With more than 333,000 new cases every year, prostate cancer is the most frequently diagnosed cancer in the U.S., and by far the most common among men. It is also the least deadly: Only about 4% of prostate cancers end up being lethal, and the 5-year survival rate is about 99%.
This paradox is in no small part due to the way it is diagnosed. A routine blood test checking for levels of a biomarker called prostate-specific antigen (PSA) is followed, if this protein is elevated, by a systematic biopsy to find cancerous tissue. This two-step process is effective at detecting cancer, even in its earliest stages. It may be too effective, in fact: Up to 70% of new prostate cancer diagnoses are low grade and in no need of treatment, as the risk of the disease turning deadly is negligible.
Yet as many as 50% or more of men with such clinically insignificant disease get treated in the U.S., according to data from the American Urological Association Quality Registry; there are even providers who treat essentially all patients with low-grade cancer.
A good number of prostate cancer experts think these low-grade lesions “shouldn’t even be called a cancer,” said Scott Eggener, a professor of urology at the University of California, Los Angeles. The ubiquity of prostate cancer, he and these other experts argue, is an overdiagnosis problem.
It’s a particularly American issue. Elsewhere in the world, the approach to diagnosis is so different that very often low-grade tumors aren’t found to begin with — let alone diagnosed as cancer.
In the last 15 years, MRI scans of the prostate have emerged around the world as the preferred test to conduct after detecting elevated PSA levels, and before a potential biopsy. Between 30% and 50% of patients can avoid a biopsy by doing an MRI, significantly reducing the risk of finding clinically insignificant cancer (that doesn’t need treatment) and of complications caused by biopsies.
A pre-biopsy MRI is the standard of care in Europe, Canada, Australia, and the U.K., and has been included in prostate cancer detection guidelines in the U.S. since 2020. The National Comprehensive Cancer Network strongly recommends it, though the American Urological Association guidelines, as well as American Society of Clinical Oncology (ASCO), give pre-biopsy MRI a conditional recommendation, even as they acknowledge it’s backed by high-level evidence.
Nonetheless, the latest available data show MRIs were used ahead of biopsies in only about a third of cases in the U.S. in 2022. For all other cases, systematic biopsies followed elevated PSA levels, even as studies (in particular, the 2018 PRECISION trial) have shown more cancer is found, and fewer men diagnosed with clinically insignificant disease, if an MRI is done prior to the biopsy. The reasons are many, ranging from the slow adoption of new medical technologies, to many urologists’ unfamiliarity with interpreting MRI scans, to the loss of income from doing fewer biopsies.
“It’s one of the world’s worst global scandals that the richest country in the world denies [most] of its men access to something that is proven at level one evidence and that the rest of the world has adopted,” said Mark Emberton, a professor of Interventional Oncology at University College London who has devoted his career to treating prostate cancer in the least invasive way possible.
Prostate biopsies can catch too much, and too little
“A very rare disease.” This is how in 1853 John Adams — a fellow of the Royal College of Surgeons in England and the first to diagnose prostate malignancy by differentiating healthy and diseased tissue in enlarged prostates — described the “cancer of the prostate gland.”
Nearly two centuries later, his assessment could not be further from reality. The rise of biopsies may be the biggest reason.
The first biopsies of the prostate date back to the early 20th century, but it wasn’t until 1989 that diagnoses saw a dramatic increase. That’s when a new biopsy methodology was introduced, called sextant, or systematic. Rather than simply selecting a random spot on the prostate, or only biopsying a lesion, doctors would randomly sample tissue along a grid identifying six core areas of the prostate, with the goal of diagnosing the disease even if it was imperceptible at a physical exam or invisible in imaging. The number of samples eventually grew to up to 12, and systematic biopsies became the gold standard of care for men presenting with abnormal physical exams or elevated PSA levels, despite their limited sensitivity — 50%, or even less, according to some studies.
Prostate biopsies aren’t a breeze: The walnut-size gland, which produces seminal fluids and helps control ejaculation and urination, is located below the bladder and in front of the rectum — a spot complex to reach and scan. Complications are not infrequent. Transrectal procedures, which are more common, carry an infection risk of up to 7% (with up to 3% risk of sepsis); transperineal ones, which carry less of an infection risk, are more complex and require heavier anesthesia.
Systematic sampling carries a high risk of catching too much, and too little. Depending on where the needle is inserted, it can find the most advanced cancer cells in the prostate and grade the disease accurately, or it can miss these cells and catch less advanced cells in some other spot, and grade the cancer lower than the actual disease.
But there is another outcome: Biopsies can detect low-grade cancer cells, which are present in at least 30% of men above age 50, and in a majority of men over 80 as part of aging prostate tissue even when there is no evidence of advanced cancer elsewhere in the prostate.
