Lung cancer is predicted to be the leading cause of cancer-related death among men and women in the US in 2023.1 The majority of lung cancers are classified as non-small cell lung cancer (NSCLC) and most are diagnosed at the advanced stage, with a 5-year survival rate of 7% (Figure 1).1-3 Cough is the most common symptom of NSCLC, and other symptoms include hemoptysis, dyspnea, and chest pain.2
Precision oncology, in which specific molecular alterations in a tumor are identified and then matched targeted therapies are incorporated into treatment plans, holds particular promise for NSCLC.4 In nonsquamous NSCLC, which accounts for 75% of NSCLC cases, more than half of tumors have a molecular alteration that can be treated with an approved targeted therapy.5 However, in a study of 38,068 patients with newly diagnosed advanced NSCLC, only 36% of patients received biomarker testing and an appropriately matched targeted treatment. It is estimated that nearly half of these patients did not receive appropriate biomarker testing and targeted therapy due to issues with receiving biomarker screening and results.6 Thus, optimizing the biomarker testing process for patients with an advanced NSCLC diagnosis represents a large opportunity for improving patient care and outcomes.
Types of Biomarker Testing
Biomarker tests can be performed on tumor tissue samples obtained via biopsy or on blood samples (also referred to as liquid biopsy).7 Currently, liquid biopsy analyses are mainly limited to the analysis of circulating tumor DNA isolated from blood plasma, whereas tissue samples can be analyzed by various methods, including DNA sequencing, fluorescence in situ hybridization, and immunohistochemistry.7,8 In a study of real-world biomarker testing in a community oncology network, the vast majority of patients with a known biopsy type (n=2726, 84%) received only a tissue biopsy; 12% of patients (n=385) received both tissue and liquid biopsies, and 4% (n=118) received only a liquid biopsy.9
While tissue-based biomarker screening remains the primary means of analysis, data on the utility of liquid biopsy are increasing. In paired plasma and tissue samples from patients with advanced NSCLC, genomic alterations detected by tissue-based and liquid biopsy-based next-generation sequencing (NGS) were highly concordant.10 Other studies reported that more actionable mutations were detected in advanced NSCLC when liquid biopsy was used alongside tissue biopsy for biomarker screening than with tissue biopsy alone, providing further support for the potential value of liquid biopsy in this patient population.9
Tissue-based and plasma-based biomarker screening methods each have advantages and limitations. Tissue samples can be analyzed with a wider variety of methods that can assess non-DNA biomarkers, such as programmed death-ligand 1 (PD-L1) expression levels, and can provide valuable pathologic information.8 However, tissue-based biomarker analysis is often limited by the amount of tissue available, and procedures to obtain tissue samples are invasive, costly, and can be associated with complications. Liquid biopsy has the advantage of overcoming the sampling issues tissue biopsy specimens face due to tumor heterogeneity, potentially providing a more comprehensive view of genomic tumor alterations.7,8
Depending on the methodology employed, biomarker screening may be very targeted (often examining 1 type of mutation in 1 or 2 genes) or much broader, providing information on a panel of genes, the whole exome, or the whole genome. More targeted methods include polymerase chain reaction (PCR)-based tests, fluorescent in situ hybridization, and immunohistochemistry, whereas NGS can be used for broader biomarker screening.7 As NGS technology has advanced, its use for biomarker screening in NSCLC has increased in clinical practice.8,9
Guideline Recommendations for Biomarker Testing
The first guidelines regarding biomarker screening in NSCLC were issued in 2011 by the American Society of Clinical Oncology (ASCO), providing a provisional recommendation for EGFR mutation testing.11 Since then, several other professional societies have issued guidelines with recommendations for biomarker testing in advanced NSCLC. In 2013, the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology (CAP/IASLC/AMP) published guidelines that set the standard of care for biomarker screening in NSCLC, including recommendations on which genes should be screened (EGFR and ALK), testing methods, and acceptable testing turnaround time (<14 days).12 Updated guidelines from CAP/IASLC/AMP and guidelines from other organizations, such as ASCO and the National Comprehensive Cancer Network (NCCN), are largely in line with the 2013 CAP/IASLC/AMP recommendations, although the list of target genes recommended for testing has expanded (Table 1).13-15
International guidelines generally are in concordance with US guidelines.7 For example, the European Society of Medical Oncology and the Chinese Society of Clinical Oncology provided joint guidelines recommending screening for EGFR and BRAF mutations, ALK and ROS1 rearrangements, and PD-L1 immunohistochemistry in 2018.16
These various guidelines also provide recommendations on the types of biomarker screening that should be employed based on clinical evidence. In general, due to the large number of relevant genomic alterations in NSCLC, broader testing with NGS-based methods is recommended.7,13,15 Current guidelines are generally grounded in tissue-based biomarker screening, but several recent updates have recommended that plasma-based biomarker screening be used in place of or concurrent with tissue testing.8,15
