In cancer research, one never-ending quest is the hunt for biomarkers, proteins in the blood that reveal tumors deep in the body. The goal is to find a reliable predictor that enables early diagnosis and better treatment of disease. Most biomarkers identified so far have been disappointing, but millions of men are tested for one of them: PSA, or prostate-specific antigen, which cells in the prostate gland churn out at higher levels when cancer is present.
But some men with high PSA levels don't have the disease, leading to unnecessary biopsies, and some with low PSA levels do. PSA testing is routine in some places, yet large clinical trials in the United States and Europe are questioning how big an impact it has on reducing cancer deaths. This week, a group in Iceland suggests a new way to assess PSA results: Acknowledge that under normal circumstances some men produce more (and some produce less) PSA, and individualize healthy and high levels for each man tested by focusing on genetic variants that affect PSA levels.
“Let's say that a PSA level of 4 is considered worrisome,” says William Catalona of Northwestern University Feinberg School of Medicine in Chicago, Illinois. He developed the original PSA test and is a co-author of the new work, published in Science Translational Medicine. “You might be able to take something like a tongue depressor and scrape a man's cheek,” and with DNA testing “you might find out this man is a high PSA secretor” normally, reducing concern.
Adjustable baseline.
A man's genes affect normal PSA levels. The border marking the danger zone for cancer risk (dotted line) may shift, depending on an individual's DNA.
The researchers on the PSA study, led by geneticists Julius Gudmundsson and Kari Stefansson of deCODE Genetics in Reykjavik, began by scanning the genomes of about 16,000 men to identify places in the genome that modify the PSA level in blood. They found six, including three that were previously identified. Then the group compared more than 5000 men with prostate cancer and 41,000 without. They assessed whether variants at the six sites modified PSA and prostate cancer risk. Although it's difficult to disentangle genetic effects on PSA levels from those on prostate cancer risk, the researchers concluded that two of the variants influenced only PSA levels and two others had only a marginal effect on cancer, making all four useful for testing.
PSA levels for the men in the study varied widely. The key was whether genetic analysis would shift the men into different categories—for example, whether a man whose PSA level might merit a prostate biopsy would escape biopsy once his genes were taken into account. The numbers here were modest: About 6% had their PSA measurement reclassified as either safe or unsafe based on their genetics. “Basically what we're talking about is changing the parameters of detection of disease,” says Richard Hayes, an epidemiologist at New York University who has studied some of these gene variants. In theory, the approach could be applied to biomarkers for other cancers, too, making them more precise and more clinically useful.
The study looked back in time, so the genes didn't influence health care decisions. And Hayes and others agree that although the concept of using genetics to make PSA tests more meaningful holds promise, these specific variants aren't ready for prime time. The finding “is a good start, but it's not sufficient to introduce this extensive genetic screening to everybody,” says Fritz Schröder, a urologist at Erasmus Medical Center in Rotterdam, the Netherlands.
A valid gene-based PSA analysis could help, Stefansson claims, by, for example, enabling some men with high PSA results to avoid a biopsy. But genetic analysis cannot yet be used to tackle a different puzzle: Many men with high PSA results do have cancer but an “indolent” form that grows so slowly that it's unlikely to kill them if left untreated.
There is currently no way to distinguish the men at high risk of dying from their prostate cancer from those with a minimal risk of dying. The deCODE study didn't examine whether adding genetics to the mix could help reduce mortality. The deCODE group and others now need to examine “how many people they can help,” says Stacy Loeb, chief resident in urology at Johns Hopkins University in Baltimore, Maryland, who has studied PSA genetics.
Two large U.S. and European clinical trials underscore this need. Both trials randomly assigned tens of thousands of men to get regular PSA testing, or not, and then followed them to see who developed prostate cancer and who died of it. Last year in The New England Journal of Medicine, the U.S. study reported no difference in mortality between the group that had regular PSA screening and the one that did not. The European team, led by Schröder, found that those who got PSA screening were 20% more likely to survive prostate cancer. Schröder attributes the contrasting results to different study designs; both groups are continuing to follow the men.
Meanwhile, PSA testing is in flux. Earlier this month, a cancer screening committee in the United Kingdom advised against routine PSA testing, citing concerns about overdiagnosis of slow-moving cancers. In other European countries, the popularity of PSA testing varies, says Schröder. It remains routine in the United States.
“I'm reluctant to make any predictions” about how PSA genetics might help guide early detection of prostate cancer, says Stephen Chanock, chief of the laboratory of translational genomics at the National Cancer Institute in Bethesda, Maryland, who works in this area. While he commends the deCODE group for pushing the ball forward, he says, “one really would want to see further confirmation and precision” in the number of men affected by these gene variants and the effect each variant has on PSA.
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