These kinds of cells do meet some of the criteria for cancer, though they have a near-zero chance of ever metastasizing, so ASCO recommends no treatment in the vast majority of cases — though in the U.S. a large proportion still undergoes treatment. Until recently, most men with an elevated PSA would undergo a systematic biopsy, leading to finding clinically insignificant cancers in hundreds of thousands of people.
For the past 40 years, doctors have used MRIs, too, as a diagnostic tool for prostate cancer. Given the prostate’s size and positioning, MRIs only became reliable in providing images of lesions of the gland in the past 15 years; their sensitivity — the ability to find a lesion that’s there — is now up to 93%.
The scan can guide an eventual targeted biopsy — of just the lesion — or avoid the procedure altogether. If no lesion is detected in an MRI, and there are no other patient-specific factors to suggest the need for further testing, a biopsy isn’t recommended.
Treat what you can see, or find what you can’t?
Emberton, a world-renowned oncologist, feels strongly about the need to use MRIs to diagnose prostate cancer, and just as strongly about leaving systematic biopsies behind. “Why are we using a test that is worse than tossing a coin, when there’s a much better test?” he said. “The MRI is twice as good — and no needles.”
In the U.K., where he practices, virtually all patients get a pre-biopsy MRI. Afterward, as in Europe, the guidelines recommend a targeted biopsy checking the tissues corresponding to the lesions shown in the MRI, rather than the whole gland. “The two things that an MRI allows you to do is avoid a biopsy and to do a better biopsy, so it tells you the area of high probability so you can stick your needles into the tumor rather than not in the tumor,” Emberton said.
This approach dramatically reduces the incidence of finding clinically insignificant disease elsewhere in the prostate, even though occasionally doctors may still do a systematic biopsy to ensure no MRI-invisible lesions are present.
U.S. guidelines say something different. If a lesion is found on an MRI, the recommendation is to do a targeted biopsy to characterize the cancer tissue. But alongside it, a systematic biopsy is performed, too, to rule out the risk of further malignancy in other areas of the prostate.
Doctors disagree about the need for a systematic biopsy in these circumstances, with some saying it almost always turns up lesions that pose no danger. “If you look hard enough, you find most of us as we age, will harbor some cancers,” said Gilbert Welch, an internist at the Center for Surgery and Public Health at Brigham and Women’s Hospital. “It’s not in people’s best interest to look as hard as possible to see if something’s wrong, because we will find things wrong, and they will raise questions and lead people to feel more vulnerable — it will certainly cost them more, they’ll be involved in more loops of repetitive testing and questions about what should be done,” he said. “And this is one of the major challenges for medicine going forward: How hard should we be looking for things to be wrong in people who have no symptoms?”
Others have a different perspective. “If I’m a public health expert trying to say ‘How do we find the only cancers we want and not get too many overdiagnoses?’, then the answer is MRI-targeted [biopsy] alone,” said Tyler Seibert, an associate professor at the University of California, San Diego. “If I’m an oncologist treating a patient, which is what I do more, I want the information from the systematic biopsy. Both of those strategies are very reasonable and appropriate and even data-driven. … It’s not so clean and easy that one is absolutely better than the other in my mind.”
Studies have shown that targeted biopsies at times underestimate the grade of the cancer, and that combining systematic and targeted biopsies found more cancer that needed to be treated compared to either type of biopsy alone. However, proponents of performing targeted biopsies alone say the marginal risk of missing cancers should be weighed against the benefits of reduced overdiagnoses on quality of life, especially since patients who undergo targeted biopsies typically are monitored through routine PSA tests and potentially MRIs.
‘The right thing to do’
About one point, guidelines and experts are aligned on both sides of the Atlantic: “The right thing to do is to get an MRI every time,” said Seibert, who said he routinely requests one prior to biopsies, and believes that to be the standard in most large medical centers. But uptake is still very low in many areas of the U.S., especially in rural communities or among the Medicaid population, as well as among Black patients. There are many reasons behind the disparities, and in some cases they are why physicians still advise a systematic biopsy.
Michael Ahdoot, an assistant professor of urology at Cedars-Sinai in Los Angeles, has conducted extensive research on the role of MRIs in prostate cancer detection. His paper published in 2020 in the New England Journal of Medicine established the diagnostic value of pre-biopsy MRIs for the U.S., leading insurance companies to cover a procedure they had routinely denied until then.
Six years later, he said, some doctors may still mistakenly believe that they wouldn’t be able to get an MRI for their patients covered. But he points to other reasons that keep pre-biopsy MRI use low — chief among them, what he calls a “knowledge deficit.” “There’s a learning curve and that leads to an adoption barrier,” he said: Since it’s only relatively recently that MRIs became integrated in the diagnostic process, many urologists are not comfortable ordering or interpreting them. “A doctor’s ability to read an MRI is very heterogeneous,” he said. “I would say the vast majority [of urologists] don’t know how to read a prostate MRI … even nowadays, many residents don’t come out knowing how to read a prostate MRI reliably.”
