February 28, 2017 | by Jyoti Madhusoodanan
Next-generation sequencing (NGS) tests can quickly pinpoint tumor mutations that can be targeted with specific drugs, offering a route to precision therapies for many cancer types.
Coupled with new drugs that target tumor-specific genomic changes, NGS tests carry the potential to transform modern cancer care. But the practical clinical value of this approach had yet to be proven.
Now, a new report by City of Hope researchers suggests that NGS tests can indeed identify targeted therapy options, and should be performed early in treatment. When used in clinics where patients can be matched to clinical trials, the genomic tests could benefit patients with metastatic breast cancer.
Two cancer centers have previously conducted large-scale prospective clinical trials on NGS. In one, 2,000 patients with advanced cancers were screened, and 83 enrolled into clinical trials based on tumor genomic information. Another multicenter study conducted in France enrolled more than 400 breast cancer patients, but only 55 were matched to clinical trials.
“Given these low numbers, it has been unclear what the utility of these assays is in the clinical setting,” said breast cancer researcher Yuan Yuan M.D., Ph.D., assistant professor at City of Hope who led the new study. “Bear in mind that the NGS assay is not cheap, either. In this scenario, are we doing the right thing for patients by conducting these tests?”
To answer that question, Yuan and her colleagues conducted a retrospective analyses of 44 patients with metastatic breast cancer who were treated at City of Hope between January 2014 and May 2016 and underwent NGS.
More than half the patients had already received more than three lines of chemotherapy prior to the genomic test. Ninety-five percent of the study participants had cancers bearing actionable mutations – in other words, therapies targeting these mutations are already in the market or in clinical trials. Twenty-three patients began therapies based on the NGS test results; eight experienced clinical benefits. Many others declined treatment or had transitioned to hospice care.
“We were happily surprised to find that we had a pretty good clinical benefit rate in this small patient group,” Yuan said. “The usual response rate by the third or fourth line of therapy is only about 10 percent, so this 34 percent clinical benefit rate is pretty phenomenal.”
Precisely why their results were so strikingly different from the earlier studies needs further investigation, she added.
Using NGS also helped identify treatments that may not usually be considered for patients with breast cancer. For example, 24 patients in the cohort had metastatic triple-negative breast cancer (TNBC), a type that’s particularly difficult to target with current therapies. Thirteen of these patients ended up receiving mutation-targeted treatments that are approved for other cancers but not TNBC, such as everolimus and pazopanib, and five benefited from these nontraditional lines of treatment.
To Yuan, the data suggest that using NGS tests early in care could help identify novel treatment routes for some patients, particularly when combined with "basket" trials that assign patients to specific arms of a clinical trial based on their genomic data.
“Next generation sequencing is not yet part of standard care,” she said. “Our data are an early signal that this can be an appropriate way to identify potential targeted therapy for a given patient, especially in the context of available mutation-driven basket trials such as NCI-MATCH.”
Much remains to be done to refine the clinical use of NGS, according to Yuan. NGS typically tests homogenized tumor tissue, which can carry myriad genomic aberrations, making it difficult for clinicians to choose the best one to target with treatments. In several cases, even when mutations are identified, drugs targeting them may not be approved or easily available.
For now, sequencing tests are likely to play an important part in helping to match patients to ongoing trials for new drugs that target their mutations. Their long-term impact remains to be determined. “Whether this approach truly benefits patients by extending their survival is a tough question to answer,” Yuan said. “Hopefully in a few years we’ll have that answer.”