The Importance of NGS-Biomarker Testing in Lung Cancer

Moleculart testing is essential for diagnosing lung cancer, effective treatment planning and surveillance. Unfortunately too many patients with NSCLC are not undergoing testing

Charles H. Weaver, MD
6–10 minutes
Home » Lung Cancer » Lung Cancer Overviews » The Importance of NGS-Biomarker Testing in Lung Cancer

It’s never been more important for individuals suspected of having lung cancer to undergo molecular testing. The top 3 reasons to obtain molecular testing are simple according to Dr. Charu Aggarwal M.D., the Leslye M. Heisler Associate Professor of Lung Cancer Excellence, section chief of Thoracic and Head and Neck Medical Oncology, and director of Precision Oncology Innovation at the Penn Center for Cancer Care Innovation at the University of Pennsylvania. To personalize therapy, improve outcomes, and reduce side effects. The results of molecular testing are used to inform an initial diagnosis and develop a treatment plan, to monitor the impact of targeted therapy and immunotherapy, and to determine long-term responses . Despite guidelines recommending testing, patients with non-small cell lung cancer (NSCLC) are still not undergoing appropriate molecular testing.1  

Traditionally, lung cancers were defined by how they looked under the microscope into two broad categories. Small cell (SCLC) and non-small lung cancer (NSCLC). NSCLC was further divided in squamous and non-squamous sub types. Treatment decisions were based solely on these classifications.

Doctors now understand that NSCLC’s may differ from one another based on what genes have cancer growth driving mutations, and “genomic testing” can be performed on the tissue biopsy or from cells circulating in the blood to identify the specific genetic abnormality driving the growth of the lung cancer.

Since 2015 over 15 new precision cancer medicines have been developed and approved for the treatment of NSCLC with specific cancer-causing genetic mutations.

Today all patients with lung cancer should undergo genomic biomarker testing at the time of diagnosis in order to determine if they have a mutation that can be treated with a precision cancer medicine, are eligible for participation in a clinical trial evaluating newer precision cancer medicines and for ongoing surveillance with sequential liquid biopsies to assess the effectiveness of treatment – the effectiveness of treatment can be monitored by following cancer specific DNA in the blood.1-3 

Actionable genomic alterations occur in approximately 50% of all patients with non-squamous NSCLC. Integrating blood based testing into clinical practice, concurrent with the use of a tissue biopsy, has demonstrated an improved detection of molecular alterations in NSCLC while also improving the delivery of targeted agents and improving survival.15-17 

When Should Testing be Performed?

Because NSCLC is increasingly treated with systemic chemo-immunotherapy before surgery molecular testing should be performed on the original diagnostic tissue biopsy specimen and blood when possible.

Tissue verses Blood?

Most but not all molecular tests can be performed on tissue or blood. Tissue testing is preferred because not all cancers will have released markers into the blood at sufficient levels for testing, and PDL-1 a biomarker that helps determine the role of immunotherapy can only be tested on tissue and and tissue allows for the development of a “tumor informed” ctDNA test that can be used for post treatment surveillance to identify early recurrence and the effectiveness of immunotherapy.  Testing both tissue and blood identifies more markers than tissue or blood alone and is preferred when available.

What Tests Should be Performed?

At a minimum all tissue samples should be tested for PD-1, and the ALK, EGFR and ROS mutations. When considering long term treatment planning it makes even more sense to perform comprehensive genomic testing for all known mutations and this approach is being implemented at most major cancer centers. 

A recent analyses of 1,542 patients revealed that approximately 75% of patients with NSCLC are initially diagnosed with stage IV disease but only about 50% of patients are tested for ALK and about 60% receive testing for EGFR at any point during their care.

PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade an attack by the body’s immune cells. Checkpoint inhibitor drugs that block the PD-1 pathway enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the lung cancer cells.4-7

Overall two thirds of lung cancer patients have some expression of PD-1, and one third are “high expressers” meaning over 50% of the tested tumor expresses PD-1. A diagnostic test to measure the level of PD-L1 is available and checkpoint inhibitors are a standard treatment in the management of lung because they improve survival.8,9,10

What is circulating tumor DNA (ctDNA)?

Circulating tumor DNA (ctDNA) is 150–200-base-pair fragments of DNA, which originate from cancer cells and are present in the bloodstream or other body fluids. A “tumor specific” ctDNA assay can be developed to detect ctDNA in the blood from the tissue obtained a biopsy and be assessed repeatedly using a liquid biopsy.

How can ctDNA help manage cancer?

There are currently four clinical applications of ctDNA to guide precision medicine in patients with cancer:13

  • Detection of minimal residual disease (MRD) following surgery.
  • Monitoring the treatment response in the metastatic setting.
  • Identifying genomic drivers of therapeutic sensitivity and resistance.
  • Guiding treatment strategies to overcome resistance to treatment.

