Few Cancer Patients With Tumor Profiles Enter Genotype-Matched Trials, But Response Rate is Higher

NEW YORK (GenomeWeb) – Only a small fraction of advanced cancer patients who obtained molecular profiles of their tumors enrolled in genotype-matched clinical trials as a result, but those who did had a higher response rate than those who went on to genotype-unmatched trials, according to a recent study by a team based in Toronto.

The researchers, led by Philippe Bedard, a staff medical oncologist at the Princess Margaret Cancer Centre, have now teamed up with several other academic centers for the Ontario-wide Cancer Targeted Nucleic Evaluation (OCTANE) study, which will offer targeted panel sequencing to advanced cancer patients and is currently recruiting participants.

Results from the original study, which enrolled a total of 1,893 patients with advanced solid tumors as part of the Integrated Molecular Profiling in Advanced Cancers Trial (IMPACT) and the Community Molecular Profiling in Advanced Cancer Trial (COMPACT) between 2012 and 2014, were published in Genome Medicine last month. Both trials were part of the same study, one enrolling patients at Princess Margaret, the other taking patients treated at other hospitals in the region.

"Like many other cancer centers, we wanted to try and apply advances in terms of sequencing technology to a cohort of patients who were receiving standard treatment," Bedard, who is also an associate professor of medicine at the University of Toronto, told GenomeWeb, "with the idea being that it is increasingly relevant to identify patients who have specific genotype alterations in their cancer for early-phase clinical trials."

Patients with a variety of tumor types, including ovarian, breast, lung, colorectal, and pancreatic cancer, were consented when they saw their oncologist. One of the prerequisites for enrollment was the availability of archival formalin-fixed paraffin-embedded tumor tissue for molecular profiling. In their paper, the researchers noted that enrollment for the study was fast, which "reflects the high level of motivation of patients and their oncologists to pursue genomic testing," an observation other groups have made before.

The results of the test were included in their electronic health record and returned to their treating oncologist. Pathogenic germline results were disclosed to patients by a genetic counselor or medical geneticist after an expert review.

Bedard said his center initially used Sequenom's MassArray assay, which looks at 279 mutations in 23 genes and was available at their clinical lab at the time, to profile patient samples. About halfway through the study, they switched to next-generation sequencing, using the Illumina TruSeq Amplicon Cancer Panel, which covers certain regions of 48 genes, and MiSeq sequencing for most patients. For about one percent of patients who did not have sufficient tumor tissue available, they used the Ion AmpliSeq Cancer Panel, which covers areas of 50 genes, and Ion Proton sequencing because that assay works with smaller amounts of DNA.

Bedard said results from the sequencing assays will be included in the first data release of the American Association for Cancer Research's Genomics, Evidence, Neoplasia Information Exchange (GENIE), an international initiative to share NGS results and outcome data from cancer patients that was launched a year ago.

Overall, almost 90 percent of patients who enrolled in the study, or 1,640, obtained molecular profiling results. After 18 months of follow-up, just 15 percent of those, or 245, had enrolled in therapeutic clinical trials.

These included 84 patients, or a mere 5 percent, who went on to genotype-matched trials. This small number, Bedard said, is in line with other studies that genotyped patients with similar targeted assay.

A study by researchers at the MD Anderson Cancer Center that involved 2,000 patients and was published in the Journal of Clinical Oncology last year, for example, found that of 789 patients with potentially actionable mutations, only 11 percent, or 4 percent of all patients tested, went on to genotype-matched trials. That study used a 46-gene or a 50-gene Ion AmpliSeq Cancer panel for most patients.

There were several reasons for the lack of enrollment, according to the Toronto researchers, which included patients getting worse, non-availability of clinical trials, and unwillingness of patients to travel for a trial.

Whether or not a larger panel would have resulted in a greater percentage of patients enrolling in genotype-matched trials remains an open question. "The reality is, even though these are relatively small assays, they do cover the most frequent mutation hotspots, particularly ones for which we have drugs available in clinical trials," Bedard said.

But even though their number was small, patients who went on genotype-matched studies had a higher likelihood of responding to the treatment — their response rate was 19 percent — than patients treated in genotype-unmatched trials, who had a response rate of just 9 percent.

However, the jury is still out whether molecular profiling of tumors has wide clinical utility. "I don't think we can say, based on our study, that it necessarily has utility in the sense that all patients should have some form of targeted sequencing done," Bedard said. "I think it does indicate that the approach can be used in a subset of patients [where] it identifies those who can go onto matched targeted therapies that may have some benefit. But we need more studies to know whether or not it's really clinically useful."

The strength of the study, he said, was that it was relatively large and had good follow-up data, which is often a challenge. He noted that it focused on patients participating in investigational trials and did not include patients receiving off-label treatment, which he said is not very frequent in Canada.

In the meantime, Bedard and his colleagues have initiated a new province-wide study, called Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE). That trial, which officially launched in August and will run for five years, will recruit up to 10,000 patients at five academic cancer centers in Ontario. Besides Princess Margaret Hospital, the only center currently enrolling patients, participating centers are the Juravinski Cancer Centre, the Kingston General Hospital, the London Health Sciences Centre, and the Ottawa Hospital Cancer Centre.

Bedard said the new study will be very similar to the published one but larger, and Princess Margaret will be using a more extensive sequencing panel to profile patient tumors.

Also, because there is a single provincial payer under Canada's healthcare system, the study will be able to link to patient health and outcomes data across the province, he said.

The researchers plan to develop a province-wide registry of targeted sequencing test results for the study that will be made available to other cancer researchers. In addition, they will collect tumor tissue and blood samples from study participants for future research at the Princess Margaret-Ontario Institute for Cancer Research Translational Genomics Laboratory, including circulating tumor DNA testing. Samples will be stored at a biobank, maintained by the Ontario Tumour Bank.

 

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