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After a Year of Lessons Learned, Michigan Looks to Expand Comprehensive Clinical Cancer Sequencing

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One year after launching a clinical cancer sequencing protocol, the University of Michigan has sequenced more than 100 patients, identifying actionable results in about half. The team has recently launched a pediatric cancer sequencing pipeline for which it has sequenced around 10 patients, and it is also looking to scale up its adult cancer sequencing pipeline to be able to handle more than the 10 to 20 patients per month it currently analyzes.

The so-called Mi-OncoSeq pipeline, for which the team published its proof-of-principle study last year in Science Translational Medicine, involves whole-exome sequencing and whole-transcriptome sequencing of patients with advanced cancer. After sequencing, a tumor board convenes to discuss what mutations are actionable and should be included in a report to a physician to help guide treatment (CSN 12/7/2011).

So far, sequencing has been done primarily on the Illumina HiSeq 2000, but the team plans to purchase a HiSeq 2500 to reduce turnaround time and is also evaluating Life Technologies' Ion Proton machine. There is also a MiSeq in the lab, used primarily for targeted assays.

Arul Chinnaiyan, who is heading the project, told Clinical Sequencing News that the group plans to continue its current approach of exome and transcriptome sequencing.

"We need the combo to be comprehensive," he said. "We get quite a bit of information from the RNA, especially on gene fusions."

Chinnaiyan said the lab is currently in the process of becoming CLIA certified, which he expects to happen by the end of January. After the lab is certified, he said the team will work on certifying each of its assays, starting first with the Sanger sequencing that it uses for validation, and then moving into the next-gen sequencing-based assays.

Streamlining the Workflow

In implementing the protocol, Chinnaiyan said that one of the main technical challenges was getting "the entire sequencing infrastructure in place." The computation pipeline, in particular, was challenging to do "in a systematic way with a reasonable number of patients coming in per month."

Another challenge has been meeting the goal for turnaround time of four weeks. In general, the team has returned results in the range of four to six weeks, Chinnaiyan said.

Going forward, Chinnaiyan said, the center is interested in increasing its volume of patients, which will mean reducing turnaround times.

One way he hopes to do this is by bringing in systems like the HiSeq 2500, which has a run time of around one day. Additionally, he said he is evaluating the Ion Proton for this purpose as well.

The group will also consider triaging the cases to be heard by the tumor board, Chinnaiyan said. Currently, after patients are sequenced, the sequence results are discussed by the board, which includes the patient's treating physician, oncologists, bioinformaticians, bioethicists, and genomicists.

The board convenes about twice a month and hears about eight to 10 cases. Right now, every patient is discussed by the tumor board. "But that's not very scalable," Chinnaiyan said.

Rather, Chinnaiyan said, the group is considering implementing a "triage system," where if a patient's sequence data identifies a mutation that is clearly actionable, that patient could bypass the tumor board.

"If we identify something clearly actionable and that doesn't require too much deliberation and we have a parallel CLIA test, those could be reported directly to the physician," he said.

Conversely, if the sequence data does not identify anything actionable, the board could hold off hearing those cases.

The group is also considering developing a panel of around 1,000 genes that the team has found to be the most commonly mutated. Chinnaiyan envisions performing the panel test as a first screen on all patients coming in, and if nothing actionable is found in that first screen, then the patient would move on to exome sequencing.

"We've worked up the targeted assay, but are still optimizing whether that might be the best approach," he said. "It would help in terms of turnaround time and the volume of patients we could see."

Access to Drugs

While around half of the patients that go through the Mi-OncoSeq protocol harbor actionable mutations — defined as mutations for which approved drugs, off-label drugs, or clinical trials are available — Chinnaiyan said that one major hurdle has been gaining access to such drugs or clinical trials.

Only around 10 percent to 15 percent of the total patients sequenced have since been treated or enrolled in a trial as a result.

One problem, said Chinnaiyan, is that often a drug will only be approved for a specific indication. So even if a patient has the mutation for which the drug is approved, it may be in a cancer of a different etiology. In those cases, it becomes difficult to convince insurance companies or Medicare to pay for the drugs.

Similarly, mutations are often found for which there are clinical trials of targeted drugs, but, again, these trials tend to be for specific types of cancers. Special exception has to be won to enroll the patient.

Additionally, the trial location itself sometimes makes it difficult for patients to enroll, Chinnaiyan said. Other times, patients pass away before their mutational findings can be acted upon — yet another reason for reducing turnaround time, he noted.

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