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With New Funds, BC Cancer Agency Aims to Sequence 300 Patients for Personalized Onco-Genomics Trial


NEW YORK (GenomeWeb) – A few years ago, researchers at the British Columbia Cancer Agency were able to use advanced sequencing techniques to arrive at a personalized treatment strategy for a patient with a rare type of oral cancer without therapeutic options. 

After that early success story, the BC Cancer Agency has been trying to do the same for other cancer patients through the so-called Personalized Onco-Genomics (POG) clinical trial program. To expand this effort, the agency raised $5 million in funding through a BC Cancer Foundation gala last year, and the foundation has committed $12.5 million for POG.

Now researchers leading that study have announced they are hoping to sequence the whole genomes of 300 cancer patients in an effort to find the best treatment options for them. 

While running the POG trial on a smaller scale since 2012, researchers have so far sequenced the genomes of more than 150 patients, according to Steven Jones, head of bioinformatics and the associate director of the BC Cancer Agency's Michael Smith Genome Sciences Center. Jones led the study, published in Genome Biology in 2010, in which researchers analyzed the tumor genome and transcriptome sequences of a man with a rare type of tongue adenocarcinoma. 

"It was so rare that this condition had no treatment options at all," Jones recalled. "The genomic analysis was able to point to some key pathways and ultimately pointed to some key targeted drugs that actually did help the patient and reduced the tumor burden over a period of a year, which we were quite amazed with."

Within the POG clinical trial, researchers use the Illumina HiSeq 2500 platform to analyze the tumor genome at 100x coverage and at 30x to 40x coverage for the full sequencing of the matched germline DNA. "That's a differentiating factor in what we're doing [compared] to what some others are doing," Jones told GenomeWeb. "We made the decision early on that we didn't want to have an abbreviation of the genome in any way."

Within the POG program, researchers have steadily increased their ability to analyze patients' genomes. "We started off slowly," Jones said, recalling that in the early days of the project, researchers were sequencing one patient per month. But a key focus at the POG program has been to gauge whether researchers can sequence genomes in a clinically relevant timeframe. As such, the group ramped up to one patient a week and now, "we're closer to three to four patients a week in our throughput," Jones said. "But certainly a goal is to be doing one whole-genome sequence per business day."

As Jones described it, automated analysis of the tumor to detect somatic variants takes a week. The de novo assembly of the tumor takes effort and resources but it "helps us resolve a lot of the complex rearrangements within those tumors," he said. BC Cancer Agency researchers then use different tools to look at different types of genomic variations.

After automated analysis, researchers take another week to figure out what a patient's particular genomic characteristics mean in the context of his or her cancer. Jones and his team consider, for example, the characteristics of the patients' tumors in light of what's known in that cancer type, which genes in which pathways are upregulated or downregulated that correlate with that cancer type or any other cancer type, and which genes and their expression are unusual for that type of tumor.

"What that [process] helps us do is ... identify what we think are the key pathways that are activated in that person's tumor," he noted. "Sometimes the mutations will indicate certain drug sensitivities, for instance, or insensitivities to a therapeutic that the clinician might be considering." After the second week, the results from the analysis are presented to a tumor board, where researchers and doctors discuss what treatment course they might take for a patient based on the data.

With the tongue adenocarcinoma patient, for example, the patient was given Tarceva based on the fact that his tumor overexpressed EGFR, but he didn't respond to treatment. With a more detailed picture after sequencing the tumor and the transcriptome, researchers prescribed Pfizer's Sutent (sunitinib), which stabilized the disease for five months during which no new tumor nodules were seen.

Eventually, the patient experienced metastasis to the lung, and at that point, he was given Bayer's Nexavar (sorafenib) and Merck's anti-inflammatory drug Clinoril (sulindac). This again stabilized his disease for another three months until his disease recurred on his tongue, and he developed a fast-growing skin nodule in the neck as well as progressive and new lung metastases.

Jones noted that in the POG program, using their sequencing and analysis methods, researchers have been able to home in on actionable information that helps clinicians make a treatment decision for more than 50 percent of patients. However, there are times when the patient's genomic findings suggest that he or she would respond to a drug but that drug is not accessible because it's off label and not covered. "But we would still consider that genomic analysis … as an actionable item," Jones said.

Luckily for Trish Keating, a colorectal cancer patient who was being treated by Howard Lim, an oncologist at the BC Cancer Agency, the off-label drug that was identified through the POG trial was available and affordable. Over a period of five years, Keating underwent multiple surgeries, chemotherapy, and radiation therapy. In November 2014, Trish had advanced cancer that had spread to multiple sites including her lymph nodes. She was told she had two years to live, but then Lim told her about enrolling in POG.

Genomic analysis revealed that a protein was upregulated in her tumor that usually isn't in other advanced colorectal cancer patients. With this understanding, researchers put her on a drug commonly used to treat high blood pressure that also happens to target the upregulated protein. Jones couldn't reveal the name of the drug, but noted that it was affordable in Keating's case. "The major thing was that the drug was readily available and it wasn't an issue getting a hold of the drug," Jones said. "It wasn't an expensive drug … [and] it wasn't an oncology-related drug."

POG researchers want to know how many other patients with genomic characteristics like Keatings' might be helped by this same treatment strategy. "It really speaks to the modality of the personalized genomics approach," Jones reflected. "This drug helped that person and helped that person really quite profoundly but in a very personalized way. What we'd like to know is how many other people could benefit if they showed similar genomic features. I think we do know that's still going to be a small percentage of cancer patients."

Toward that end, POG is storing patients' data so investigators can compare patients, their genomic features, and the treatment modalities that worked and those that didn't. With just over 150 patients sequenced, researchers' comparative powers are limited, but stand to be improved with the planned expansion of the study cohort to 300.

For the time being, researchers are comparing patients' data with information in larger resources, such as the Cancer Genome Atlas. "We're very cognizant that a lot of the power of this is going to come from careful storage and reanalysis of this data as we go along," Jones said. "Certainly, part of the reason why the patients are involved is not only that they can have the potential personalized approach to treat their tumor but that this would benefit other patients down the line."

On the BC Cancer Foundation's website, there is an appeal for donations to ensure POG can grow and researchers can continue to learn from the unique genomic underpinnings of patients' cancers. The cost for each patient to go through the POG program – about $27,000 – is covered by the foundation and its donors . The genome sequencing, specifically, costs around $3,500.

"It's not a thousand dollar genome," Jones said. However, "compared to any modern cancer drug that costs $10,000 a month, even now, this actually makes a lot of sense in terms of getting the right answers for those patients."