Earlier this year, Caris Life Sciences added next-gen sequencing to its portfolio of tumor profiling services. The company has since sequenced thousands of patients using Illumina's TruSeq targeted cancer panel on the MiSeq and is developing its own customized 60-gene assay that it plans to launch in the first quarter of next year.
According to David Spetzler, the company's VP of research and development, by doing comprehensive molecular profiling of patients' tumors — including the next-gen assay, mRNA fragment analysis of the EGFR gene, and immunohistochemistry assays to look for clinically relevant copy number alterations — the firm is able to provide information on about 43 different approved drugs. In about 95 percent of patients, the suite of tests identifies actionable results, defined as either matching an alteration to an available drug, finding evidence that a drug will not be effective, or identifying an available clinical trial.
Additionally, the company has a registry of about 1,800 patients for which it is gathering outcome data and has found that in about 80 percent of cases physicians follow the recommended guidance from the test.
"We have a very high adoption rate of the information that's being provided," Spetzler told Clinical Sequencing News. "And because we focus so heavily on therapies that are available today, it is really only in the situation where those therapies have been exhausted that the physicians reflex to clinical trials."
Spetzler said that since the company introduced its TruSeq panel, which it validated in its CLIA laboratory as MI Profile in February, it has added an additional two MiSeq systems to its fleet for a total of five, in order to keep up with demand. The firm profiles around 12,000 patient tumors per year. Most patients receive all three tests — the sequencing panel, EGFR analysis, and IHC — but occasionally a physician will order a single test, he said.
Turnaround time for the sequencing assay is on average eight days, with 97 percent of cases signed out within two weeks. The company focuses on rare and refractory cancers and can run about 50 patient samples per day through its sequencing systems.
However, Caris plans to launch a custom designed sequencing panel in the first quarter of next year because the current panel "misses some markers where there are good clinical associations," Spetzler said, such as somatic mutations on the BRCA1 and 2 genes, which are associated with response to PARP inhibitors; and androgen receptor mutations that have shown to be important in prostate cancer.
The panel will analyze around 1,000 amplicons associated with 60 cancer-related genes, Spetzler said. For sample prep, the firm decided to use a microfluidic system designed by Fluidigm in order to better handle low-input samples. The system requires just 10 nanograms of input DNA to achieve sufficient coverage, about 90 percent less DNA than what is currently required, Spetzler said.
Caris aims to achieve 1,000-fold average coverage. "We want 99 percent statistical confidence that we're making the appropriate call" for both mutant and wild type alleles, Spetzler said. "For some genes, like KRAS, it is very important to say you have a wild-type [allele]," Spetzler said, since that will indicate sensitivity to erlotinib, a lung cancer drug marketed by Genentech as Tarceva.
Spetzler said that the company has been considering exome sequencing, but "getting 1,000-fold coverage on an exome is really challenging and would force us to go to a situation where we run one patient every 14 days," as opposed to the 50 samples per day that it can currently run.
Additionally, he said that exome sequencing is still too much of a research tool because it turns up information that may be relevant in the future, but that "no one knows what to do with today."
Spetzler added that the targeted next-gen assay is proving especially useful in identifying clinically relevant well-characterized alterations in cancer lineages where the mutation is not necessarily expected to be found.
For instance, he said there was one case of a woman with late-stage colorectal cancer who was entering hospice care because treatment options had been exhausted. Tumor profiling identified a HER2 alteration indicating sensitivity to the Genentech drug Herceptin. After starting the medication she gained back 70 pounds, was able to return home, and four years later is still doing well. Despite it being an off-label use of the drug, which is approved for breast cancer, Spetzler said the physician was able to prescribe it and convince the insurance company to pay for it due to the patient's HER2 overamplification.
Spetzler said that the Caris tests have found HER2 overamplifications at a surprisingly high rate outside of breast cancer cases, for example, in colorectal and prostate cancer cases.
He added that such findings are becoming increasingly common and that the way of defining cancer by the organ in which it originates will likely become obsolete. "As molecular medicine advances and targeted therapies become more refined, limiting [drugs] to a particular lineage is not going to last very long," he said.
In general, he said that over the last year reimbursement rates for molecular tests have improved. "Insurance companies are beginning to see the benefit," he said.