Combining MRI-Targeted and Standard Biopsy Methods Improves Prostate Cancer Diagnosis: What 2,103 Men Can Teach Us

Table of Contents

• Key Points
• Why This Research Matters
• Understanding Prostate Biopsy and Cancer Grading
• How the Study Was Conducted
• Key Findings: What the Researchers Discovered
• The Prostatectomy Sub-Study: Checking the Biopsy's Accuracy
• What This Means for Patients
• Study Limitations
• Recommendations for Patients and Doctors
• Frequently Asked Questions
• Source Information

Key Points

• In a study of 2,103 men with MRI-visible lesions, combined biopsy found more prostate cancers than either MRI-targeted or systematic biopsy alone.
• Adding MRI-targeted biopsy to systematic biopsy detected 208 extra cancers, including 59 clinically significant ones (grade group 3 or higher).
• MRI-targeted biopsy alone missed 8.8% of clinically significant cancers, so systematic biopsy should not be skipped when lesions are visible.
• Before surgery, combined biopsy reduced upgrading to grade group 3+ to 3.5%, versus 16.8% for systematic biopsy alone.
• The study included only men with MRI-visible lesions; results may not apply to men without such lesions.

Why This Research Matters

Prostate cancer is not a single disease. Some prostate cancers grow so slowly that they may never cause harm during a man's lifetime, while others are aggressive and potentially lethal. This dramatic range in behavior—from indolent to deadly—makes accurate diagnosis absolutely critical. Low-grade prostate cancer (grade group 1, also known as Gleason score 3+3=6) has been shown in large clinical trials to carry a very low risk of cancer-specific death. In stark contrast, cancers in grade groups 3 through 5 have significantly higher metastatic potential (the ability to spread to other parts of the body) and are responsible for the majority of the estimated 31,620 deaths from prostate cancer projected in the United States in 2019.

This variation in how lethal different prostate cancers can be highlights a central challenge: how do we accurately determine which men have harmless disease and which have dangerous disease? The answer has profound consequences for treatment decisions.

For decades, the standard method for diagnosing prostate cancer has been the transrectal, ultrasound-guided, 12-core systematic biopsy. In this procedure, a doctor uses ultrasound imaging to guide a needle and takes 12 tissue samples from carefully mapped regions of the prostate. The word "systematic" is key—the samples are taken in a grid-like pattern to sample the whole gland, not because the doctor sees a suspicious spot to target.

In most other types of cancer, biopsies target abnormalities that doctors can see on imaging or feel on physical examination. But with systematic prostate biopsy, no such targeting occurs. The biopsy needle samples the prostate somewhat "blindly," relying on spacing rather than vision to find cancer. Not surprisingly, this approach has significant limitations. It can miss cancers that are present, and it can under-gauge the aggressiveness of the cancer that is found.

This diagnostic inaccuracy has serious consequences. Upgrading or downgrading of the cancer diagnosis after radical prostatectomy (complete surgical removal of the prostate) is common. One troubling consequence is overtreatment: men with low-grade, slow-growing disease may undergo aggressive treatment because doctors worry that a dangerous cancer was missed by the biopsy. Research shows that 43% of prostatectomies are performed in men who are subsequently confirmed to have indolent (non-aggressive) disease when the removed prostate is examined under a microscope. Similarly, 60% of men who receive radical therapy (radiation or surgical removal of the prostate) are found to have had grade group 1 cancers on their pre-operative biopsy. On the other end of the spectrum, when aggressive disease is missed, patients risk undertreatment—a potentially deadly mistake.

Understanding Prostate Biopsy and Cancer Grading

Before diving into the study's results, it helps to understand how prostate cancer is graded. When a biopsy sample is examined under a microscope, pathologists assign a Gleason score ranging from 6 (the lowest grade of cancer) to 10 (the highest grade). The score is the sum of two numbers: the grade of the most common cancer pattern (the first number) and the highest grade pattern detected (the second number).

To make these scores more useful in clinical practice, doctors now group them into grade groups from 1 to 5:

• Grade group 1 (Gleason score 3+3=6): Clinically insignificant disease with very low risk of spreading
• Grade group 2 (Gleason score 3+4=7): Favorable intermediate risk
• Grade group 3 (Gleason score 4+3=7): Unfavorable intermediate risk and above
• Grade groups 3 through 5: Considered clinically significant cancers with higher risk of progression

In this study, researchers defined "clinically significant cancer" as grade group 3 or higher, although they also reported detection of grade group 2 or higher throughout the paper, since some physicians consider that lower threshold more clinically relevant.

