Study Sparks Debate on Accuracy of Genome Tests for Cancer Patients

Finding suggests tests could lead doctors to prescribe ineffective drugs in up to half of cases

A new study has triggered a dispute over the accuracy of genomic tests that are increasingly used to match cancer patients with drugs that attack their tumors. WSJ’s Ron Winslow reports.

A new study has triggered a dispute about the accuracy of genomic tests that are increasingly used to match cancer patients with drugs that attack their tumors.

The study, published Wednesday by researchers at Johns Hopkins’ Sidney Kimmel Comprehensive Cancer Center, suggests that such tests could lead doctors to prescribe an ineffective drug in up to half of cases. The reason: The tests, which analyze tumor DNA, typically don’t also analyze normal DNA from the same patient, a step the researchers said could eliminate false positive results.

But Foundation Medicine Inc., the most prominent provider of such tests, disputes the finding, saying it has confidence in the accuracy of the analyses it provides doctors and patients without sequencing normal DNA.

Moreover, a researcher at MD Anderson Cancer Center, while acknowledging some risk that tumor-only DNA could lead to wrong treatments, said normal DNA tests aren’t necessary to accurately identify most of the mutations considered to drive tumor growth.

The much bigger problem, said Kenna Shaw, executive director of MD Anderson’s Khalifa Institute for Personalized Cancer Therapy, who wasn’t involved in the study, is that only a fraction of patients matched to potentially effective medicines actually are being treated with them.

The divergent views reflect growing pains in the burgeoning effort to use genetic information to improve cancer treatment, a strategy known as precision medicine.

A growing number of cancer centers routinely sequence the DNA of many patients’ tumors to hunt for genetic mutations that fuel a cancer’s growth. Doctors use the test results to guide treatment, either by prescribing an approved drug that targets the mutations or by referring patients to a clinical trial testing an experimental treatment.

This strategy is beginning to transform cancer treatment, with more drugs becoming available for a variety of cancers and with scores of trials underway to test such agents.

“There is a lot of excitement about precision medicine,” said Victor Velculescu, co-director of the Cancer Biology Program at Johns Hopkins University School of Medicine and senior author of the study, which appears online in the journal Science Translational Medicine. But “we cannot have precision medicine without precision genomics.”

Genetic alterations are present in both tumors and in a person’s normal, or germline, DNA. But alterations found in both cancer and the normal tissue would be present essentially in all cells and in most cases not a cause of the cancer, researchers said.

Dr. Velculescu and his colleagues analyzed both tumor and normal DNA from 815 cancer patients and found 33% of so-called “actionable” mutations—those considered culprits when found in tumors—also were in a patient’s germline DNA. When multiple mutations were considered, such false positives affected 48% of the patients studied, the researchers said.

“We were surprised by the magnitude of the errors that can come out of this type of analysis” without also testing normal tissue, he said. “It would be a shame to use these targeted therapies and not use the right ones.”

Dr. Velculescu and his colleagues are co-founders of a company called Personal Genome Diagnostics Inc., which generated the data in the study and which markets a genomic test designed to evaluate both tumor and normal-tissue DNA. The study wasn’t critical of any specific company’s diagnostic test.

The study drew a rebuff from Foundation Medicine. “At best, it’s naive,” said Phil Stephens, chief scientific officer of the Cambridge, Mass.-based company. “At worst, it’s completely misleading.”

He agreed that mutations present in both the tumor and germline DNA generally aren’t driving the cancer. But he said “no responsible diagnostic company would ever report out” most of the mutations the Hopkins study considers as false positives.

Dr. Stephens said Foundation Medicine uses the entire medical literature on cancer-related genetic mutations to evaluate tumor DNA results. “We fundamentally believe we can find 100% of the druggable alterations that should be reported to physicians,” he said.

At MD Anderson, Dr. Shaw said, “it’s an overreach to suggest that we’re misdirecting so many patients” by not analyzing normal DNA. The role of the vast majority of detected alterations isn’t known—even in genes broadly regarded as potential culprits, she said. If the cancer role of specific mutation isn’t known, it generally isn’t reported to clinicians as a potential drug target.

MD Anderson is among the leaders in trying to match cancer patients with clinical trials testing potentially helpful drugs. Despite the excitement around precision medicine, though, Dr. Shaw said currently only 10% to 20% of patients with actionable mutations end up on a drug or in a trial. “The problem isn’t that we’re putting patients on the wrong drug,” she said.

Corrections & Amplifications:
Phil Stephens is chief scientific officer of Foundation Medicine. An earlier version of this article incorrectly stated his title was chief medical officer.

Write to Ron Winslow at

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