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CRUK's Personalized Breast Cancer Program Aims to Develop Clinical Sequencing Framework

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NEW YORK (GenomeWeb) – Cancer Research UK has launched a personalized breast cancer program that aims to sequence the whole genomes and transcriptomes of breast cancer patients and report back results from 16 actionable genes to guide treatment.

The program kicked off this September with  £1.1 million ($1.38 million) in funding from Addenbrooke's Charitable Trust for phase one, which will enroll 250 breast cancer patients.

Jean Abraham and Carlos Caldas at CRUK are heading up the program, which will be open to CRUK breast cancer patients regardless of their subtypes, and will include both metastatic patients and those who have been diagnosed earlier in the course of disease.

The team is also fundraising for the second phase of the project, which is anticipated to cost between £7 million and £8 million and will run for the next five years. The second phase will involve sequencing the whole genomes and transcriptomes of 2,000 patients, Abraham told GenomeWeb.

The CRUK team is also working with Illumina, which is performing the sequencing. Abraham noted, however, that sequencing will be done in collaboration and goes beyond a service, with the two parties meeting regularly to develop the pipeline and discuss results.

The project has both clinical and research bents. Although the researchers are conducting whole-genome and transcriptome sequencing, they are only returning results from 16 so-called tier 1 genes to patients, Abraham said.

"We've been quite cautious about what we call actionable because we feel it has to be absolutely, definitely actionable," Abraham said. The 16 genes include both germline ones like BRCA1, BRCA2, and PALB2, as well as somatic alterations that indicate a targeted therapy may be effective, and some pharmacogenomics variants related to cancer drug toxicity. In addition, the list of genes will be reviewed regularly to determine if others have reached the evidence threshold to be included.

Patients who consent to the study are also given a survey both before sequencing and after they receive results to determine what their concerns are before being tested and what results they are interested in receiving back, and to see whether and how those preferences and concerns change after getting their results back.

Abraham said that the survey results will be used to inform the second phase of the project, but noted that it is currently too early to draw conclusions about patients' preferences since the study just launched.

The group has also set up an oncogenetics review board that reviews and signs off on patients' sequencing results. Alterations deemed tier 1 and tier 2 will be returned to the physician and the tier 1 results will also go to the patient. The tier 2 list will include alterations for which "there is a lot of evidence, but not enough for the result to change clinical practice," she said. That would include mutations to cancer genes that have been found to be relevant for other tumor types, for instance, she said.

The remainder of the genome and transcriptome sequence data will stay in the research domain. "We'd like to collaborate with researchers around the world and work with them to do meta-analyses of the data," she said. In addition, Abraham said that her team would be interested in collaborating with the Genomics England 100,000 Genomes Project, although there is no formal agreement in place yet.

Part of the aim of the Personalized Breast Cancer Program will be to figure out best practices for incorporating genomic data into clinical care, regardless of whether that data is generated by whole-genome sequencing, exome sequencing, or targeted panels, Abraham said. For instance, she said, the oncogenetics review board is something that could be applied to other tumor types and would be relevant for any type of molecular testing.

In addition, she said, the group is looking to ensure that data is delivered back to patients in clinically relevant time frames. Currently, turnaround time from when a tumor sample is received to when results are returned to patients is 12 weeks or less. That is about the time it takes for a patient to complete three rounds of chemotherapy and "is usually a decision point," she said.

The project could also have implications for how the UK's National Health System decides to incorporate genomics into clinical cancer care. Currently, tumor sequencing is not standard of care within the NHS although the agency is looking at how to use genomics in clinical practice, Abraham said. "Whether that will be whole-genome sequencing is not quite clear" and will likely come down to the cost, she said. "The great thing about whole-genome sequencing is you have a huge amount of data forever," she said. While a panel is useful at the time its run, 10 years down the road it won't be as up to date.

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