By: Dan Sperling, MD

The discovery of the source of the Nile River is credited to John Hanning Speke in 1858. For at least a thousand years, explorers had searched in vain; even the pharaohs of Egypt had a theory but history would prove them wrong. Speke, an officer in the British Indian Army, finally located the river’s source after a difficult trek into Africa’s interior. He relied on guides, existing maps, and navigational tools like the compass to satisfy the Victorians’ thirst for correct knowledge of the known world.

The search for a definitive blood test that could locate the source of a suspicious PSA or DRE is ongoing. The scientific explorers are closing in on their goal, much like Speke in 1858. He knew in which direction to travel—but he did not know exactly where he would find what he sought, what it would look like, and the best way to get there. Had it been available, he would have improved his available resources by adding a satellite view to show the overall topography, and specific photos to enable him to identify the precise source.

The exploration for improved biomarkers is important because they can help rule a biopsy in or out. A new research study out of Germany[i] shows that science is closing in. Boegemann et al. compared several PSA-based biomarkers and a base clinical model to determine which combination produced the most accurate prediction of significant and insignificant prostate cancer (PCa) prior to biopsy. They were specifically interested in diagnostic accuracy for men aged 65 and under. This is important for younger patients because a) PCa may be faster-growing for them and b) men who are still active and have high quality urinary and sexual quality of life must consider the impact treatment may have on their work and lifestyle. The sooner they know the extent and aggression of their disease, the more treatment options they are likely to have.

The researchers used conventional clinical factors as a base model: age, prostate volume, digital rectal exam, total PSA and percent free PSA. For comparison, they used the percentage of prostate-specific antigen (PSA) isoform [-2]proPSA (called p2PSA, which measures an isoform of free PSA that was identified as the most PCa-specific form found in tumor extracts[ii]) and the Prostate Health Index (PHI). PHI is calculated according to an algorithm using the p2PSA results combined with PSA and free PSA test results to provide a probability of PCa. According to National Comprehensive Cancer Network (NCCN) guidelines, PHI results are “intended to be used as an aid in distinguishing prostate cancer from benign prostatic conditions in men 50 years of age and older with total PSA results in the 4 – 10 ng/mL range and negative digital rectal examination (DRE) findings,” and a PHI value greater than 35 is “strongly suspicious for prostate cancer.”[iii]

The team enrolled 769 men aged < 65 years (from four different medical sites) who were scheduled for an initial or repeat biopsy based on total PSA levels ranging from 1.6-8.0 ng/mL. Upon enrollment, blood samples were analyzed for

• Total PSA (t-PSA)
• Free PSA (f-PSA)
• p2PSA
• PHI (calculated as p2PSA/f-PSA x ?t-PSA)

They determined that p2PSA and PHI were the best predictors of PCa detection at initial and repeat biopsy. For the detection of significant PCa, these two tests were equal in best performance over t-PSA and f-PSA. When combined with the base model of clinical factors, PHI was strongest in predicting PCa. The team concluded that both p2PSA and PHI are “equally superior for counselling patients before biopsy.”

From a urologic perspective, this study provides a strong case for the use of one or both p2PSA and PHI before biopsy. In cases where PHI > 35, a biopsy is definitely warranted, but since there is no definitive lower cutoff to rule a biopsy out, some men will still undergo unnecessary biopsies conducted in hopes of resolving doubt. Even then, the biopsy needles might miss the PCa, or miss its most aggressive cells.

Biomarkers might be thought of as the resources that pointed Speke in the right direction. Eventually he located the Nile’s source. However, the use of 3T multiparametric MRI (3T mpMRI) can be a validating adjunct to blood tests in the same way that satellite images and a photograph of the exact source could have saved Speke a lot of groping through the jungle.

While the latest blood tests may prove to be highly cancer-specific, 3T mpMRI provides precise imaging that no biomarker can equal. Ferda et al.[iv] demonstrated the capacity of this technology to deliver results. They achieved 97.6% sensitivity (positive identification of cancer) and 85% specificity (areas correctly identified as not being cancerous).

In terms of whether or not to biopsy, blood-based analyses like PHI and p2PSA are relatively cost-effective means by which urologists can recommend a biopsy. However, before conducting this invasive procedure—with its accompanying risks of infection or other side effects—having the powerful information provided by 3T mpMRI can make the journey to successful search for the source of a suspicious PSA much more efficient, less painful, and rewarding for both patient and doctor.

[i] Boegemann M, Stephan C, Cammann H et a. The percentage of prostate-specific antigen (PSA) isoform [-2]proPSA and the Prostate Health Index improve the diagnostic accuracy for clinically relevant prostate cancer at initial and repeat biopsy compared with total PSA and percentage free PSA in men aged ?65 years. BJU Int. 2015 Mar 28. doi: 10.1111/bju.13139. [Epub ahead of print]

[ii] Mikolajczyk SD., Millar LS., Wang TJ., et al. A precursor form of prostate-specific antigen Is more highly elevated in prostate cancer compared with benign transition zone prostate tissue. Cancer Res 2000 Feb 1;60:756-759.

[iii] http://prostatehealthindex.us/2014/02/19/the-benefits-of-phi/

[iv] Ferda J, Kastner J, Hora M, Hes O et al. A role of multifactorial evaluation of prostatic 3T MRI in patients with elevated prostatic-specific antigen levels: prospective comparison with ultrasound-guided transrectal biopsy. Anticancer Res. 2013 Jun;33(6):2791-5.