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Lung cancer is the second most diagnosed cancer in men and women in the United States and is the leading cause of cancer death.¹?Non¨Csmall cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers.¹

NSCLC is commonly diagnosed at a late stage.²?Treatment focuses on improving survival and minimizing disease-related adverse events.³?Chemotherapy remains an important part of treatment; however, the survival rates for metastatic NSCLC are low.⁴?First-line, targeted therapies that are based on genetic alterations in the tumor have reduced NSCLC mortality and improved survival.⁵?Testing to identify gene variants (biomarkers) present in the tumor can identify patients who are mostly likely to benefit from specific treatments.⁶

Therapeutic advances linked to specific biomarker testing of tumor tissue have been shown to improve the outcomes of patients with NSCLC diagnosed at all disease stages.⁷?However, an estimated 40% of patients with NSCLC do not receive recommended biomarker testing.⁸

This article discusses diagnosis of NSCLC and the importance of biomarker testing for determining prognosis and guiding therapy.

NSCLC epidemiology, deaths, and survival rates

The American Cancer Society (ACS) estimates that in 2022 there will be about 237,000 new cases of lung cancer and about 130,000 lung cancer deaths (new cases and deaths are approximately equal between men and women).¹?Lung cancer accounts for almost 25% of cancer deaths; more people die each year due to lung cancer than colon, breast, and prostate cancers combined.¹?The greatest risk factor for lung cancer is smoking, but other factors can also increase risk (see Sidebar).^1,9?Screening (see Sidebar) is recommended only for persons at high risk.¹⁰

More than 50% of patients have stage III or IV disease at the time of diagnosis; 40% of cases are diagnosed at stage IV.^2?The overall 5-year relative survival rate for patients with NSCLC is 26% (2011-2017).⁴?However, survival decreases markedly with more advanced-stage disease (Table).

Table. Non¨CSmall Cell Lung Cancer Stage at Diagnosis and 5-Year Relative Survival^a

^a?Relative survival: a method of comparing the survival of people with a specific disease with those who do not have the disease. Relative survival is calculated by dividing the percentage of patients with the disease who are still alive at the end of a time period (in this case 5 years) by the percentage of people in the general population of the same sex and age who are alive at the end of the same time period.

NSCLC symptoms, diagnosis, and subtypes

The most common symptoms of lung cancer include⁹

• Chronic/worsening cough
• Chest pain
• Hemoptysis
• Malaise
• Weight loss
• Dyspnea
• Hoarseness

Diagnosis requires pathologic examination of a lung biopsy specimen to assess histologic type and other tumor characteristics. A biopsy is typically performed if chest computed tomography (CT) identifies a >8 mm solid nodule(s), or part-solid nodules with a solid component ¡Ý6 mm.⁶

The main histological subtypes of NSCLC are adenocarcinoma (about 78% of NSCLCs) and squamous cell carcinoma (about 18% of NSCLCs), with other rare subtypes comprising about 4% of cases.¹¹?Squamous NSCLC tends to occur at an older age and to be detected at more advanced disease stage, and the median survival is about 30% shorter than for other NSCLC subtypes.¹²

NSCLC biomarkers

Most biomarkers with respect to NSCLC are gene variants (eg, mutations, rearrangements, fusions) in tumor cells.⁶?A notable exception is programmed death-ligand 1 (PD-L1) expressed on tumor cells (discussed below).⁶?Identification of biomarkers has substantially improved the outcomes of patients with NSCLC because they can indicate increased sensitivity to specific treatments. For example, the 2-year relative survival rate for patients with NSCLC increased from 34% during the period of 2009 through 2010 to 42% from 2015 through 2016.⁷?One factor that likely contributed to the survival gains was the development of epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) targeted against the most common NSCLC driver variants.¹³

National Comprehensive Cancer Network (NCCN^?) guidelines, as well as those of other professional organizations, recommend testing for specific gene variants in patients with NSCLC.^6,14?Relevant genes include?ALK,?BRAF,?EGFR,?ERBB2?(HER2),?KRAS,?METex14,?NTRK1/2/3,?RET, and?ROS1.⁶

Biomarkers are typically categorized as actionable (a specific treatment exists that can improve outcomes in patients with the biomarker) or emerging (study suggests that treatment based on the biomarker may improve outcomes).⁶?Testing methods include fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and next-generation sequencing (NGS).⁶