Advances in prostate multiparametric magnetic resonance imaging (MRI) have opened a new frontier in diagnosis. Instead of sampling blindly, doctors can now see suspicious lesions on MRI and guide biopsy needles directly to them—a technique called MRI-targeted biopsy. Previous studies have shown that MRI-targeted biopsy detects high-grade cancers at a higher rate than systematic biopsy. However, debate has persisted about whether MRI-targeted biopsy should replace systematic biopsy entirely, or be used alongside it. Two key controversies remained: should doctors still perform the systematic biopsy when an MRI lesion is present, and should a patient's previous biopsy history influence which method is used?

How the Study Was Conducted

The Trio Study was initiated at the National Cancer Institute (NCI) in 2007 and continued through January 2019. It was a substudy of a larger clinical trial called "Use of Tracking Devices to Locate Abnormalities During Invasive Procedures" (ClinicalTrials.gov number, NCT00102544). The study was funded by the National Institutes of Health (NIH), among other funders.

Adult men aged 18 years or older were eligible if they had an elevated serum prostate-specific antigen (PSA) level (a blood test used to screen for prostate cancer) or an abnormal digital rectal examination (a physical exam of the prostate). Eligible men underwent prostate MRI, and those found to have a visible lesion who consented to biopsy were enrolled. Exclusion criteria included previous treatment for prostate cancer, no visible MRI lesions, or an inability to undergo MRI (for reasons such as body size incompatible with the MRI equipment, ferrous metallic implants, or claustrophobia). All patients provided written informed consent.

A total of 2,732 men underwent prostate MRI during the study period. Of these, 2,180 had MRI-visible lesions and underwent both types of biopsy in the same clinical setting. After excluding 77 men who had undergone previous treatment, the final analysis included 2,103 men.

Here is how the biopsy procedures worked:

1. MRI scanning: All initial scans were performed using a 3-tesla MRI (Achieva, Philips) with an endorectal coil (BPX-30, Medrad, Bayer). The endorectal coil was omitted for rare contraindications such as latex allergy, anal fistula, active hemorrhoids, or absence of a rectum. Each MRI was reviewed by one of two expert genitourinary radiologists, each with more than a decade of experience reading prostate MRIs.
2. Lesion scoring: MRI lesions were assigned a Prostate Imaging Reporting and Data System (PI-RADS) score of 1 to 5, with higher scores indicating more clinically suspicious lesions. (Before April 2015, the team used a 5-point NIH-developed scoring system that was subsequently translated to PI-RADS scores.) A maximum of five targets were labeled for biopsy per patient.
3. MRI-targeted biopsy: Using the UroNav Fusion Biopsy System (Philips)—a device developed through a cooperative research-and-development agreement between the NIH and Philips—doctors superimposed the labeled MRI images onto real-time ultrasound scans. This fusion technology allowed them to aim precisely at the MRI-visible lesions. Two biopsy cores were taken from each targeted lesion using an end-fire transrectal ultrasound probe.
4. Systematic biopsy: After the MRI overlay targets were removed from the ultrasound screen, a second physician performed a standard 12-core extended sextant biopsy using only ultrasound guidance. Systematic cores were taken using standard segmentation to acquire medial and lateral samples from each of the six prostate regions.

Importantly, the radiologist who interpreted the MRI and assigned targets was never the same person who performed the biopsies. If a doctor noticed targeting information from the MRI-targeted biopsy (such as hemorrhage tracts) during the systematic biopsy, the doctor was instructed to ignore it. Biopsies were performed by urologists, radiologists, or both working together.

If a patient underwent multiple biopsies, only the results of the first combined biopsy were included in the primary biopsy cohort. A single, highly experienced genitourinary pathologist interpreted all biopsy specimens and whole-mount histopathological slides (the full cross-section of the removed prostate gland after surgery), ensuring consistent and expert review. Results were reported following the recommendations of the START (Standards of Reporting for MRI-Targeted Biopsy Studies) Consortium.

Key Findings: What the Researchers Discovered

Of the 2,103 men included in the analysis, prostate cancer was diagnosed in 1,312 men (62.4%) by the combined use of both biopsy methods. The majority of participants (79.3%) had undergone at least one biopsy at an outside institution before enrolling in the study, meaning most men were being evaluated either for a suspicious prior finding or to clarify an uncertain previous biopsy result.

