Doctors turn to MRI to improve prostate cancer screening accuracy

Prostate cancer is the most diagnosed cancer in the U.S., with over 333,000 new cases annually, making it the most common among men. Despite its prevalence, it remains the least deadly, with only about 4% of cases being lethal and a 5-year survival rate nearing 99%.

This situation is largely due to diagnostic methods. A routine blood test measures prostate-specific antigen (PSA) levels, and if elevated, a systematic biopsy is conducted to locate cancerous tissue. This two-step detection process identifies cancer even at early stages but may be overly effective. Up to 70% of newly diagnosed prostate cancers are low grade and do not require treatment, as the risk of becoming lethal is minimal.

However, data from the American Urological Association Quality Registry indicates that over 50% of men with clinically insignificant prostate cancer are treated in the U.S. There are even healthcare providers who treat nearly all low-grade cancer cases.

Several prostate cancer experts believe these low-grade lesions “shouldn’t even be called cancer,” according to Scott Eggener, a urology professor at the University of California, Los Angeles. He and others argue that the prevalence of prostate cancer is due to overdiagnosis.

This is particularly an American issue. In other parts of the world, diagnostic approaches are different, often resulting in low-grade tumors going undetected and undiagnosed as cancer.

In the past 15 years, MRI scans have become the preferred method worldwide for examining elevated PSA levels before considering a biopsy. By using an MRI, 30% to 50% of patients can avoid a biopsy, reducing the discovery of clinically insignificant cancer and minimizing complications from biopsies.

In Europe, Canada, Australia, and the U.K., a pre-biopsy MRI is standard practice and has been part of U.S. guidelines since 2020. The National Comprehensive Cancer Network strongly endorses it, although the American Urological Association and the American Society of Clinical Oncology (ASCO) offer only a conditional recommendation, despite strong evidence supporting it.

Yet, data reveals that in 2022, MRIs were used before biopsies in just about a third of U.S. cases. In other instances, elevated PSA levels led directly to systematic biopsies, despite studies like the 2018 PRECISION trial showing more cancers detected and fewer insignificant cases diagnosed when an MRI precedes a biopsy. Factors like slow adoption of new technologies, lack of expertise in reading MRI scans, and financial incentives for more biopsies contribute to this.

“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,” stated Mark Emberton, a professor of Interventional Oncology at University College London.

Prostate biopsies can catch too much, and too little

In 1853, John Adams, a fellow of the Royal College of Surgeons in England, described prostate cancer as “a very rare disease” when he first diagnosed prostate malignancy by distinguishing healthy from diseased tissue in enlarged prostates.

Nearly 200 years later, this description is far from accurate, with biopsies playing a significant role in the increased detection of prostate cancer.

The earliest prostate biopsies date back to the early 20th century, but it wasn’t until 1989 that diagnoses surged, thanks to the introduction of a new biopsy methodology known as the sextant or systematic approach. Unlike random spot selection or lesion-only biopsies, this method involves systematically sampling tissue along a grid identifying six core areas of the prostate to diagnose even imperceptible disease. The number of samples eventually increased to 12, making systematic biopsies the gold standard for men with abnormal exams or elevated PSA levels, despite having limited sensitivity—50% or less, according to some studies.

Prostate biopsies are complex procedures: The gland, which is responsible for producing seminal fluids and aiding in ejaculation and urination, is situated below the bladder and in front of the rectum, making it difficult to reach and scan. Complications are common. Transrectal procedures, more frequently used, have an infection risk of up to 7% (including a 3% risk of sepsis); transperineal methods, though carrying less infection risk, are more complex and require heavier anesthesia.

Systematic sampling can lead to overdiagnosis or underdiagnosis. Depending on needle placement, it can identify the most advanced cancer cells and accurately grade the disease, or it might miss these cells and detect less advanced ones, leading to a lower grade assessment than the true disease state.

Alternatively, biopsies might uncover low-grade cancer cells, which are found in at least 30% of men over 50 and a majority of those over 80 as part of the natural aging process of prostate tissue, even without signs of advanced cancer elsewhere in the gland.