Actionable NSCLC biomarkers include

• ALK?(anaplastic lymphoma kinase) gene rearrangements⁶
  • ALK?encodes a receptor tyrosine kinase and rearrangement results in dysregulation and inappropriate signaling.
  • ALK?rearrangements are associated with responsiveness to oral ALK TKIs.
• BRAF?(B-Raf proto-oncogene) point mutations⁶
  • BRAF is a serine/threonine kinase, and activating variants of?BRAF?result in unregulated signaling through the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAP/ERK) pathway.
  • The presence of a specific mutation resulting in a change in amino acid position 600 (p.V600E) is associated with responsiveness to combined therapy with oral inhibitors of BRAF and mitogen-activated protein kinase kinase (MEK).
• EGFR?(epidermal growth factor receptor) gene mutations⁶
  • EGFR is a receptor tyrosine kinase present on the surface of epithelial cells that is overexpressed in a number of human malignancies.
  • The most common EGFR variants (eg, exon 19 deletions) are associated with responsiveness to oral EGFR TKI therapy.
• ERBB2?(erb-B2 receptor tyrosine kinase 2; also known as HER2) variants and/or amplification^6?are
  • Associated with resistance to EGFR TKIs.
  • Targets for fam-trastuzumab deruxtecan-nxki in adults with unresectable or metastatic NSCLC.
  • Included as an actionable biomarker in the most recent NCCN guidelines.
• KRAS?(KRAS proto-oncogene) point mutations⁶
  • KRAS is a G-protein with intrinsic GTPase activity; activating variants result in unregulated signaling through the MAP/ERK pathway.
  • The presence (compared with absence) of a?KRAS?variant is prognostic of poor survival.
  • KRAS?variants are associated with reduced responsiveness to EGFR TKI therapy.
  • The?KRAS?p.G12C variant is associated with responsiveness to an oral KRAS G12C inhibitor, which was designed specifically for this variant.
• METex14 (mesenchymal-epithelial transition) exon 14 skipping variants⁶
  • MET is a receptor tyrosine kinase; a variant resulting in loss of exon 14 (METex14) results in dysregulation and inappropriate signaling.
  • The presence of?METex14 skipping mutation is associated with responsiveness to oral MET TKIs.
• NTRK1/2/3?(neurotrophic tyrosine receptor kinase) gene fusions⁶
  • NTRK1/2/3 are tyrosine receptor kinases, and variants result in dysregulation and inappropriate signaling.
  • NTRK1/2/3?gene fusions are associated with responsiveness to oral tropomyosin receptor kinase (TRK) inhibitors.
• PD-L1⁶
  • T cells express PD-1, a negative regulator that binds to ligands including PD-L1 (CD274) and PD-L2 (CD273). T cell activity is suppressed in the presence of PD-L1.
  • PD-L1 can be expressed on tumor cells and inhibits T cell¨Cmediated tumor-cell death.
  • ¡°Targeted therapies¡± or ¡°immunotherapies¡± that include therapeutic antibodies (eg, pembrolizumab [KEYTRUDA^?]) act by blocking the PD-1 and PD-L1 interaction.
  • This mode of action, called checkpoint inhibition, improves the antitumor effects of endogenous T cells.
• RET?(rearranged during transfection) gene rearrangements⁶
  • RET is a receptor tyrosine kinase, and rearrangement of the?RET?gene results in dysregulation and inappropriate signaling through the RET kinase domain.
  • The presence of a?RET?rearrangement is associated with responsiveness to oral RET TKIs.
• ROS1?(ROS proto-oncogene 1) gene rearrangements⁶
  • ROS1 is a receptor tyrosine kinase that can be rearranged in NSCLC, resulting in dysregulation and inappropriate signaling through the ROS1 kinase domain.
  • The presence of a?ROS1?rearrangement is associated with responsiveness to oral ROS1 TKIs.

An emerging NSCLC biomarker is

• METamp (METamplification)^6,15
  • A?MET?copy number >10 is considered high-level MET amplification.
  • High-level MET amplification is predictive of response to immunotherapy and specific drugs (eg, tepotinib).

Circulating tumor DNA

Examining peripheral blood for circulating tumor DNA¡ªalso referred to as ¡°liquid biopsy¡±¡ªis a less invasive method of detecting NSCLC and other tumors but should not be used in in lieu of a histologic tissue diagnosis.⁶

Clinical situations in which a liquid biopsy may be useful⁶

• A patient is medically unfit for invasive tissue sampling
• Insufficient material for molecular analysis remains following pathologic confirmation of an NSCLC diagnosis
• Tissue-based testing does not assess all recommended biomarkers
• As a complement to tissue-based, to reduce turnaround time and increase the detection yield for alterations
• Monitoring response to therapy^16,17

Several considerations should be noted when performing or interpreting results from a liquid biopsy⁶

• Cell-free tumor DNA testing is considered to have very high specificity but low sensitivity, with up to a 30% false-negative rate.
• Standards have not been established for analytical performance characteristics of cell-free tumor DNA testing.
• Cell-free tumor DNA testing can identify alterations that are unrelated to a lesion of interest¡ªfor example, clonal hematopoiesis of indeterminate potential (CHIP).

