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Ontario Institutions Exploring NGS Cancer Panel Screening to Inform Future Basket Study


NEW YORK (GenomeWeb) – Investigators at the Ontario Institute for Cancer Research will use a next-generation sequencing panel from Thermo Fisher Scientific to characterize the genomic events associated with treatment failure in breast cancer patients in an effort to identify drugs that can target those molecular changes and prevent recurrence.

The findings from a retrospective analysis of 400 samples from patients with invasive breast cancer will inform a basket trial that OICR is designing with Canadian Cancer Trials Group and planning to launch in the next year or two.

Women with localized breast cancer are 99 percent as likely as women in the general population to live for five years after diagnosis, but the statistics get worse depending on how invasive the cancer is. Women whose cancer has spread regionally (i.e. the lymph nodes and breast tissue) have a five-year relative survival rate of 85 percent, but if the disease has spread more extensively, the five-year relative survival rate dwindles to 26 percent.

John Bartlett, director of OICR's Transformative Pathology Program, noted that one in four women at high risk of relapse experience disease recurrence in the first four years. "We want to find out why that is so we can treat those patients on the basis of the genetic alterations that drive treatment failure," Bartlett told GenomeWeb.

In the retrospective study, led by Bartlett and Harriet Feilotter from Queen's University, researchers will use an NGS panel from Thermo Fisher analyzing more than 150 genes to identify mutations and copy number changes in breast cancer samples and try to assess whether these markers can be targeted by marketed drugs, or addressed in ongoing clinical trials.

Bartlett estimated there are currently several hundred cancer drugs under development that are targeted specifically at genomic changes. "We are in a target-rich, drug-rich environment," he said. "So, our challenge isn't to develop new drugs necessarily … but use the right drug against the right molecular make up of cancer."

The 400 patient samples are from a Phase III clinical trial in which women with breast cancer received adjuvant treatment. OICR researchers have already used data from The Cancer Genome Atlas, for example, to investigate the molecular features of tumors in that study. "We've identified a number of different pathways that we think we will validate that are linked to treatment failure," Bartlett said. He is hopeful that the findings from this study will inform next-generation breast cancer therapies.

For example, a patient with ER-positive breast cancer getting endocrine therapy will experience different molecular changes than a ER-negative patient treated with chemotherapy. "We need to understand in the context of that treatment what are the molecular events that drive treatment failure," he said. "Those are probably the molecular events we want to treat for those patients so they don't relapse."

Simultaneously, Bartlett and Feilotter are also working with six Ontario labs — Hamilton Health Sciences, London Health Sciences Center, Ottawa General Hospital, Sunnybrook Health Sciences Center, Sudbury Health Science North, and University Health Network — to gauge the ability of Thermo Fisher's 143-gene Oncomine Comprehensive Assay to reproducibly assess breast cancer samples at different sites. The data from this study will allow researchers to standardize the use of a single platform to recruit patients for the future basket trial.

Basket trials are being increasingly used by researchers and drug companies to quickly explore precision medicine hypotheses based on the molecular features of a tumor, and in some cases such studies are providing an alternative to the traditional three-phase clinical trial paradigm. The NCI-MATCH is one such example being conducted in the US using the Oncomine Comprehensive Assay, and researchers have validated and standardized gene sequencing across four sites with greater than 96 percent concordance for analyzing mutations in 143 genes on the panel. 

Although OICR researchers are also evaluating other NGS platforms and comparing them to Oncomine, they went with Thermo Fisher's assay for this particular project because of its use in NCI-MATCH and because the test can be performed at the pathology lab, near where patients are treated and diagnosed.

"It's something we can demonstrate will be reproducible across pathology labs here in Ontario, and that will give us confidence it can be delivered across wider communities," Bartlett said. "So, we looked for tools that can be used by the pathologist for their local diagnostics."

In parallel projects OICR and collaborators are also assessing the ability of the NGS platform to yield reproducible results when analyzing DNA from smaller and smaller samples. It is particularly challenging in metastatic breast cancer, for example, to garner adequate tissue samples for genomic analysis. "We're reluctant to go in with aggressive intervention just to get a sample for research or diagnosis if it's not going to change treatment," Bartlett explained.

OICR and its partners are testing out precision oncology approaches in breast cancer as it is still the most common cancer among Canadian women and the second leading cause of cancer deaths. Last year there was an estimated 25,000 Canadian women who were diagnosed and 5,000 women who died from the disease. In Ontario last year, 9,800 women received a breast cancer diagnosis and 1,900 died from it.

Although the identification of molecular markers and treatment advances have improved five- and 10-year outcomes in some women with breast cancer, for example, those with estrogen positive tumors, Bartlett highlighted data that has demonstrated that these women continue to be at risk of recurrence for much longer. "So, they get through their first five years of treatment, and they remain at risk of recurrence for up to 20 years after diagnosis," he said. "That means more women are coming back with aggressive disease and dying of their disease."

"We're learning that [breast cancer] is not as easy to treat as we thought it was," Bartlett added. "We still need to innovate treatments in this area and use that as a paradigm for innovating in other cancers as well."

OICR is hoping to have the results from the 400-sample retrospective analysis and the reproducibility study across labs in the next three to six months. Bartlett is hopeful that the results from these evaluations will be robust enough to support broad implementation of an NGS platform that can screen patients more quickly and cost effectively compared to single-gene assays. "If that were the case, it could change practice and support innovations in the short term," he said.