NGS in Routine Cancer Testing

NGS in Routine Cancer Testing

Current efforts and obstacles for use of next-generation sequencing in routine oncology practice

Georgia McDonald, BSc, MSc, MPhil, PhD

Georgia McDonald is a London-based science writer with a PhD in immunology from University College London. Her research furthered the understanding of the role of T cells in the development...

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Published:Mar 13, 2020
|4 min read

Major advancements in the field of cancer therapy, and a push toward personalized treatment strategies, have led to a decline in the overall rate of cancer mortality in the US. In fact, the most recent available data from 2016–2017 reveals the largest ever recorded reduction in cancer-related deaths. Moreover, observational studies have revealed a correlation between improvements in progression-free survival and the use of molecular-guided drug regimes. How does next generation sequencing (NGS) fit into the rapidly evolving landscape of cancer therapies, and what are the obstacles to its universal use in routine cancer care?

What is NGS?

The term NGS is used to describe a number of modern sequencing technologies that apply bioinformatics analysis of millions of small laterally sequenced DNA fragments to the human reference genome. The development of NGS has enabled faster, cheaper, and simpler sequencing of tumoral DNA, allowing the technology to rapidly migrate from the lab bench into the clinic. These attributes have been key to advancements in the widespread clinical application of personalized cancer therapy. 

Clinical use of NGS

The cancer NGS test market represents the second largest global NGS market after reproductive health. It was valued at $838.8 million USD in 2017 and is forecast to reach $4.1 billion by 2022. A significant section of the global cancer NGS market is located in the US, Canada, and Mexico, although this is predicted to be superseded in 2022 by the faster growing markets of China and India. Some experts also forecast that early cancer detection tests such as liquid biopsies will expand at a more rapid rate outside of the US. 

A recent study of 1,281 US-based oncologists revealed how NGS testing is currently used in the clinic to guide decisions on cancer treatment. 75.6 percent of oncologists included in the study reported using NGS within the previous 12 months; however, its use varied according to a number of factors including the oncologist’s age, patient load, patient type, and training. Younger oncologists treating patients with solid malignancies, with fewer than 50 patients per month and with access to genomic training or testing facilities were most likely to utilize the technology within their clinic. Oncologists treating patients with rare cancers, cancers of unknown origin, and those with an initial diagnosis of cancer were less likely to employ NGS testing in their clinic. Clinicians were found to use NGS testing in three main clinical circumstances: Advanced refractory disease treatment when first line treatments have failed; determination of eligibility for clinical trials; and off-label use of FDA-approved drugs. 

Gene panel tests based on NGS have been developed to integrate the technology into daily clinical practice. These NGS panel tests can be individualized to a specific malignancy and can be updated regularly as novel genes are uncovered. Several have already been granted US Food and Drug Administration (FDA) approval as in vitro diagnostic tools, highlighting their relevance in current oncological care. The MSK-IMPACT test, which analyses 468 genes and can be used to guide treatment options in a wide range of tumor settings, was the first commercial or academic NGS test to receive FDA approval. The Oncomine Dx Target Test was the first targeted NGS diagnostic test for non-small cell lung cancer (NSCLC), and detects 368 variants in 23 NSCLC-associated genes. The test can be used as a companion diagnostic device in order to select patients that would benefit from targeted treatments such as gefitinib for those with EGFR L858R and exon 19 deletions or crixotinib for those with ROS1 fusion. Finally, the FoundationOne CDx test analyzes changes in 324 genes and can be used as a companion diagnostic for five malignancies that can be treated with over 18 targeted therapies: NSCLC, melanoma, breast cancer, colorectal cancer, and ovarian cancer.  

NGS panels offer a number of benefits over more traditional single gene tests. Clinicians can use these tests to identify alterations in genes that are targetable at a molecular level by a range of drugs. This information helps inform clinicians of which patients would benefit from targeted treatments that have already been awarded regulatory approval or that are currently in clinical development. NGS panels also accommodate the ability to concomitantly delineate a subset of patients with gene alterations associated with drug resistance within a single test. This would provide actionable information to clinicians for treatment strategy decision making. Moreover, NGS technology is particularly invaluable in the identification and investigation of clinically heterogeneous inherited disorders.

Obstacles to adoption in routine testing

A number of obstacles may impede the universal use of NGS in routine cancer care. Clinicians report a lack of clarity on evidence-based clinical guidelines; over 10 different guidelines on the standardization of clinical NGS use are currently in circulation from a number of medical or professional associations. A concerted effort to amalgamate existing policies is evidently required. Several initiatives are already tackling this problem including a report on the application of current research to genomic medicine by the National Academies of Sciences, Engineering, and Medicine’s roundtable and the National Human Genome Research Institute’s Implementation of Genomics in Practice project

Clinicians have also reported that NGS testing presents a large volume of genetic data that can be difficult to interpret. A number of commercial and academic groups are attempting to resolve this limitation with online decision support platforms such as OncoKB and My Cancer Genome

Finally, before any cancer treatment is adopted in the clinic, an economic evaluation of its costs versus benefits must be made. High costs associated with NGS panel tests and associated targeted therapies may be offset by the avoidance of those associated with ineffective therapies. The cost-effectiveness of NGS testing may depend on the type of technology adopted, and clinicians often lack clear data on the clinical benefits of the new commercial and non-commercial genomic tests available. 

As advancements in NGS technology continue to evolve, the longitudinal benefits of its application to personalized cancer care will be further elucidated. Furthermore, continued development of novel molecularly targeted drugs will expand the number of patients with clinically translatable NGS panel results.