The study's primary outcome compared cancer detection rates between MRI-targeted and systematic biopsy, broken down by grade group. The differences were striking:

• Grade group 1 cancers (clinically insignificant): MRI-targeted biopsy detected significantly fewer of these than systematic biopsy (P<0.001). This is actually good news—it means MRI-targeting was less likely to find harmless cancers that might lead to unnecessary treatment.
• Grade groups 3, 4, and 5 cancers (clinically significant): MRI-targeted biopsy detected significantly more of these than systematic biopsy (P=0.004, P<0.001, and P=0.003, respectively). This means MRI-targeting was better at finding the dangerous cancers that matter most.

Overall, systematic biopsy alone detected cancer in 1,104 men (52.5%), while MRI-targeted biopsy alone detected cancer in 1,084 men (51.5%). But the real value of this study lies in what happened when the two methods were combined.

Combined Biopsy: More Cancers Found, More Cancers Correctly Classified

Adding MRI-targeted biopsy to systematic biopsy led to 208 more cancer diagnoses (9.9%) than either method alone. Of these new diagnoses, 59 (28.4%) were clinically significant cancers (grade group 3 or higher). In other words, nearly one-third of the cancers that would have been missed without MRI-targeting were dangerous ones.

The combined approach also improved the accuracy of cancer grading. Among men whose systematic biopsy found grade group 1 (clinically insignificant) cancer, 134 men were upgraded to grade group 2 or higher based on MRI-targeted biopsy findings. This upgrading is crucial because it changed their risk category—and likely their treatment plan—from "watch and wait" to "this needs treatment." At the same time, MRI-targeted biopsy found 74 new grade group 1 cancers in men for whom systematic biopsy had found no cancer at all.

In total, MRI-targeted biopsy was responsible for upgrading the cancer classification in 458 patients (21.8%) when added to systematic biopsy. This means that for more than one in five men, the MRI-targeted approach provided critical additional information that changed their diagnosis to a higher-risk category.

Here is a striking finding: the combined biopsy reduced the number of men classified as having clinically insignificant (grade group 1) cancer from 454 to 394—a net reduction of 60 patients. This matters because being incorrectly labeled as having "harmless" cancer can lead to under-treatment, while being incorrectly labeled as having "aggressive" cancer can lead to unnecessary surgery or radiation.

The Dangerous Blind Spots of MRI-Targeted Biopsy Alone

Some experts have argued that MRI-targeted biopsy alone could replace systematic biopsy entirely. This study shows why that approach would be risky.

MRI-targeted biopsy alone detected clinically significant cancers (grade group 3 or higher) in 425 of 466 patients (91.2%) in whom such cancers were found by combined biopsy. That sounds excellent—but it means 8.8% of clinically significant cancers would have been missed if only MRI-targeted biopsy had been performed. In absolute numbers, MRI-targeted biopsy alone would have failed to detect:

• Cancers of grade group 2 or higher in 123 patients (5.8%) of the total study population
• Cancers of grade group 3 or higher in 41 patients (1.9%) of the total study population

Put another way, if doctors had skipped the systematic biopsy, they would have missed the opportunity to reclassify 330 patients (15.7%) into a higher-risk category. These are men who might have been told their cancer was low-risk when it was actually aggressive.

Interestingly, the reverse was also true. Of the 466 patients with grade group 3 or higher cancers detected on combined biopsy, 175 (37.6% of those with clinically significant cancer) were detected by MRI-targeted biopsy only, and 41 (8.8%) were detected by systematic biopsy only (P<0.001). Each method caught dangerous cancers that the other one missed—which is precisely why they work better together.

The Prostatectomy Sub-Study: Checking the Biopsy's Accuracy

The ultimate test of a biopsy's accuracy is what happens when the entire prostate is removed and examined. In this study, 404 of the 1,312 men diagnosed with cancer (19.2% of all participants) underwent radical prostatectomy at the NCI. The median time between biopsy and surgery was 98 days (interquartile range, 74 to 134 days).

Researchers compared the grade group determined on biopsy with the grade group determined on whole-mount histopathological analysis—that is, examining the entire prostate gland, sliced and mounted on slides, after surgical removal. This comparison revealed how often the biopsy misclassified the cancer's true aggressiveness.

