leveraging tissue or plasma NGS for newly diagnosed patients with lung cancer, Dr. Pennell believes that one of the simplest ways to improve broad molecular testing within institutions is to promote internal communication. “Have a conversation with all the stakeholders— the pathologists, the interventional radiologists, the pulmonologists, the surgeons—to make sure everyone knows the importance of molecular testing and ensures that it’s a priority.”

Dr. Pennell hopes that these conversations will boost lung cancer to the same level as breast cancer in terms of molecular testing. “You’d be shocked if you walked into any oncology office in America to see a woman with breast cancer who did not have a pathology report listing estrogen-receptor, progesterone- receptor, and HER2 FISH status along with the diagnosis and grade,” he explained. “Molecular testing has become a standard component of breast cancer care. And yet when we talk about lung cancer, molecular testing doesn’t get that same gut-level understanding of how important it is. It almost seems more optional, and it’s not,” Dr. Pennell said. ✦

1. Jordan EJ, Kim HR, Arcila ME, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 2017;7(6):596-609.

2. Nadler E, Espirito JL, Pavilack M, Boyd M, Vergara-Silva A, Fernandes A. Treatment Patterns and Clinical Outcomes Among Metastatic Non-Small-Cell Lung Cancer Patients Treated in the Community Practice Setting. Clin Lung Cancer. 2018;19(4):360-370.

3. Gutierrez ME, Choi K, Lanman RG, et al. Genomic profiling of advanced non-small cell lung cancer in community settings: gaps and opportunities. Clin Lung Cancer. 2017;18(6):651- 659.

4. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Thorac Oncol. 2018;13(3):323-358.

5. Kalemkerian GP, Narula N, Kennedy EB, et al. Molecular Testing Guideline for the Selection of Patients With Lung Cancer for Treatment With Targeted Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update. J Clin Oncol. 2018;36(9):911-919.

6. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Non-Small Cell Lung Cancer, Version 3.2020. Available at: Accessed April 27, 2020.

7. Pennell NA, Mutebi A, Zhou ZY, et al. Economic impact of next-generation sequencing versus single-gene testing to detect genomic alterations in metastatic non–small-cell lung cancer using a decision analytic model. JCO Precis Oncol. 2019;3:1-9.

8. Rolfo C, Mack PC, Scagliotti GV, et al. Liquid biopsy for advanced non–small cell lung cancer (NSCLC): a statement paper from the IASLC. J Thorac Oncol. 2018:13(9):1248-1268.

9. Aggarwal C, Thompson JC, Black TA, et al. Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non-small cell lung cancer. JAMA Oncol. 2019;5(2):173-180.