Pre-biopsy magnetic resonance imaging (MRI) is negative in 20% to 40% of cancer-naïve patients with elevated prostate specific antigen (PSA) suspicious for prostate cancer (PCa).^1,2 European Association of Urology (EAU) guidelines recommend that prostate biopsy be discussed with the patient in case of negative MRI and low clinical suspicion of PCa.³ MRI has been suggested as a “triage test” for the indication of biopsy to decrease the number of unnecessary biopsies, as well as overdiagnosis and overtreatment of nonclinically significant (noncs) PCa. MRI has been shown to have a negative predictive value between 85% and 95% for PCa. In addition to MRI results, other clinical (prostate volume, age, body mass index [BMI], family history of PCa, T-stage) or biological factors (PSA kinetics, PSA density [PSAd]) with negative MRI can increase the diagnostic accuracy of MRI by reducing the risk of false-negatives. Validation of the negative predictive value of MRI and other factors can be performed by correlation of MRI result to histopathological reference standards, such as template prostate biopsies or radical prostatectomy specimens.¹ It can also be assessed by longitudinal evaluation of clinically significant PCa incidence over time.

Figure. Patient inclusion and exclusion flowchart. GG, grade group. SB, systematic biopsy.

In this study, we observed what would have happened if, in the case of a negative MRI in a biopsy-naïve population, we would have omitted biopsy. What would have been the clinically significant PCa cumulative incidence after long-term followup?

We conducted a single center, retrospective cohort study of consecutive cancer and biopsy-naïve patients referred with PSA or digital rectal examination (DRE) suspicious for PCa who underwent biopsy series after pre-biopsy MRI from January 2007 to December 2017 (see figure). Clinically significant cancer was defined using 2 definitions. Definition 1 (csPCa-1) consisted of grade group 1 associated with criteria of tumor extent (maximum cancer core length >5 mm or ≥3 positive systematic biopsies) in addition to grade group ≥2, while definition 2 (csPCa-2) consisted of grade group ≥2 and any tumor extent. Definition of high risk csPCa was grade group ≥3.

A total of 503 patients with negative MRI were included. Biopsy at baseline was positive for PCa in 31%. It was positive for csPCa-1 in 9% (45 patients, 95% CI 6–11), csPCa-2 in 6% (29, 95% CI 4–8), high grade cancer in 1.6% (8, 95% CI 0.5–2.7) and non-csPCa in 22% (111, 95% CI 19–26).

Out of 503 patients 415 remained untreated after first biopsy series (patients on active surveillance and patients without cancer). After a median followup of 4 years (IQR 1.6–7.1, range 1–10), 31% (130/415, 95% CI 27–36) of these 415 untreated patients underwent at least a second MRI because of rising PSA. At a mean followup of 30 months, 24% (98/415, 95% CI 20–28) underwent at least a second biopsy series, which was positive for csPCa-1 in 5% (21, 95% CI 3–7), csPCa-2 in 2% (7, 95% CI 1–3) and noncsPCa in 8% (33, 95% CI 5–11). Among significant PCa cases diagnosed during followup, none was at metastatic stage. Overall incidence at the end of analysis was 13% (66/503, 95% CI 7–21) for csPCa-1, 7% (36/503, 95% CI 5–9) for csPCa-2 and 2% (12/503, 95% CI 1.1–3.7) for high risk PCa.

At multivariate analyses, family history of PCa OR 2.31 (95% CI 1.12–5.26), abnormal DRE OR 2.43 (95% CI 1.12–5.26) and PSAd OR 1.06 (95% CI 1.03–1.10) were significantly associated with csPCa-1 diagnosis at first biopsy series in men with negative MRI (see table). Use of PSAd threshold ≥0.15 ng/ml/ml in negative MRI patients would have reduced the risk of missing clinically significant PCa from 9% to 4.6%, while avoiding biopsy in 65% of the negative MRI cases. Used in combination, PSAd ≥0.15 ng/ml/ml or abnormal DRE or family history with MRI results would decrease the risk of missing a csPCa-1 from 9% to 2.4% and of avoiding biopsy in 56% of the negative MRI cases.

Can biopsy be omitted in case of elevated PSA and normal MRI? Our results supported this diagnostic pathway, which was previously promoted by Panebianco⁴ and Norris⁵ et al.

Yes, we can omit biopsies, telling the patient that his risk of missing a clinically significant PCa in case of no biopsy is less than 3% if PSAd is less than 0.15 ng/ml/ml, DRE is normal and he has no family history, in addition to negative MRI. This situation concerns roughly 20% of our patients. Then he would need to be followed by PSA, which may with time lead to a diagnosis of clinically significant cancer in 2% to 5% of cases. To add confidence to these results, we need a longer median followup and detailed oncologic outcomes after treatments for the clinically significant cancers diagnosed during followup. This approach of triage tests before biopsy, combining MRI and biological or clinical factors, minimizes harms of screening.