Researchers suggests that cancer progression can be accurately predicted in ~ 8 weeks using ctDNA obtained by liquid biopsy – long before conventional imaging techniques could make a definitive call. This blood-based approach is consistent across multiple types of cancer and treatments, including immunotherapy. 

ctDNA molecular response’s can identify patients with NSCLC less likely to attain favorable clinical outcomes and this opens a therapeutic window of opportunity for treatment intensification for patients with molecular disease progression.11,12

Learn About Precision Cancer Medicine and Testing for NSCLC

Connect With Others for Support and information

Cancer Connect was the first social network created for people with cancer. Founded by oncologists to support cancer patients and their caregivers, over 40 million individuals have accessed Cancer Connect programs since 1997. Cancer Connect is used by leading cancer centers like Dana Farber to support their patients. Join the conversation, ask questions, share your experience, and learn how the best cancer centers are treating cancer from others. Share your experience, ask a question, or start a conversation by posting on Cancer Connect.

All patients with lung cancer should undergo molecular testing that can be used to guide their physicians in determining which therapies are more likely to increase the chance of survival while limiting the potential for adverse effects.

Keep Current with Advances in Lung Cancer Treatment Here.

References:

  1. J Thorac Oncol 2016;11[11S]:S249-S250, PMID: 27969441
  2. Lung Cancer Overview
  3. Aggarwal C, Abreu D, Felip E, et al. Prevalence of PD-L1 expression in patients with non-small cell lung cancer screened for enrollment in KEYNOTE-001,-010, Annals of Oncology. 2016;27(6). Abstract #1060P.

  4. Reck M, et al “Updated analysis of KEYNOTE-024: Pembrolizumab versus platinum-based chemotherapy for advanced non — small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater” J Clin Oncol 2019; DOI: 10.1200/JCO.18.00149.

  5. Brahmer J, Reckamp KL, Bass P, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. New England Journal of Medicine. 2015;373(2):123-35. Abstract. doi: 10.1056/NEJMoa1504627.

  6. Borghaei H, Paz-Arez L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. New England Journal of Medicine. 2015;373(17):1627-39. doi: 10.1056/NEJMoa1507643.

  7. Bristol-Myers Squibb Announces Top-Line Results from CheckMate -026, a Phase 3 Study of Opdivo (Nivolumab) in Treatment-Naïve Patients with Advanced Non-small Cell Lung Cancer [news release]. Bristol-Myers Squibb website. Available at: http://investor.bms.com/investors/news-and-events/press-releases/press-release-details/2016/Bristol-Myers-Squibb-Announces-Top-Line-Results-from-CheckMate–026-a-Phase-3-Study-of-Opdivo-nivolumab-in-Treatment-Nave-Patients-with-Advanced-Non-Small-Cell-Lung-Cancer/default.aspx. August 5, 2016.

  8. Zhou C, Wu Y-L, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomized, phase 3 study. Lancet Oncology. Early online publication July 22, 2011.

  9. Leighl NB, Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase 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 Guideline. Journal of Clinical Oncology. 2014;32(32):3673-79. Available at: http://jco.ascopubs.org/content/32/32/3673. Accessed September 30, 2016.

  10. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. New England Journal of Medicine. 2015;372(21):2018-20. Abstract. doi: 10.1056/ NEJMoa1501824.

  11. Sivapalan, L. et al. Liquid biopsy approaches to capture tumor evolution and clinical outcomes during cancer immunotherapy. J. Immunother. Cancer 11, e005924 (2023).

  12. Stewart, M. D. & Anagnostou, V. Liquid biopsies coming of age: biology, emerging technologies, and clinical translation—an introduction to the JITC expert opinion special review series on liquid biopsies. J. Immunother. Cancer 11, e006367 (2023). 3. Anagnostou, V. et al. Immuno-oncology trial endpoints: capturing clinically meaningful activity. Clin. Cancer Res. 23, 4959–4969 (2017). 4. https://www.nature.com/articles/s41591-023-02598-9

  13. https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.9022

  14. Aggarwal C. ctDNA in lung cancer. Presented at: 18th Annual New York Lung Cancers Symposium; November 11, 2023; New York, NY.

  15. 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. doi:10.1001/jamaoncol.2018.4305 

  16. Aggarwal C, Marmarelis ME, Hwang W-T, et al. Association between availability of molecular genotyping results and overall survival in patients with advanced nonsquamous non–small-cell lung cancer. JCO Precision Oncol. 2023;7:e2300191. doi:10.1200/PO.23.00191 

  17. Thompson JC, Aggarwal C, Wong J, et al. Plasma genotyping at the time of diagnostic tissue biopsy decreases time-to-treatment in patients with advanced NSCLC—results from a prospective pilot study. JTO Clin Res Reports. 2022;3(4):100301. doi:10.1016/j.jtocrr.2022.100301

, , , , ,

You May Be Interested In