It’s ego as much as lack of training, he adds: “Some people think that they can just get a good biopsy anyway,” he said.
Shortly after his 2020 paper, Ahdoot set out to study the outcome of systematic versus targeted biopsies. “We initially set out to try to argue that systematic biopsies were no longer needed,” he said. “But when we analyzed the data, we found that patients who had a systematic biopsy in addition to the targeted biopsy had about 8% more clinically significant cancer detected.”
That too, he said, has at least something to do with physician skills. “There are many [urologists] who just don’t know how to do an MRI-targeted biopsy or have the technology to do so,” he said. Eggener adds that the quality of MRIs in the U.S. varies dramatically, as does the ability to get one, especially in rural areas. “Access to MRI isn’t so easy in certain parts of the country, and the quality of MRI pictures can be all over the map,” he said.
Studies have also shown that MRI interpretation can vary significantly. All of this, he said, can help explain the value of a systematic biopsy in identifying more cancer.
There are other factors at play, too. Prostate biopsies are lucrative for urologists, who can do them in their practice and therefore have an incentive to order them, and so is finding clinically insignificant cancers that can be actively monitored, potentially through further biopsies. Plus, patients often push for further testing, wishing to know as much as they can about their cancer status.
What’s so special about prostate cancer?
The debate between targeted and systematic biopsy is very lively, but Emberton’s practice has been pushing things further. He thinks MRIs say all doctors and patients need to know about whether a cancer requires intervention. This means that he treats all visible lesions, which in his view always contain clinically significant cancer, even if biopsies come back negative.
On the flip side, he does not believe MRI-invisible tumors need to be found, viewing prostate cancers like all other solid tumors: no lesions, no treatment. A negative prostate MRI is, he said, “just like … a normal mammogram, normal brain scan, normal lung scan.” It does not warrant any intervention. “Subclinical disease doesn’t matter in any cancer: It doesn’t matter in breast [cancer], it doesn’t matter in lung, it doesn’t matter in kidney, it doesn’t matter in brain. Why should the least lethal of all these cancers somehow have this incredibly lethal, non-visible subclinical entity?” he said, referring to the likelihood of invisible prostate cancer being deadly. “Madness.”
He notes that it takes at least a decade for masses to consolidate, and only once they are detectable the growth accelerates, making it important to target a visible mass, and unnecessary to do so with an invisible one. “To become visible, you need to be very lucky as a cancer,” Emberton said. “Most of the invisible ones, I think, are taken out by the immune system or, more likely, have a lethal mutation — and we just never see them.“
Like all American specialists STAT spoke with, Eggener is unconvinced. “Mark Emberton is one of my heroes. He is a friend and a colleague. He has contributed a ton to what we know about prostate cancer. He feels very strongly about it,” he said. “And I can give you a half a dozen reasons why I disagree with him.”
MRIs are imperfect. Targeted biopsies sometimes miss the spot (“we are not perfect at getting the needle into the right area”). Perhaps most important, he said, “every study that’s out there shows that there can be meaningful cancers that aren’t seen by MRIs.” Emberton, he added, “argues if you can’t see them on an MRI, they probably don’t matter. That’s not proven at all — there is some evidence suggesting it, but it’s far from proven.” A recent study published in JAMA Oncology, for instance, found that only 3% of men with negative MRIs developed clinically significant prostate cancer within three years of monitoring.
A clinically significant cancer identified through a systematic biopsy has to be treated regardless of whether it was visible on the MRI, Seibert said. “You still have to treat the same way you would any other grade group 4 cancer, because almost all the evidence for how we treat patients comes from clinical trials from before we had MRI,” he said. “So it’s silly to say, well, because this isn’t visible on MRI, I don’t need to treat it. … It may be true, but right now that’s too risky.” Though he says some evidence is starting to collect pointing to the possibility that Emberton is right, he said he would not feel comfortable adopting active surveillance for patients who have clinically significant, MRI-invisible cancer.
Gray zones abound. Emberton’s approach is followed by some practitioners in Europe, but it is far from the standard. Now he hopes to bring more clarity to the decision, and is working on the design of a trial that would test forgoing the biopsy entirely, with the aim of evaluating whether that changes patient outcomes.
One thing American urologists should come around to, he said, is to avoid unnecessary diagnoses, procedures, risks — and costs. “Everything changes once you put a needle in the prostate,” he said. “If you don’t have to put a needle in the prostate, you’re far better off not doing it.”
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