Utility of Biomarker Screening and Personalized Treatment in NSCLC
As biomarker testing and personalized treatment have become more common in clinical practice, an increasing amount of real-world evidence has emerged supporting the benefits of precision medicine for treating NSCLC. In a study of 28,784 patients with advanced NSCLC, those who received biomarker screening as recommended in the guidelines had a significantly lower risk of mortality (hazard ratio [HR]=0.89, 95% CI, 0.86, 0.92; P <.01) and modestly longer overall survival (15.4 vs 14.2 months; P <.01) than patients who did not undergo the recommended screening.18
Several other studies have demonstrated that patients who receive biomarker testing and targeted therapy in accordance with guideline recommendations have improved survival outcomes, including improved overall survival and progression-free survival.5,18 Additionally, patients who received first-line immunotherapy based on NCCN guidelines and which was biomarker-driven had a lower risk of treatment discontinuation than those receiving chemotherapy.18
Optimizing Biomarker Testing at NSCLC Diagnosis
Despite the potential benefit of biomarker screening and treatment with targeted therapies in accordance with current guidelines, many patients with NSCLC do not receive biomarker-driven treatment.7 The first step to increasing the number of patients who can benefit from targeted therapies is to optimize biomarker testing at diagnosis to identify actionable mutations.
Undertesting for biomarkers is a national problem, despite the fact that the vast majority of patients undergo an initial biopsy.6 Rates of biomarker testing have increased over time, but studies have shown that patients are not always screened for biomarkers in accordance with clinical guidelines.5,7 While a study of 17,513 patients with advanced NSCLC found that 89.3% of patients (n=15,635) received at least 1 biomarker test, nearly 1/3 of patients with advanced or metastatic NSCLC did not receive the recommended broad NGS-based biomarker screening recommended in various guidelines.5 Another study found that while 90% of patients with advanced NSCLC received at least 1 biomarker test, only 46% were tested for all 5 recommended biomarkers (EGFR, ALK, ROS1, BRAF, and PD-L1), and <50% underwent NGS-based screening.9 Other studies report low NGS-based testing rates in US practices, with 1 large study finding up to a third of patients receiving no biomarker testing.19
Barriers to Biomarker Testing
Several barriers to biomarker testing have been identified that could be addressed to optimize biomarker testing at NSCLC diagnosis and increase concordance with guidelines regarding diagnosis and treatment for NSCLC7; a retrospective study analyzing a multisource database that included commercial and Medicare claims and laboratory data found that biomarker tests were not ordered at all for 17.5% of patients.6 The testing rate could potentially be increased with reflex testing, in which biomarker tests are automatically ordered.7,9 In a survey on biomarker testing and treatment among US oncologists, only 21% of respondents reported that reflex testing occurred, demonstrating there is still a large margin for improvement in this domain.20
Another issue in biomarker testing is inadequate tissue samples. Approximately 4% of biopsy samples are inadequate for biomarker screening, and 9.6% of tissue samples of adequate size do not have enough tumor cells for biomarker testing.6 Other studies have found that as few as 18% of patients with NSCLC have enough tissue sample to screen for the 8 guideline-recommended biomarkers.8 Several approaches can help address this issue; first, as described above, liquid biopsy is becoming more widely accepted as an alternative to tissue samples for biomarker testing, and the use of broad NGS testing rather than single-gene tests can both conserve tissue and could be potentially less expensive in the long run.
Turnaround time is another barrier to incorporating precision oncology into clinical practice and is a concern among clinicians.7 In 2 studies published in 2022, reported median turnaround times for NGS-based biomarker screening ranging from 10 to 19 days.5,9 Despite concerns regarding turnaround time, a study on real-world biomarker testing found that only 4% of patients did not receive biomarker testing results before treatment decisions had to be made, and 13.1% of patients did not receive results in <14 days, per the CAP/IASLC/AMP recommendations.6 Additionally, specific testing protocols can be put in place at institutions for tissue triaging and allocation to allow for basic testing with more rapid assays while preserving valuable material if more extensive testing is needed.7
Summary
In cancers such as NSCLC with a high rate of potentially actionable mutations, biomarker testing and biomarker-driven treatment can improve treatment outcomes. Despite guideline recommendations, rates of NGS-based biomarker screening remain low in clinical practice. Optimizing biomarker testing at NSCLC diagnosis represents an opportunity to improve concordance with clinical guidelines, guide the appropriate use of targeted therapies, and improve patient outcomes.
