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Foundation Medicine Shares Results From Validation of FoundationOne Heme in New Study

NEW YORK (GenomeWeb) – Foundation Medicine and collaborators from Memorial Sloan Kettering Cancer Center have published a study describing in full the validation of the firm's FoundationOne Heme test.

According to Foundation Medicine, the publication, which appeared online earlier this month ahead of print in an upcoming issue of the journal Blood, may help spur adoption of the test by clinical oncology practices. In addition to technical validation data, the study also included reports on thousands of clinically tested samples showing frequent identification of clinically useful diagnostic and prognostic markers.

Commercially launched in 2013, FoundationOne Heme is a comprehensive targeted NGS panel integrating both DNA/RNA sequencing. Performed on archived FFPE, blood, or bone marrow samples, the test simultaneously detects all classes of genomic alterations in 405 cancer-related genes and employs RNA sequencing across 265 genes to capture a broad range of gene fusions.

In the validation study, MSKCC researchers who developed the new Heme test in collaboration with Foundation Medicine put it through its paces by comparing results from the newer assay with those of Foundation's original DNA-only FoundationOne test in order to assess its analytic accuracy in detecting substitutions, insertions and deletions, and copy number alterations.

In the validation study, the MSKCC investigators first reanalyzed 47 samples that were previously profiled with FoundationOne, in which 169 alterations were initially identified in 55 genes common to both assays. Comparing results of the Heme test against the original FoundationOne results, the concordance between the two was 99.4 percent, the authors wrote.

The group also performed an experiment using pooled cell lines with known genomic rearrangements to create mixtures representing a range of clinically relevant tumor fractions, and compared the genomic rearrangements detected in the pooled samples relative to the initial constituent cell lines.

According to the authors, FoundationOne Heme's sensitivity for fusion detection at 20 to 100 percent tumor fraction was 100 percent, and it remained 98 percent sensitive even down to a 10 percent tumor fraction. There were also only a few false-positive calls, yielding a positive predictive value of more than 98 percent.

In addition to this comparison, the MSKCC researchers performed blinded comparisons with CLIA-certified diagnostic assays, including a Sequenom assay, RT-PCR, FISH, and PCR fragment analysis for 76 clinical specimens.

These specimens had been previously tested for 214 clinically relevant alterations in 11 genes that are known and routinely tested in clinical practice in hematologic cancers including AML, ALL, and MDS. In this comparison the overall concordance between FoundationOne Heme and these other assays was 99 percent.

More specifically, of 101 genomic alterations identified by the Sequenom assay or by PCR fragment analysis, 100 were also called by FoundationOne Heme.

Meanwhile, amongst the negative genomic alterations reported previously using the other assays, FoundationOne Heme confirmed 111 negative calls and identified two additional IDH2 R140Q mutations that were not detected by the reference methods. These two IDH2 alterations were later confirmed in an independent validation using the Ion Torrent AmpliSeq platform.

In addition to the concordance analysis, genomic profiling of the 76 test samples using FoundationOne Heme also identified 126 additional somatic alterations including clinically relevant genomic alterations in KRAS, TET2, EZH2, and DNMT3A.

Importantly, the study also showed that the molecular information supplied by the test can help accurately match patients with a particular targeted therapy.

In the study Foundation Medicine shared clinical data from genomic profiling of 3,696 hematologic malignancies submitted to its CLIA-certified, NYS-approved lab.

More than 90 percent of the specimens — 3,433 out of 3696 — were successfully characterized. The test identified at least one driver alteration in 95 percent of the tumor specimens, and results showed that 77 percent of the cases harbored at least one alteration linked to a commercially available targeted therapy or one that is in clinical development, the MSKCC researchers reported.

In addition, 61 percent of the cases harbored at least one alteration with known prognostic relevance in that tumor type.

In discussion of the results, the study authors argued that clinical merit of the test was underscored by the demonstrated ability to identify genetic lesions with prognostic and therapeutic relevance in specific diseases.

For example, the authors wrote, "In the case of B-cell ALL … the challenge has been that the critical genes … can be altered by whole gene/intragenic deletions, DNA base-pair substitutions, and larger indels, as well as chromosomal, intergenic, and cryptic rearrangements, which lead to expression of fusion transcripts."

"Currently, most centers use an amalgam of DNA, FISH, and gene-specific RNA approaches to identify a subset of the most critical genetic lesions in B-ALL. Our assay provides a single profiling platform that can reliably identify all known actionable disease alleles relevant to B-ALL to improve diagnosis and risk-adapted therapy for B-ALL patients," they wrote.