The Lynx Group

Next-Generation Sequencing Provides Value to Multiple Stakeholders

September 2014, Vol 5, No 7

Los Angeles, CA—An understanding of the genomic drivers of cancer and linking therapy to these genetic alterations provides value to all stakeholders, including oncologists, payers, researchers, and patients, said Gary Palmer, MD, JD, MBA, MPH, Senior Vice President of Medical Affairs at Foundation Medicine. Next-generation sequencing is the best way to study the cancer genome to identify a patient’s mutations, Dr Palmer said at the Fourth Annual Conference of the Association for Value-Based Cancer Care.

Our understanding of cancer is growing. In 2003, no alterations were known in lung adenocarcinoma. By 2012, in addition to KRAS and EGFR, the known genetic mutations were ALK fusions, ERRB2, BRAF, PIK3CA, AKT1, MAP2K1, NRAS, ROS1 fusions, and RET fusions.

Next-generation sequencing is becoming a critical component of the diagnosis in many situations. Matching the correct targeted therapy to the correct patient will improve the tumor response and overall outcomes, but it is diagnostically challenging with the growing number of clinically relevant genomic alterations identified.

Next-generation sequencing allows for the simultaneous and rapid sequencing of hundreds of millions of DNA molecules. Of the approximately 20,000 genes in the human genome, only a few hundreds are unambiguously associated with cancer. By contrast, whole-genome targeted sequencing only sequences a limited subset of genes.

“You’re going to miss a lot of rarer alterations, or even some novel alterations that I think will turn out to be very treatable, if you don’t use a next-generation sequencing type approach,” said Dr Palmer. Next-generation sequencing “lets the tumor in a sense tell you what the drivers are, without looking for any specific ‘hot spots’.”

The 5 types of genetic alterations are base substitutions, short insertions and deletions, focal amplification, homozygous deletion, and gene fusion.

“All of them can be detected by next-generation sequencing done by world-class computational biologists,” Dr Palmer said. Value to Oncologists

Foundation Medicine provides a patient report for the oncologist that details genetic alterations in that individual patient that are identified by next-generation sequencing and the appropriate targeted therapies for those alterations.

Of the first 2000 cases in which next-generation sequencing has been used, 82% have had “actionable” findings. Overall, a mean of 3 to 4 reportable genetic alterations and a mean of 1.6 actionable alterations have been found per patient.

The typical patient for whom next-generation sequencing is done has exhausted recommended therapies. That patient is “still viable. The doctor still wants to treat the patient; the patient still wants to be treated,” Dr Palmer said.

Rather than pick a therapy regimen off the shelf, “it makes sense, at some level, to look for a target and use a targeted therapy,” he said. “Our data suggest now that 6% of our lung cancer cases will have HER2 alterations that are potentially treatable,” he said. “That’s more than the ENO4 ALK. You could make a case that if you’re checking for ENO4 ALK…that you should be checking for HER2 alterations.”

Value to Payers
Foundation One has come up with a list of proposed indications for the use of next-generation sequencing (Table), which includes patients newly diagnosed with carcinoma of unknown origin. In such patients, the clinical utility lies in the approximately 75% who are found to have actionable alterations leading to precise treatment decision-making. It may, therefore, not be as important to pinpoint the organ of origin to identify a treatment approach, adding even more clinical utility, said Dr Palmer.

Next-generation sequencing for the indications listed in the Table can displace other genetic tests that currently cost thousands of dollars, he said.

In approximately 10% of patients, either no driver mutation is found or a genomic alteration for which there is no FDA-approved therapy or clinical trial options is found. A finding of no actionable alterations is strong evidence against the use of a targeted agent, adding further value to the testing.

Value to Researchers
Next-generation sequencing also has value to researchers and to drug developers, said Dr Palmer. First is a shift in the design of clinical trials to multiarm biomarker-driven protocols. These protocols can improve efficiency with homogeneous patient populations and consistent eligibility. Grouping multiple studies reduces screening failures, allowing for a high “hit rate.” “It cuts the cost of the trial,” Dr Palmer said. “It cuts the time it takes to get people into the trial, and I think it will lead to an approval process in which drugs will be approved based on their genomic implications, the patients’ indications, rather than the histology of the particular tumor.”

Approximately 66% of BRAF-mutated tumors have ?1 additional actionable alteration that may benefit from combination therapy that may be tested in clinical trials. Although these data will not currently help oncologists select treatment when there are multiple driver mutations, these multiple targets would not have been discovered without the use of next-generation sequencing.

Related Articles

Subscribe to
Value-Based Cancer Care

Stay up to date with personalized medicine by subscribing to recieve the free VBCC print publication or weekly e‑Newsletter.

I'd like to recieve: