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Illumina Details NCI Effort to Validate NGS Oncology Panel for Liquid Biopsies


NEW YORK (GenomeWeb) – After launching the tissue-directed TruSight Oncology 500 panel late last year, Illumina has now cemented a partnership that, along with potential others, will validate the firm's comprehensive sequencing assay for an eventual liquid biopsy application.

Researchers from the Molecular Characterization Laboratory at the National Cancer Institute's Frederick National Laboratory said last month that they plan to use TSO 500 to support multiple clinical studies, assessing liquid biopsy samples from up to 7,000 subjects.

The effort will include validation of a liquid biopsy version of the TSO 500 kit, as well as a number of analyses focused on variant detection in rare tumor types and on blood-tissue mutation concordance.

In an email, an Illumina representative said this week that the first customer shipment for its TSO 500 tissue assay was in early January. "We had a very successful early access program, and now we see strong momentum for the assay in tissue," the firm said.

According to Illumina, a robust interest in liquid biopsy application is following suit, which means that Frederick National Lab is not necessarily the only group that will be working to prove the technology. There may be other "potential collaborators" ahead of the launch of an official TS Oncology 500 cfDNA kit, the company's spokesperson wrote.

In its announcement of the FNL collaboration, Illumina projected a sense of caution regarding liquid biopsy, stating that it is "still in its infancy and requires additional validation to more fully demonstrate clinical utility." Responding to questions this week, however, the company clarified that these comments are specific to the question of large assays like TSO 500, and not directed at the larger field.

Although blood-based sequencing assays are now on the market for both research and clinical customers, most profile smaller panels of genes if not single genes or mutations. Guardant Health has launched its own 500-gene assay but has limited marketing of that panel to the research community thus far. Baltimore-based Personal Genome Diagnostics has also developed 500-plus-gene assays for both tissue and blood, with plans to advance FDA-approved kit versions.

But overall, few kits have been launched so far, and most — like Thermo Fisher's Oncomine panels, Roche's Avenio kits, and others — have been limited to research use and to sub-500 gene panels.

While Illumina restricted its own comments on the state of the liquid biopsy field to the question of very large panels, the debate over the validity and utility of blood-based comprehensive sequencing tests — even the more limited assays already being marketing and sold for clinical use — continues.

In an email, a representative from the FNL team that will be working with TSO 500 cited, for example, the special article published in the Journal of Clinical Oncology last year, in which the American Society of Clinical Oncology and the College of American Pathologists issued a joint statement concluding that there is limited evidence of true clinical validity, let alone utility, for ctDNA assays outside of specific targets EGFR in lung cancer and KRAS in colorectal cancer.

"We expect our planned use of TSO 500 … [will] further add to the clinical validity of ctDNA testing," the FNL spokesperson wrote, adding more specifically that the team hopes that using the assay in greater numbers of patients with rare tumor types, and to prospectively select patients for therapies, should increase the potential that it can meet thresholds of validation that other research may have fallen short of.

In addition to validating the cfDNA version of TSO 500 that Illumina plans to eventually launch as a kit, FNL's recently-announced partnership with the company includes using the assay to test "several thousand" plasma samples from more than 5,000 patients who have been or are being screened as part of enrollment in the NCI-MATCH trial. 

From this data, researchers will assess the concordance of ctDNA with corresponding results from solid tumor specimens, as well as measurements of microsatellite instability and TMB in blood versus tissue.

They also plan to specifically study the ability of the TSO 500 panel to detect ctDNA in plasma from the rarer tumor types enrolled in NCI-MATCH.

Finally, the group will use the assay in studies within the NCI's Experimental Therapeutics Clinical Trials Network over the next several years. This will be mainly retrospective, "looking for candidate mechanisms of resistance and response to therapy," the FNL spokesperson said.

"We also plan to use the … test to screen patients at NCI's Developmental Therapeutics Clinic in Bethesda," the representative added.

An FNL representative said in an email that the lab considered adopting other assays before deciding to work with Illumina. Investigators viewed TSO 500 as having "mature chemistry and a well-developed informatics pipeline for error correction and variant calling." But the main differentiating feature was its breadth compared with other panels, and what the investigators said is the kit's ability to achieve this broader coverage "without compromising assay performance." 

With coverage of more than 500 genes, for example, the assay opens an opportunity to "accurately call tumor mutational burden in plasma," the FNL spokesperson added.

TMB has very quickly gained attention as a biomarker for predicting patient responses to cancer immunotherapies. Companies like Foundation Medicine already offer a calculation of TMB as part of tissue sequencing services, and the field has begun to pay attention to the need for standardization and the ability to compare what are likely to be different assay cutoff points as various sequencing panels are turned toward TMB.

Foundation has said that it is pushing toward blood-based TMB as well, with an agreement to develop a companion diagnostic to Roche/Genentech’s immnunooncology drug atezolizumab (Tecentriq) in first-line treatment of non-small cell lung cancer patients.

Guardant Health has said that its 500-gene GuardantOMNI test can support TMB analysis. And researchers working with the company's smaller Guardant360 assay published a study last year in which that test could accurately reproduce the predictive ability of TMB as calculated from tumor tissue exome data.

Illumina has a deal in place with Bristol-Myers Squibb to develop a diagnostic version of the tissue TSO 500 kit that would include a readout of TMB. But the company declined to comment on whether it had had discussions with the drugmaker regarding a blood-based version within that existing agreement.