Could a blood test reveal a man's risk of developing prostate cancer more than 15 years before diagnosis? Researchers at the University of Oxford have identified proteins in the blood that may offer early clues, including biological signals associated with aggressive forms of the disease.
The findings raise the possibility of identifying men who need closer monitoring long before cancer is diagnosed, while sparing others unnecessary tests and procedures. But researchers stress that the discovery is still at an early stage and has not produced a clinically validated prediction test.
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Prostate cancer risk may leave traces in blood more than 15 years before diagnosis
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One of the biggest challenges in prostate cancer screening is that not all tumors behave the same way. Some grow so slowly that they may never cause harm, while others develop aggressively and can become life-threatening.
The widely used prostate-specific antigen, or PSA, blood test can help doctors identify men who may need further investigation. However, elevated PSA levels do not necessarily mean a man has dangerous cancer, and testing can lead to biopsies and treatment for tumors that might otherwise never have caused problems.
The possibility of assessing individual risk years in advance could eventually help doctors decide who should be screened more frequently and who may safely undergo fewer tests.
"PSA is not a test designed to assess long-term cancer risk, but rather to raise suspicion of cancer that may already be present," explains Dr. Miki Haifler, head of the Urologic Oncology Unit in the Urology Department at Meir Medical Center, part of Clalit Health Services.
According to Haifler, the findings could eventually allow doctors to tailor screening schedules more closely to each patient's risk.
"For people identified as being at high risk, it might be possible to conduct screening more frequently to try to detect cancer at its earliest stages," he says. "For people at low long-term risk, it might be possible to space out the tests, which would also reduce the burden on the healthcare system."
More than 6,000 proteins examined
The study, published in the medical journal European Urology and presented at the annual meeting of the American Society of Human Genetics, analyzed blood samples collected as part of the European Prospective Investigation into Cancer and Nutrition, known as EPIC.
Researchers measured more than 6,000 proteins in blood collected years before participants were diagnosed with prostate cancer.
The analysis included 982 men who subsequently developed the disease and a randomly selected sample of 1,573 men from the same research population. The groups overlapped: 79 men in the random sample later developed prostate cancer and were also included among the cases.
The median potential follow-up period was approximately 16.5 years.
Of the men diagnosed with prostate cancer, 290 had disease classified as aggressive. The definition included high-grade tumors, advanced-stage cancer, PSA levels above 20 at diagnosis or death from prostate cancer.
When researchers examined how the associations changed according to the time between blood collection and diagnosis, they identified 12 proteins linked to prostate cancer diagnosed more than 15 years after the samples were taken.
They also found seven proteins associated with aggressive prostate cancer.
Dr. Zhe Huang, the study's first author and a postdoctoral epidemiologist at Oxford Population Health, emphasized that prostate cancer encompasses several biologically different forms, ranging from slow-growing tumors to aggressive disease.
By studying thousands of proteins in blood collected long before diagnosis, Huang and his colleagues hope to understand how men who eventually develop aggressive cancer differ biologically from those who do not.
Those differences could eventually help scientists identify better markers of risk and understand what drives the most dangerous forms of the disease.
Clues from the immune system
One of the study's most intriguing findings involved a protein called GZMK, produced by immune cells involved in recognizing and destroying abnormal cells.
Higher levels of GZMK were associated with a lower risk of prostate cancer diagnosed more than 15 years after blood collection.
The researchers suggest this association could reflect more effective immune activity or an early immune response to biological changes associated with cancer. However, the study does not establish the mechanism behind the relationship.
The blood proteins that could reveal prostate cancer risk more than 15 years early
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Other proteins involved in inflammatory processes were associated with increased risk.
When researchers focused specifically on aggressive prostate cancer, another protein stood out: ANKRD1.
Its blood levels were consistently associated with several serious forms of the disease, including high-grade tumors, advanced cancer and cases that ultimately resulted in death from prostate cancer.
The study also identified associations involving proteins linked to cell adhesion and the formation of new blood vessels, biological processes that can influence how tumors develop and progress.
Alongside the protein measurements, the scientists conducted genetic analyses to help evaluate their findings.
They examined proteins produced by genes already known to play important roles in prostate cancer, including ERBB3, KRAS and NRAS.
These proteins were associated with aggressive prostate cancer diagnosed approximately a decade after the original blood samples were collected.
Professor Karl Smith-Byrne, one of the study's senior authors, said identifying proteins associated with established cancer-driving genes so many years before diagnosis offers new insight into the earliest biological processes linked to the disease.
Combining protein measurements with genetic evidence could eventually help researchers identify biological pathways that might be targeted to prevent aggressive prostate cancer.
What should men do in the meantime?
For now, Haifler emphasizes that the new findings do not replace existing prostate cancer screening and monitoring.
He recommends that men generally begin urological follow-up around age 50. Between ages 50 and 75, he says, PSA testing is the principal initial screening tool, with the frequency of testing determined by individual results and risk factors.
"For people with a family history of prostate cancer, we begin earlier, at age 45," he says.
If a PSA result is elevated, doctors can recommend additional investigations to determine whether cancer may be present.
These recommendations reflect Haifler's clinical guidance; screening decisions should be individualized according to medical history, risk factors and the potential benefits and harms of testing.
What would it take to turn the Oxford findings into a blood test that patients could actually undergo at a clinic?
"We need to confirm the results in additional studies and also examine the cost of the test," Haifler says. "If the findings are validated, this could certainly become a test that greatly helps patients and doctors."
He believes identifying men at particularly low risk could be just as valuable as identifying those at high risk. Less frequent screening for lower-risk patients might reduce unnecessary testing, medical procedures and healthcare costs.
Why the discovery is not yet a screening test
Despite the promising results, an important distinction remains: the researchers identified associations between certain blood proteins and future prostate cancer diagnoses. They did not demonstrate that a blood test can reliably predict which individual men will develop dangerous tumors.
Nor did the study establish that the protein signals could accurately distinguish slow-growing cancers from aggressive ones in individual patients.
The interval between blood collection and diagnosis also does not necessarily represent the time before symptoms appeared. The findings do not establish whether a cancerous process had already begun when the original blood samples were taken.
Several findings received support from additional population studies or genetic analyses, but validation was incomplete. Most individual protein associations were relatively modest.
Information about tumor characteristics was missing for a substantial proportion of cases, and some subgroup analyses involved relatively small numbers of patients.
Further research in larger and more diverse populations is needed to determine whether combining these proteins can improve risk prediction beyond existing clinical and genetic factors.
For patients, the distinction matters. The study offers an important glimpse into biological changes associated with prostate cancer risk many years before diagnosis, but it does not yet offer a test that can tell an individual man whether he will develop the disease.
If future studies validate the findings, blood proteins could one day help physicians identify who needs closer surveillance and who can safely be screened less often. For now, the promise lies in understanding risk earlier, not in claiming to predict cancer 15 years in advance.