For the outcome that matters most clinically—upgrading to grade group 3 or higher (meaning the biopsy underestimated the cancer as lower-risk than it actually was)—the combined biopsy approach was clearly superior:

• Combined biopsy: Only 3.5% of men were upgraded to grade group 3 or higher after surgery
• MRI-targeted biopsy alone: 8.7% of men were upgraded to grade group 3 or higher
• Systematic biopsy alone: 16.8% of men were upgraded to grade group 3 or higher

This is one of the most powerful findings in the study. When both biopsy methods were used, the risk of under-estimating a cancer's severity was less than one-quarter of the risk with systematic biopsy alone (3.5% vs. 16.8%). For men facing the life-altering decision of whether to have their prostate removed, this accuracy is invaluable.

The patient population in the prostatectomy cohort was typical of men undergoing surgery for prostate cancer: their mean age was 62.0 years, their median PSA was 6.9 ng/ml, and 45.6% had PI-RADS score 5 lesions (the most suspicious category) on MRI.

What This Means for Patients

This study provides strong evidence that for men with MRI-visible prostate lesions, the most accurate diagnostic approach is combined biopsy—performing both MRI-targeted and systematic biopsy in the same session. The combined approach detected more cancers overall, found more clinically significant cancers, and dramatically reduced the risk that a man would be told his cancer was low-grade when it was actually high-grade.

Here's what this means from a patient's perspective:

• You want the most accurate grade possible. The grade group determined on biopsy drives treatment decisions—whether to choose active surveillance, surgery, radiation, or focal therapy. An inaccurate grade can lead to either unnecessary aggressive treatment or dangerous under-treatment.
• MRI-targeted biopsy alone is not enough. Even though MRI-targeting found more high-grade cancers than systematic biopsy, it still missed 8.8% of clinically significant cancers. Skipping the systematic biopsy would leave these dangerous tumors undiscovered.
• The combined biopsy is not just about finding more cancer—it's about finding the right cancer. The combined approach reduced how many men were labeled as having clinically insignificant cancer (grade group 1) from 454 to 394, meaning fewer men were incorrectly placed in the "low-risk" category.
• Previous biopsy status matters but does not eliminate the benefit of combined biopsy. The majority of men in this study (79.3%) had undergone a prior biopsy before entering the study. The combined approach still found significant additional cancers in these men, showing that even after a previous negative or positive biopsy, both methods together provide the most complete picture.

Study Limitations

Every study has limitations, and this one is no exception. It is important for patients to understand these caveats so they can interpret the findings appropriately.

First, this was a single-institution study conducted at the National Cancer Institute, a specialized research center with extraordinary expertise in prostate MRI and biopsy. The radiologists had more than a decade of experience, and a single expert pathologist reviewed every specimen. Results might differ in community hospitals or smaller practices with less specialized experience. The consistency of expert review is both a strength (ensuring accuracy) and a limitation (reducing generalizability).

Second, the study did not compare treatment outcomes. It shows that combined biopsy provides more accurate diagnosis and grading, but it does not prove that this diagnostic accuracy translates into improved survival or quality of life. That would require a much longer randomized trial.

Third, the prostatectomy cohort (404 men) represents only a subset of the men diagnosed with cancer, and men who choose surgery may differ from men who choose other treatments. The upgrading data therefore may not apply equally to all patients.

Fourth, the study focused exclusively on men with MRI-visible lesions. Men with no visible lesions on MRI (552 of the original 2,732 who underwent MRI) were excluded from the analysis, so the findings cannot be generalized to men whose MRIs show no suspicious areas.

Finally, some statistical analyses were performed post hoc (after the data had already been examined) during the peer review and revision process, which carries a slightly higher risk of finding patterns that might not be reproducible in a new dataset.

Recommendations for Patients and Doctors

Based on the study's comprehensive data, the authors conclude that among patients with MRI-visible lesions, combined biopsy led to more detection of all prostate cancers. Notably, MRI-targeted biopsy alone underestimated the histologic grade (aggressiveness) of some tumors, while after radical prostatectomy, upgrades to grade group 3 or higher on histopathological analysis were substantially lower after combined biopsy.