References
1. Siegel RL, Miller KD, Wagle NS, Jemel A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48. doi:10.3322/caac.21763
2. Duma N, Santana-Davila R, Molina JR. Non-small cell lung cancer: epidemiology, screening, diagnosis, and treatment. Mayo Clin Proc. 2019;94(8):1623-1640. doi:10.1016/j.mayocp.2019.01.013
3. Lung and bronchus: recent trends in SEER age-adjusted incidence rates, 2004-2019. Surveillance Research Program, National Cancer Institute. Updated March 7, 2023. Accessed March 8, 2023. https://seer.cancer.gov/statistics-network/explorer/
4. Mateo J, Steuten L, Aftimos P, et al. Delivering precision oncology to patients with cancer. Nat Med. 2022;28(4):658-665. doi:10.1038/s41591-022-01717-2
5. Hess LM, Krein PM, Haldane D, Han Y, Sireci AN. Biomarker testing for patients with advanced/metastatic nonsquamous NSCLC in the United States of America, 2015 to 2021. JTO Clin Res Rep. 2022;3(6):100336. doi:10.1016/j.jtocrr.2022.100336
6. Sadik H, Pritchard D, Keeling DM, et al. Impact of clinical practice gaps on the implementation of personalized medicine in advanced non-small-cell lung cancer. JCO Precis Oncol. 2022;6:e2200246. doi:10.1200/PO.22.00246
7. Pennell NA, Arcila ME, Gandara DR, West H. Biomarker testing for patients with advanced non–small cell lung cancer: real-world issues and tough choices. Am Soc Clin Oncol Educ Book. 2019;39:531-542. doi:10.1200/EDBK_237863
8. Rolfo C, Mack P, Scagliotti GV, et al. Liquid biopsy for advanced NSCLC: a consensus statement from the International Association for the Study of Lung Cancer. J Thorac Oncol. 2021;16(10):1647-1662. doi:10.1016/j.jtho.2021.06.017
9. Robert NJ, Espirito JL, Chen L, et al. Biomarker testing and tissue journey among patients with metastatic non-small cell lung cancer receiving first-line therapy in The US Oncology Network. Lung Cancer. 2022;166:197-204. doi:10.1016/j.lungcan.2022.03.004
10. Park S, Olsen S, Ku BM, et al. High concordance of actionable genomic alterations identified between circulating tumor DNA-based and tissue-based next-generation sequencing testing in advanced non-small cell lung cancer: the Korean Lung Liquid Versus Invasive Biopsy Program. Cancer. 2021;127(16):3019-3028. doi:10.1002/cncr.33571
11. Beasley MB, Milton DT. ASCO provisional clinical opinion: epidermal growth factor receptor mutation testing in practice. J Oncol Pract. 2011;7(3):202-204. doi:10.1200/JOP.2010.000166
12. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol. 2013;8(7):823-859. doi:10.1097/JTO.0b013e318290868f
13. 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. doi:10.1016/j.jtho.2017.12.001
14. 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. doi:10.1200/JCO.2017.76.7293
15. Ettinger DS, Wood DE, Aisner DL, et al. Non-small cell lung cancer, version 3.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2022;20(5):497-530. doi:10.6004/jnccn.2022.0025
16. Wu YL, Planchard D, Lu S, et al. Pan-Asian adapted clinical practice guidelines for the management of patients with metastatic non-small-cell lung cancer: a CSCO-ESMO initiative endorsed by JSMO, KSMO, MOS, SSO and TOS. Ann Oncol. 2019;30(2):171-210. doi:10.1093/annonc/mdy554
17. Mosele F, Remon J, Mateo J, et al. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2020;31(11):1491-1505. doi:10.1016/j.annonc.2020.07.014
18. John A, Yang B, Shah R. Clinical impact of adherence to NCCN guidelines for biomarker testing and first-line treatment in advanced non-small cell lung cancer (aNSCLC) using real-world electronic health record data. Adv Ther. 2021;38(3):1552-1566. doi:10.1007/s12325-020-01617-2
19. Waterhouse DM, Tseng WY, Espirito JL, Robert NJ. Understanding contemporary molecular biomarker testing rates and trends for metastatic NSCLC among community oncologists. Clin Lung Cancer. 2021;22(6):e901-e910. doi:10.1016/j.cllc.2021.05.006
20. Mileham KF, Schenkel C, Bruinooge SS, et al. Defining comprehensive biomarker-related testing and treatment practices for advanced non-small-cell lung cancer: results of a survey of U.S. oncologists. Cancer Med. 2022;11(2):530-538. doi:10.1002/cam4.4459
Posted by Haymarket’s Clinical Content Hub. The editorial staff of Cancer Therapy Advisor had no role in this content’s preparation.
Reviewed March 2023