Risk factors for lung cancer

The single most important risk factor for the development of lung cancer is smoking. The risk of lung cancer is around 10-fold higher in persons who smoke than in lifetime nonsmokers (defined as a person who has smoked <100 cigarettes in their lifetime).^1,9?The risk increases with the quantity of cigarettes, duration of smoking, and age the person began smoking.^1,9

Smoking cessation reduces the risk of developing lung cancer, although the risk remains elevated for many years after quitting.^1,9

In addition to smoking, risk factors for developing lung cancer include⁹

• Exposure to secondhand smoke
• Increasing age, regardless of smoking status
• Occupational exposure to asbestos, arsenic, chromium, beryllium, and nickel
• Living in an area with air pollution
• Family history of lung cancer
• Human immunodeficiency virus infection
• Beta carotene supplements in heavy smokers
• Radiation exposure, including
  • Radiation therapy to the breast or chest
  • Radon exposure in the home or workplace
  • Medical imaging tests, such as CT
  • Atomic bomb radiation

Lung cancer screening and risk reduction

The United States Preventive Services Task Force (USPSTF) recommends screening for lung cancer with low-dose CT in persons at high risk of developing lung cancer: adults 50 to 80 years old who have a 20 pack-year smoking history and currently smoke or have quit smoking within the past 15 years.¹⁰

While eliminating exposure to factors that can increase the risk of developing lung cancer, the most important measure for reducing the risk of lung cancer is not smoking or, for people who smoke, quitting smoking.^9,10

How the laboratory can help

Quest Diagnostics offers testing for the diagnosis and management of NSCLC. Tissue biopsy specimens are examined by board-certified histopathologists. Multigene panels, as well as FISH, IHC, and other advanced testing, are available for identification of biomarkers and actionable targets to help guide treatment decisions and establish a prognosis.

Additional information is available at

Test Guides:

References

1. Key statistics for lung cancer. American Cancer Society. Revised February 14, 2022. Accessed September 22, 2022.?

2. Ganti AK, Klein AB, Cotarla I, et al. Update of incidence, prevalence, survival, and initial treatment in patients with non-small cell lung cancer in the US.?JAMA Oncol. 2021;7(12):1824-1832. doi:10.1001/jamaoncol.2021.4932

3. Zappa C, Mousa SA. Non-small cell lung cancer: current treatment and future advances.?Transl Lung Cancer Res. 2016;5(3):288-300. doi:10.21037/tlcr.2016.06.07

4. Lung cancer survival rates. American Cancer Society. Revised March 2, 2022. Accessed September 22, 2022.?

5. Howlader N, Forjaz G, Mooradian MJ, et al. The effect of advances in lung-cancer treatment on population mortality.?N Engl J Med. 2020;383(7):640-649. doi:10.1056/NEJMoa1916623

6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^?). Non-small cell lung cancer. Version 4.2022.Published September 2, 2022. Accessed September 12, 2022.?

7. Siegel RL, Miller KD, Fuchs HE, et al. Cancer Statistics, 2021.?CA Cancer J Clin. 2021;71(1):7-33. doi:10.3322/caac.21654

8. Robert NJ, Nwokeji ED, Espirito JL, et al. Biomarker tissue journey among patients (pts) with untreated metastatic non-small cell lung cancer (mNSCLC) in the U.S. Oncology Network community practices.?J Clin Oncol. 2021;39:(15)(suppl):9004). doi:10.1200/JCO.2021.39.15_suppl.9004

9. Non-small cell lung cancer treatment (PDQ^?)-health professional version. National Cancer Institute. Updated March 17, 2022. Accessed September 22, 2022.?

10. US Preventive Services Task Force. Screening for lung cancer: US Preventive Services Task Force recommendation statement.?JAMA. 2021;325(10):962-970. doi:10.1001/jama.2021.1117

11. Thai AA, Solomon BJ, Sequist LV, et al. Lung cancer.?Lancet. 2021;398(10299):535-554. doi:10.1016/S0140-6736(21)00312-3

12. Socinski MA, Obasaju C, Gandara D, et al. Current and emergent therapy options for advanced squamous cell lung cancer.?J Thorac Oncol. 2018;13(2):165-183. doi:10.1016/j.jtho.2017.11.111

13. Minguet J, Smith KH, Bramlage P. Targeted therapies for treatment of non-small cell lung cancer--recent advances and future perspectives.?Int J Cancer. 2016;138(11):2549-61. doi:10.1002/ijc.29915

14. Imyanitov EN, Iyevleva AG, Levchenko EV. Molecular testing and targeted therapy for non-small cell lung cancer: current status and perspectives.?Crit Rev Oncol Hematol. 2021;157:103194. doi:10.1016/j.critrevonc.2020.103194

15. Kron A, Scheffler M, Heydt C, et al. Genetic heterogeneity of MET-aberrant NSCLC and its impact on the outcome of immunotherapy.?J Thorac Oncol. 2021;16(4):572-582. doi:10.1016/j.jtho.2020.11.017

16. Nagasaka M, Uddin MH, Al-Hallak MN, et al. Liquid biopsy for therapy monitoring in early-stage non-small cell lung cancer.?Mol Cancer. 2021;20(1):82. doi:10.1186/s12943-021-01371-1

17. Smolle E, Taucher V, Lindenmann J, et al. Liquid biopsy in non-small cell lung cancer-current status and future outlook¡ªa narrative review.?Transl Lung Cancer Res. 2021;10(5):2237-2251. doi:10.21037/tlcr-21-3

Models used for illustrative purposes only.

Published date: Nov 2022