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Australian Project to Sequence 10K Tumors, Study Cost Effectiveness of Personalized Oncology

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Aiming to bring personalized medicine to the Australian health system, a consortium of researchers led by the Peter MacCallum Cancer Center in Melbourne plans to do targeted sequencing of 10,000 formalin-fixed, paraffin-embedded tumor samples, using Illumina's MiSeq and TruSeq cancer panel.

Additionally, researchers involved with the project, called Cancer 2015, will evaluate whether targeted sequencing in early-stage cancer can help increase patient survival, quality of life, and cost effectiveness compared to the current standard of care.

"The impact of genomics on personalized medicine is likely to change the way we deliver healthcare," David Thomas, a principal investigator of the Cancer 2015 project and medical oncologist at the Peter MacCallum Cancer Center, told Clinical Sequencing News.

"If it does prove that personalized medicine offers significant advantages to cancer patients, we would like to see that be made available in some structured way as part of standard of care," he added.

The ambitious project, funded by the Victorian Cancer Agency, will occur in four phases. The first phase, which occurred last year, tested the MiSeq and TruSeq Amplicon Cancer panel technology to determine the amount of sample input required and the amount of multiplexing that could be done to yield the best results.

Andrew Fellowes, a pathologist at the Peter MacCallum Center, discussed how the center is using the technology for the Cancer 2015 project last week during an Illumina-sponsored webinar.

The TruSeq Amplicon Cancer panel targets 48 genes with 212 amplicons. Fellowes said that after testing various levels of multiplexing, they determined that running 20 samples at once would yield sufficient results.

The team uses 250 nanograms of starting material and achieves about 2,000 reads per amplicon. Turnaround time from sample to analyzed sequence data is about two days.

One of the most critical lessons the researchers learned in the first phase is that samples must go through quality control before being sequenced because the FFPE material is so variable and some samples are so degraded that without quality control measures, they yield very few sequencing reads, Fellowes said.

The researchers are currently in the midst of the second phase, which involves collecting 1,000 patient samples to beta test their data- and biospecimen-collection systems and the sequencing protocol. Thomas said they are about one-third of the way through this phase and aim to have all 1,000 samples processed by the end of the year.

The third phase involves collecting and sequencing the remaining 9,000 samples, and that phase will last through the end of 2014. The study will be open to all tumor types.

In the fourth phase, the researchers will follow those patients over three years. In a subset of patients that relapse, they will resequence samples to see how the cancer genomes have changed over time and will look for diagnostic markers in the patients' peripheral blood.

Thomas said that, prior to sequencing the remaining 9,000 tumor samples, the team will have to increase both sequencing capacity and automation. The details of this have not yet been worked out, he said, but will likely involve robotic handling for sample prep and potentially the Fluidigm Access Array for multiplexing samples.

One of the first outputs of the project will be a health economic model of current cancer care delivery, and how that relates to quality of life and patient health. That model will be mapped against the initial 1,000 patients to test the parameters that will ultimately be measured in all the patients. Then the model will be applied to all 10,000 patients to "give a more precise estimate of different cancer types and where we spend our money and how that might be affected by the application of personalized medicine," Thomas said.

He added that, longer term, he hopes the information will spur greater engagement with pharmaceutical companies to provide cost-effective access to targeted therapies as well as a framework for population screening and stratification based on genotype.

Another potential output, said Thomas, is the development of sequencing-based diagnostic tests, which may or may not include validating the TruSeq panel for clinical use.

"Ultimately, the intention is to turn the molecular pathology core lab for Cancer 2015 into a reference lab for our state," Thomas said, and to "perhaps to provide a service based around the assays that at this point we're using in a research setting."

The assay or assays would likely include at least some of the content of the TruSeq panel, but there are other actionable mutations like rearrangements, copy number alterations, and other structural variations that are not detected by the TruSeq panel that would likely be included as part of a clinical test, Thomas said.

"Exactly what that looks like will be one of the later objectives of the project."

Impact of Genomics on Healthcare

The study will focus on patients with early-stage cancer because that is where the greatest potential is to impact care and outcomes and to develop a cost-effective strategy for treating cancer, Thomas said.

Along with the sequencing data, the project will collect comprehensive clinical data on each patient, including the patient's quality of life, other health measures, and expenditures on healthcare.

"If we integrate all that information … it allows comparisons between different disease states and healthcare expenditures, and if you incorporate that information along with the genomics information about the cancers, we can then start to model what the impact would be on healthcare expenditures," said Thomas.

For instance, the information could potentially be used to reduce the expense of targeted therapies by avoiding drugs that are clinically ineffective in tumors with certain mutational profiles or drugs with adverse side effects.

As part of the project, the researchers will share the sequencing results with the patients' physicians.

Because the TruSeq cancer panel looks at genes that are clinically actionable, and one of the goals of the study is to test "whether the spectrum of mutations that we identify may have clinical implications, either in terms of eligibility to trials or gaining access to targeted therapies," all the patients involved in the study have prospectively consented to having results returned, Thomas said.

The results will be returned with the caveat that the results were generated in a research context, so they will have to be validated with a clinical test if a physician wishes to use the results to help guide treatment.

"We explicitly intend to report back, although in a research context, the results to the treating clinician so the patients under the study potentially get some benefit that may influence their care," said Thomas.

Another goal is to change the classification of cancer from body-site specific to mutation specific, said Thomas. By sequencing 10,000 tumors from a variety of sites, he is hoping to get an idea of the prevalence of different types of mutations across all cancer types to create better methods of stratifying patients.

For example, during last week's webinar, Fellowes presented a result from one of the 1,000 patients that have already been sequenced as part of the Cancer 2015 project.

The tumor's primary origin was unknown, but sequencing identified a clinically actionable PIK3CA mutation. The primary tumor site "doesn't really matter," said Fellowes. "It's an actionable mutation and a driver" and there are currently "drugs in clinical trials that are able to inhibit this tyrosine kinase," he said. "It's quite an exciting result for us."

While this one-off result is exciting, Thomas added that the project will ultimately have a much broader impact on the standard of cancer care in Australia.

"Personalized medicine has enormous implications for the cost of healthcare," he said. "What we are aiming to do … is to try to put some parameters around what those impacts might be and then use that information to try and entice the government to engage with and proactively manage those costs in the interest of the community, rather than becoming passively carried along as the field evolves."