These cells meet some cancer criteria but have nearly no chance of metastasizing, thus ASCO recommends no treatment in most cases—yet a significant number of men in the U.S. still receive treatment. Until recently, most men with an elevated PSA underwent systematic biopsies, resulting in the discovery of clinically insignificant cancers in hundreds of thousands of individuals.

For the past 40 years, doctors have used MRIs as a diagnostic tool for prostate cancer. Given the prostate’s size and location, MRIs have only become reliable for imaging gland lesions in the last 15 years, with a sensitivity of up to 93%.

The scan can guide a targeted biopsy—focusing solely on the lesion—or eliminate the need for the procedure. If an MRI doesn’t detect a lesion and there’s no other patient-specific reason for further testing, a biopsy is not advised.

Treat what you can see, or find what you can’t?

Emberton, a renowned oncologist, is a strong advocate for using MRIs to diagnose prostate cancer and moving away from systematic biopsies. “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 undergo a pre-biopsy MRI. Following that, as in Europe, guidelines recommend a targeted biopsy focusing on tissues linked to the lesions shown in the MRI rather than the entire 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 significantly reduces the discovery of clinically insignificant disease elsewhere in the prostate, although doctors may still perform a systematic biopsy to ensure there are no MRI-invisible lesions.

U.S. guidelines differ. If an MRI detects a lesion, the recommendation is to conduct a targeted biopsy to assess the cancer tissue. However, a systematic biopsy is also performed to rule out additional malignancies in other prostate areas.

Doctors have differing views on the necessity of systematic biopsies in these cases, with some arguing that they typically reveal lesions that pose no real threat. “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’

On one point, guidelines and experts agree across the Atlantic: “The right thing to do is to get an MRI every time,” said Seibert, who routinely requests one before biopsies and believes it to be standard in most large medical centers. Yet, MRI uptake remains low in many U.S. regions, particularly in rural areas or among the Medicaid population, and also among Black patients. Various factors contribute to these disparities, and in some instances, they are why physicians still recommend systematic biopsies.

Michael Ahdoot, an assistant professor of urology at Cedars-Sinai in Los Angeles, has extensively researched MRIs’ role in prostate cancer detection. His paper published in 2020 in the New England Journal of Medicine established the diagnostic value of pre-biopsy MRIs in the U.S., prompting insurance companies to cover a procedure they previously denied.

Six years on, he notes that some doctors may still mistakenly believe they can’t get MRI coverage for their patients. He also highlights other factors keeping pre-biopsy MRI use low, primarily what he terms a “knowledge deficit.” “There’s a learning curve and that leads to an adoption barrier,” he said, explaining that because MRIs have only recently become part of 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.”

According to him, this is as much about ego as it is about lack of training: “Some people think that they can just get a good biopsy anyway,” he said.

Shortly after his 2020 paper, Ahdoot embarked on a study comparing systematic and 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.”

He attributes this partly to 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 MRI quality varies widely in the U.S., as does the availability of the procedure, 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 significant variability in MRI interpretation. All of this, he said, helps explain the value of a systematic biopsy in identifying more cancer.

Other factors are at play, too. Prostate biopsies are lucrative for urologists, who can perform them within their practice and hence have an incentive to order them. The detection of clinically insignificant cancers, which can be actively monitored through subsequent biopsies, is also financially beneficial. Additionally, patients often push for more testing, eager for as much information as possible about their cancer status.

What’s so special about prostate cancer?

The debate between targeted and systematic biopsy remains robust, but Emberton’s practice is pushing boundaries further. He believes MRIs provide all the information needed about whether a cancer requires intervention. Consequently, he treats all visible lesions, which he believes always contain clinically significant cancer, even if biopsies return negative results.

Conversely, he doesn’t think MRI-invisible tumors need to be discovered, viewing prostate cancers like other solid tumors: no lesions mean no treatment. A negative prostate MRI, he said, is “just like … a normal mammogram, normal brain scan, normal lung scan.” It doesn’t 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 questioned, 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 does their growth accelerate, 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 more importantly, 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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