When and how should next-generation sequencing and comprehensive genomic profiling assays be performed?

I have worked as a respiratory physician in a community hospital for 8 years. During that time, lung cancer treatment has undergone a major paradigm shift. Targeted therapy for lung cancer has expanded, and most patients with non-small cell lung cancer (NSCLC) are now being evaluated using genetic analysis with a next-generation sequencing or a multiplex reverse transcriptase polymerase chain reaction assay. Ishida et al. provide an excellent study that explains the utility of comprehensive genomic profiling assays.¹ However, the hospital where I work is a community hospital and access to these tests is limited. I was inspired by this study and would like to share two clinical questions regarding current companion diagnostics. And if possible, I would like to hear an experts opinion on genomic medicine.

First, is it possible to measure all genes with only one next-generation sequencing test? In the case of epidermal growth factor receptor (EGFR), discrepancies between next-generation sequencing and PCR have been reported.² In Sakaguchi et al., EGFR-tyrosine kinase inhibitors were reported to be successful even in cases reported as negative by next-generation sequencing and positive for EGFR by PCR. For the ALK fusion gene, 15.5% of immunohistochemistry-positive patients are negative for next-generation sequencing tests.³ Therefore, the usefulness of immunohistochemistry in detecting ALK-positive patients has also attracted attention. Next-generation sequencing is also useful for measuring the resistance mechanism of EGFR-positive lung cancer,^{4, 5} and it might be important to use targeted therapy for sequencing in the future. Which test should a patient with lung cancer undergo first at diagnosis? Should each of these tests be performed separately or simultaneously? Adequate solutions to these problems have not yet been found.

The second question is whether there is a need for more than two tests using next-generation sequencing. The study by Ishida et al. is a high-impact paper discussing the usefulness of comprehensive genomic profiling assays.¹ (In their paper, comprehensive genomic profiling assays refers to FoundationOne and the OncoGuide NCC Oncopanel System.) Their paper demonstrated that new targets were found in people who had already undergone a gene test and subsequently undergone comprehensive genomic profiling assays. Noteworthy in their paper are the details of the 20 individuals for whom new therapeutic targets were found. Was their first test a single-plex test or an Oncomine Dx Target Test Multi-CDx? What were the histological type, sex, and smoking history of theese 20 patients? These information will help us determine which patients should undergo comprehensive genomic profiling assays. As mentioned in their paper, Oncomine Dx Target Test Multi-CDx and comprehensive genomic profiling assays might detect different variants.⁶ Although the usefulness of comprehensive genomic profiling assays is clear, it is questionable whether those tests should be repeated for patients who have already undergone Oncomine Dx Target Test Multi-CDx. Unfortunately, Japanese insurance policies allow patients to receive comprehensive genomic profiling assays only once in their lifetime. Working in a hospital that cannot perform comprehensive genomic profiling assays, I wonder when and which patients should undergo comprehensive genomic profiling assays.

As mentioned above, there is no perfect test, and it is important to take advantage of the characteristics of each test and perform it in a timely manner. We need to provide optimal medical care without overlooking the genetic mutations of the patients, and at optimal cost. Further research and discussion are needed to answer these questions.

Tadashi Nishimura: Conceptualization; writing – original draft. Takumi Fujiwara: Writing – review and editing. Hajime Fujimoto: Writing – review and editing.

We do not receive any financial support from any company or organization.

The authors declare no conflict of interest.

Approval of the research protocol by an Institutional Reviewer Board: N/A.

Informed Consent: N/A.

Registry and the Registration No. of the study/trial: N/A.

Animal Studies: N/A.