Blood tests for cancer, known as liquid biopsies, have become available in recent years to guide treatments for people already diagnosed. But how useful are they?
A paper published last week in the journal JAMA Oncology makes the case that one such test, Oncotype DX AR-V7 Nucleus Detect, might be worth its $3,980 price tag. (Earlier this year, the federal insurance program Medicare sent positive signals about coverage but hasn’t made a final decision.)
The test, sold by Genomic Health (NASDAQ: GHDX) of Redwood City, CA, and developed by Epic Sciences of San Diego, is for men with a dangerous, advanced form of prostate cancer. It detects a variant of a protein, the androgen receptor, produced by prostate cells. The presence of this variant, known as AR-V7, is a warning that patients with castration-resistant metastatic prostate cancer have likely developed resistance to a type of popular drug called an ARS inhibitor, such as Johnson & Johnson’s abiraterone (Zytiga) or Pfizer’s enzalutamide (Xtandi). Both have a list price of more than $10,000 a month.
The test comes into play when that resistance shows up—which happens in 10 to 20 percent of patients—and the cancer gets worse, typically spreading to the bones. Doctors have two main treatment choices: Try another ARS inhibitor, or switch to a type of chemotherapy called a taxane, such as docetaxel or paclitaxel, which have generic options.
Epic Sciences chief of medical innovation Ryan Dittamore says there are about 50,000 men a year in the U.S. who reach that fork in the medical road, an estimate based on data from consultancy Decision Resources.
The new study examines what happened to a small sample of men (142 patients) after that fork in the road. The AR-V7-positive patients had longer overall survival when treated with taxanes (14.3 months) than with a second ARS inhibitor (7.3 months). And AR-V7-negative patients fared better when treated with a second ARS inhibitor (19.8 months overall survival) than those on taxanes (12.8 months).
Those numbers seem to bolster the test’s utility. If AR-V7 shows up in the nucleus of the tumor cells circulating in the patient’s blood, another expensive ARS inhibitor isn’t likely to help. A better choice would be a taxane. Conversely, a negative test should point the patient toward another ARS inhibitor.
The key word here is “should.” While the new survival data are notable, there’s no guarantee doctors will be convinced. “Changing clinical practice is a process,” says Howard Soule, executive VP and chief science officer of the Prostate Cancer Foundation in Santa Monica, CA. “This is one very positive step in the process, but it’s not a done deal.” (The foundation has funded the researcher who conducted the study, Howard Scher of Memorial Sloan Kettering Cancer Center in New York, but Soule says it has no financial ties to the test or test makers.)
Two years ago, a team led by Scher showed that AR-V7 was indeed a worthy predictor of resistance to ARS inhibitors, but at that point they still needed evidence that prescribing a drug based upon the test results could in fact improve men’s lives.
As the study authors note, there are two main caveats. First, the survival data were not statistically significant, perhaps because of the small sample size; in other words, there’s higher probability they were due to chance, with p values of .25 for the AR-V7-positive patients and .05 for the AR-V7 negative patients.
Second, the study was done retrospectively; that is, it looked back at how patients fared in real-world settings. They were not recruited and randomly assigned to one treatment or the other based on their AR-V7 status. Retrospective studies can be a problem, with investigators’ biases sometimes tainting the study design.
But Scher and Dittamore say they compensated for both limitations, first by keeping hidden as much patient information as possible to avoid bias, and second by assigning patients a risk score based on their medical records. When excluding patients at lower risk of death, the survival data remain strong and become statistically significant. (For AR-V7-negative patients, 16.9 months on ARS inhibitors vs. 9.7 months on taxanes, with a p value of .02; for AR-V7-positive patients, 14.3 months on taxanes vs. 5.6 months on ARS inhibitors, a p value of .03.)
While the Epic test is not FDA approved, Dittamore says the “collective experience” from several recent studies should help doctors make treatment decisions. There was Scher’s previous work, as well as a prospective, 120-patient study called PROPHECY, presented earlier this month, showing AR-V7-positive patients do not survive as long and do not benefit from taking a second ARS inhibitor. The study used Epic’s test as well as one that uses a different detection method, developed at Johns Hopkins, licensed to Dutch diagnostics firm Qiagen (NYSE: QGEN) and available only for research, not clinical use. “Both assays actually performed quite well in predicting response to standard-of-care therapy,” said the study’s lead investigator Andrew Armstrong of Duke University. “Most importantly [they] predicted overall survival.”
Armstrong noted that in PROPHECY, a negative AR-V7 result didn’t guarantee a good response from a second ARS inhibitor. “More work needs to go into precision medicine approaches to understand how tumors evolve over time,” he said in a video interview.
However quickly the Epic test is adopted, Soule is impressed by the technology behind it. “AR-V7 in the nucleus of the tumor cell is a bad sign,” he says. “The test is telling us a lot.”
Nucleus Detect it is not a genetic test. It takes snapshots of every tumor cell collected from a blood sample and uses software to determine if AR-V7 is present in the nucleus of the cell.
Soule also notes that other types of treatments for these particular patients are in development, so the decision—to go either with chemotherapy or with another ARS inhibitor—might become more complicated in coming years.
Scher says “it’s a very common decision” that he and his colleagues must make, faced with patients who fail a first ARS inhibitor. “It’s important to understand how to use these drugs.” While the test doesn’t account for every possible option, now or in the future, says Scher, “the fact that a liquid biopsy test goes this far is pretty impressive. This is an important milestone.”
Photo by Neeta Lind via a Creative Commons 2.0 license.