For patients facing a prostate cancer diagnosis, these findings suggest some practical takeaways:

1. Ask about MRI before your biopsy. If you are undergoing evaluation for suspected prostate cancer, ask whether a multiparametric prostate MRI can be performed to look for visible lesions that can be targeted. The study's patients all had MRI-visible lesions, and the entire benefit of MRI-targeting depends on having something to see.
2. Discuss whether both biopsy types will be performed together. The study strongly supports performing MRI-targeted and systematic biopsy in the same session (combined biopsy). Each method caught cancers the other missed, and the combined approach dramatically reduced upgrade rates after surgery.
3. Do not accept a low-risk diagnosis without confidence. If you are told your cancer is grade group 1 (clinically insignificant), it is worth confirming that the assessment was based on a robust sampling. The study found that systematic biopsy alone misclassified some men as grade group 1 who actually had more aggressive disease. Combined biopsy significantly reduced this risk.
4. Understand that imaging expertise matters. The accuracy of MRI-targeted biopsy depends heavily on the quality of the MRI and the experience of the radiologists and urologists performing the procedure. When discussing biopsy options with your doctor, ask about their experience with MRI-fusion biopsy.
5. Weigh the implications for treatment planning. An accurate grade group is the foundation of a sound treatment plan. Whether you're considering active surveillance, surgery, or radiation, insist on the most accurate diagnosis available—which, according to this study, means combined biopsy.

The findings from this study represent a significant step forward in the fight against one of the most common cancers in men. By demonstrating that combining MRI-targeted and systematic biopsy provides the most accurate diagnosis, the researchers have given patients and doctors a clearer path to making informed, life-changing treatment decisions.

Frequently Asked Questions

What is a combined prostate biopsy?

A combined biopsy uses two methods in one session: an MRI-targeted biopsy, where needles are guided to suspicious spots seen on MRI, and a standard 12-core systematic biopsy, which samples the prostate in a grid pattern. In a study of 2,103 men, combining them found more cancers and gave a more accurate cancer grade than either method alone.

How much better is combined biopsy at finding dangerous prostate cancers?

In 2,103 men with MRI-visible lesions, adding MRI-targeted biopsy to systematic biopsy led to 208 more cancer diagnoses than either method alone. Of these, 59 (about 28%) were clinically significant cancers (grade group 3 or higher). Combined biopsy also found more high-grade cancers overall than either method alone.

Does combining biopsy methods reduce the chance that surgery will reveal a more aggressive cancer?

Yes. Among 404 men who had their prostate removed, upgrading to grade group 3 or higher after surgery occurred in only 3.5% with combined biopsy, compared with 8.7% for MRI-targeted biopsy alone and 16.8% for systematic biopsy alone. That means combined biopsy gave the most accurate estimate of cancer severity before surgery.

Do these findings apply to men with no visible lesion on prostate MRI?

No. This study included only men with MRI-visible lesions (2,103 men). Men with no visible lesions were excluded from the analysis. If your MRI shows no suspicious area, you cannot assume the same benefits. Ask your doctor how these results might apply to your specific situation.

What should I ask my doctor about prostate biopsy?

Ask whether a multiparametric prostate MRI can be done before biopsy to look for visible lesions, and whether both MRI-targeted and systematic biopsy can be performed together in the same session. Also ask about the experience of the radiologists and urologists with MRI-fusion biopsy, since imaging expertise affects accuracy.

Source Information

Original Article: "MRI-Targeted, Systematic, and Combined Biopsy for Prostate Cancer Diagnosis"

Authors: M. Ahdoot, A.R. Wilbur, S.E. Reese, A.H. Lebastchi, S. Mehralivand, P.T. Gomella, J. Bloom, S. Gurram, M. Siddiqui, P. Pinsky, H. Parnes, W.M. Linehan, M. Merino, P.L. Choyke, J.H. Shih, B. Turkbey, B.J. Wood, and P.A. Pinto

Publication: The New England Journal of Medicine, Volume 382, pages 917–928, published March 5, 2020. DOI: 10.1056/NEJMoa1910038

Funding: The study was funded by the National Institutes of Health (NIH) and others. The electromagnetic tracking device used in the study was developed under a cooperative research-and-development agreement between the NIH and Philips, and is commercially available as the UroNav platform.

Study Registration: Trio Study, ClinicalTrials.gov number NCT00102544

This patient-friendly article is based on peer-reviewed research published in The New England Journal of Medicine. It is intended to help patients understand the study's findings and does not constitute medical advice. Patients should discuss their individual diagnostic and treatment options with their healthcare providers.