NEW YORK (GenomeWeb News) – Researchers from Foundation Medicine and the Dana Farber Cancer Institute have demonstrated that Foundation's sequencing-based assay, which it is developing for cancer diagnostics, can identify clinically actionable mutations from tumor samples.
Reporting in Nature Medicine this week, the team tested the assay on 40 colorectal cancer and 24 non-small cell lung cancer formalin-fixed paraffin-embedded biopsy samples and identified at least one potentially clinically actionable alteration in 59 percent of the samples.
Additionally, the test identified two novel gene fusions.
"These findings in aggregate show the potentially large clinical impact of a single multiplex test that requires minimal DNA from FFPE tumor biopsies," the authors wrote in the paper.
The company recently received CLIA certification from the Centers for Medicare and Medicaid Services for its genomic sequencing lab in Cambridge, Mass., and plans to commercialize its test this year.
The test analyzed 2,574 exons from 145 genes that are associated with cancer-related pathways, targeted therapy, or prognosis, plus 37 introns from 14 genes that are frequently rearranged in cancer. Sequencing was done on the Illumina platform to an average 229-fold coverage.
In the 40 colorectal cancer samples, 125 alterations were identified in 21 genes, with 39 out of 40 samples having at least one mutation. Eighty percent of the samples had mutations to TP53, a known tumor suppressor that is mutated in a broad range of cancers, and 67.5 percent of the samples had mutations to APC, a tumor suppressor gene that regulates the growth of polyps.
Twenty one samples had at least one mutation that has been linked to a clinical treatment or is currently being studied in a clinical trial of targeted therapy.
For example, mutations were found in KRAS and BRAF that predict resistance to Eli Lilly's and Bristol-Myers Squibb's Erbitux (cetuximab) or Amgen's Vectibix (panitumumab), and in FBXW7 that predict anti-tubulin resistance.
Additionally, mutations were found in BRCA2 for which there are clinical trials for PARP inhibitors, in GNAS for which there are MEK- and ERK-inhibitor trials, and in PIK3CA for which there are mTOR-inhibitor trials.
The team also detected a novel gene fusion involving ALK, suggesting that ALK inhibitors such as Pfizer's Xalkori (crizotinib) may be effective.
Among the 24 non-small cell lung cancer samples, 72 percent had at least one alteration associated with a current clinical treatment or targeted therapy trial. There were mutations to KRAS, some of which point to EGFR kinase-inhibitor resistance and others that suggest eligibility for PI3K- and MEK-inhibitor trials. Mutations in BRAS suggest eligibility for BRAF-inhibitor trials, and mutations in EGFR suggest that EGFR-inhibitors such as AstraZeneca's Iressa (gefitinib) or Genentech's Tarceva (erlotinib) may be effective.
Two novel mutations were also found. A mutation at low frequency was found in JAK2, which is commonly found in myelodysplastic syndromes, but has not previously been described in solid tumors and suggests that patients with this mutation may be sensitive to JAK2 inhibitors.
Additionally, a novel gene fusion involving RET was identified in a 44-year old 'never smoker.' The team next looked for the fusion in lung cancer samples from 121 Caucasian and 405 Asian patient samples, finding it in 0.8 percent and 2 percent of the samples, respectively. Notably, the samples with the fusion did not have any known driver mutations, suggesting that the fusion may be driving the cancer.
A different RET gene fusion is frequently found in thyroid cancers, and is sensitive to RET inhibitors. A subsequent in vitro analysis found that cells with the novel fusion were also sensitive to a number of RET kinase inhibitors, suggesting that those drugs "should be tested in prospective clinical trials for therapeutic benefit in individuals with NSCLC" with the novel fusion, the authors wrote.