Prostate cancer biomarkers improve detection while reducing unnecessary biopsies

By combining diagnostic accuracy with practical convenience, prostate cancer biomarkers offer a useful tool for evaluating men with elevated serum prostate-specific antigen (PSA) levels. Current clinical guidelines from the American Urological Association and National Comprehensive Cancer Network (NCCN) offer the use of blood- or urine-based biomarkers to better define the risk of clinically significant prostate cancer (Gleason score 7 or higher, Grade Group [GG] 2 or higher) prior to biopsy.^1,2 However, the growing assortment of biomarker tests can be a source of confusion among clinicians and likely contributes to their underutilization. In the current article, we aim to provide a brief overview of prostate cancer biomarker tests and how they can be applied to benefit a busy clinical practice.

Prostate cancer biomarkers: What, when, and why?

A biomarker is broadly defined as a characteristic that is objectively measured as an indicator of a normal or pathogenic process.³ In this case, prostate cancer biomarkers have been developed to indicate the presence or absence of GG2 or higher prostate cancer. Blood- and urine-based biomarker tests are offered for use in patients presenting with an elevated PSA level.^1,2 This is the same clinical setting in which prostate MRI is often used in current practice, and the relative merits of MRI and biomarker testing are discussed below.

NCCN guidelines include 7 commercially available biomarker tests (Table¹), each of which has been demonstrated to improve on PSA and PSA-based risk calculators for detection of GG2 or higher disease.⁴ On the whole, the strength of biomarkers lies in their remarkable accuracy as “rule-out” tests, identifying patients with a low risk of harboring clinically significant disease. Combined biomarker data spanning 2015-2023 demonstrate a median negative predictive value (NPV) of 93% (IQR, 89%-95%), confirming that patients with a negative test can confidently forgo unnecessary biopsies (and MRIs) altogether.5 At the same time, a median sensitivity of 92% (IQR, 90%-95%) and specificity of 37% (IQR, 32%-47%) tell us that applying biomarker tests to all patients who present to the clinic with an elevated PSA level would avoid nearly 40% of unnecessary biopsies/MRIs while maintaining immediate detection of 92% of GG2 or higher cancers. On a practical level, biomarkers are routinely sent from the clinic, the lab, or even the patient’s home, reducing the burden of testing on the patient and health care system.

Biomarkers and MRI: Complementary strengths

Although MRI and targeted biopsy have been clearly shown to improve detection of GG2 or higher disease,⁶ the use of MRI to rule out the need for biopsy altogether is less clearly supported. In contrast to objectively measured biomarkers, the subjective and highly variable interpretation of MRI raises concern for its application as a rule-out test. To this point, a previous study of 9 radiologists, including 4 with specific training in prostate MRI, revealed 76% NPV of MRI, including 40% in the lowest-performing radiologist.⁷ These findings were corroborated by data from a statewide collaborative, which demonstrated 77% NPV across academic and community settings.⁸ Even among expert centers, where pooled data reflect an NPV of 91%, individual sites reported NPV as low as 62%.⁹ At the same time, there are practical barriers to widespread use of MRI as a first-line test after PSA, including its limited availability in some settings, significant time and resource burden, and increased cost in the US.¹⁰ These limitations create a need for reliable, objective measures to better triage patients with elevated PSA.

As such, several authors have proposed a diagnostic pathway using biomarkers first—to triage the number of patients subjected to MRI—followed by MRI, to optimize the yield of biopsy (Figure). Such an approach capitalizes on the strengths of each modality: the high rule-out accuracy of biomarkers and the strong positive predictive value and improved detection of GG2 or higher cancer facilitated by MRI with targeted sampling.¹¹ The biomarker-MRI testing pathway is further supported by the randomized ProScreen trial, which used a 4-kallikrein biomarker test to identify patients for MRI and possible biopsy.¹² Compared with initial findings from the European Randomized Study of Screening for Prostate Cancer, in which all patients with elevated PSA levels underwent biopsy, the biomarker-MRI testing pathway used in ProScreen reduced the proportion of patients subjected to biopsy (3% vs 22%) while maintaining comparable detection of GG2 or higher cancer (1.7% vs 1.8%).^12,13 These findings demonstrate just how much the diagnostic pathway has improved in the past 2 decades, subjecting fewer patients to biopsy while preserving detection of clinically significant cancers that stand to benefit from early diagnosis and treatment.

Practice today

In recent years, biomarker assays have evolved to capture more markers than ever before, including those specifically linked to higher-grade cancers.^14,15 At the same time, testing has become easier on patients, with digital rectal exams no longer required for most urine-based tests, and at-home testing available for several assays.¹⁶ Moreover, test results are now easier to interpret for clinicians and patients, with nearly all tests providing risk of GG2 or higher relative to a validated threshold, and several tests reporting an individualized risk of detecting GG2 or higher prostate cancer on biopsy for each patient (Table).

Urologists today are armed with 2 guideline-supported modalities to reduce the burden of unnecessary biopsies while maintaining timely detection of clinically significant cancers. Given the rapid expansion of commercially available biomarkers, clinicians have reported a lack of clarity regarding which biomarker to use. With NCCN guidelines now listing the biomarker tests that meet criteria for clinical use,¹ clinicians can be confident in using any such options. Now is a great time to add biomarker testing to your clinical practice.

DISCLOSURE: Tosoian is a cofounder of and adviser to LynxDx.

REFERENCES

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