Since the release of the 2012 screening recommendations for prostate cancer, the controversy surrounding PSA testing and prostate cancer treatment has erupted and has lacked a clear direction and concise strategy. We, as urologists, have done a poor job educating the public and primary care practitioners on this heterogeneous, complex disease – one that remains the most common non-cutaneous malignancy in men and is the second leading cause of male cancer deaths, claiming the lives of over 26,000 men in 2016. Despite these statistics, many clinicians have lost confidence in PSA testing and are unclear of the significance of the test.
With the emergence of these newer blood and urine assays… we now have a clear-cut algorithmic approach in dealing with patients with elevated PSA and localized cancer.
In the last two years we have seen the emergence of blood and urine assays, radiologic studies, and genomic markers to better clarify the picture surrounding elevated PSA and prostate cancer management. In essence, we are individualizing the approach to each patient in an effort to reduce negative biopsies, identify lowrisk disease, and determine which cancers require a more aggressive approach. I would like to review in this article the current approach and utilization of these various tools for three distinct patient populations: Elevated PSA and previous negative biopsy, early-stage prostate cancer, and post-prostatectomy patients with high-risk features.
For patients with an elevated PSA and previous negative biopsy, we now have in our armamentarium 4Kscore test, prostate health index (PHI), prostate cancer antigen-3 (PCA3), and Confirm MDx. 4Kscore and PHI are blood assays. PCA3 is a urine assay, and Confirm MDx assesses methylation status in three biomarkers of a previous biopsy specimen to determine the risk of having prostate cancer on subsequent biopsy. The advantage of many of these tests is not in their diagnostic accuracy, but in their negative predictive value (NPV) – i.e., the power of the negative.
4K test and PHI both utilize a proprietary formula, utilizing PSA and free PSA, to predict the chance of harboring an intermediate or high-grade cancer; i.e., Gleason score greater than or equal to 7. Both combine the prostate exam and their formula and have been validated in clinical studies to reduce the number of biopsies by over 50%, without compromising diagnostic accuracy. Prostate biopsies are associated with potential morbidity (i.e., four percent risk of serious UTI), and the application of these tests will reduce potential harm, improve overall safety, and further reduce total healthcare costs. PCA3 is another adjunct test using patients with previous negative biopsy to help identify those who may be harboring an occult, clinically significant disease. PCA3 is a gene specific to prostate tissue and is expressed in 95% of prostate cancer specimens. The PCA3 is isolated from the urine following a thorough prostate exam. Two independent studies from the United States and Europe reported that a PCA3 cutoff score of less than 35 has a specificity of 72% for detecting prostate cancer, and a negative predictive value (NPV) of 88%. The test is minimally invasive and helps with shared decision-making for patients and physicians considering repeat biopsy
Confirm MDx (MDx Health, Irvine, California) is a genetic biomarker applied to previous negative prostate biopsy tissue to determine the risk of harboring an occult cancer. The assay looks at the methylation status of three biomarkers that are involved in DNA repair, tumor cell invasion, and cell cycle control. The application and subsequent value of this test is that the overall NPV is 80%, which can potentially decrease subsequent biopsy rates by 64%. These outcomes have been validated in clinical utility studies involving 138 men from over five practices.
A more difficult decision than deciding “whom to biopsy” is the decision of “whom to treat.” At Urology of Central Pennsylvania, when we looked at our prostate cancer population over the last five years, we identified 30% of the patients to have low-grade cancer and were candidates for “active surveillance.” The question arises, how can we confirm this? With the introduction of both the Prolaris® score and Oncotype DX® (Genomic Prostate Score™, GPS), we can apply either of these to the biopsy specimen to determine the risk of gene expression. Both tests utilize a quantitative measure of RNA expression to help determine prostate tumor cell proliferation and, therefore, the risk of disease progression. Prolaris® score is based on a 46-gene expression with a cell cycle expression, whereas the Oncotype DX® GPS score consists of the 12 cancer-related genes involved in distinct biologic pathways. Both tests have been validated in clinical utility trials, are approved by Medicare, and have incorporated into NCCN guidelines for the management of very low-risk and low-risk prostate cancer. Furthermore, the application of either test can individualize each patient’s cancer and predicts favorable pathology that in turn can further increase confidence and treatment recommendations and reduce morbidity from unnecessary treatments.
The most difficult group, and the most important clinical group in whom to make a decision regarding treatment, is post-prostatectomy patients with pathologic T3 disease who are at risk for biochemical recurrence and metastasis. The subsequent treatment strategy includes post-prostatectomy radiation to the lower pelvic area, with or without hormonal manipulation and/or chemotherapy. Application of the Decipher® genomic classification score can assist in stratifying these patients beyond their pathologic stage. The Decipher® score uses an array of 22 RNA biomarkers related to cell proliferation, differentiation, androgen signaling, motility, and immune modulation. The Decipher® score can determine the five-year risk of metastases and the eight-year cumulative incidence for biochemical failure, and distant metastases in men receiving adjunct radiation therapy following prostatectomy. Clinical utility studies and outcomes have, once again, been validated for the Decipher® score as it has demonstrated a 98% negative predictive value for five-year metastasis-free survival, with low-risk scores despite adverse pathology. This subsequently leads to reduction in postoperative radiation, reduction in morbidity, improvement in quality of life, and overall lowering of healthcare costs.
The last thing I would like to comment on is the use and value of MRI in two of these three subgroups of patients; previous negative biopsy and early-stage disease. Advances in multiparametric (mp) mpMRI allows for high-quality visualization of the prostate for cancer detection. We have applied the use of MRI in elevated PSA patients for target-directed biopsies, and as a screening modality in active surveillance patients to monitor for disease progression. I have also used it in clinical T3 patients to determine if the cancer is amenable for clear surgical removal. The radiologist applies a PIRADS score to the MRI image reflective of the diffusion coefficient, and potential for prostate cancer. A low PI-RAD score of 1 or 2 has a negative predictive value of 80-90%, whereas a PI-RAD score of 4-5 has a positive predictive value of 75%. PI-RAD score of three remains equivocal and inconclusive. In my practice, the application of MRI has been very helpful in the elevated PSA population to not only reduce the incidence of repeat biopsy, but allowing me to target PI-RADS four and five lesions, and thereby increasing my accuracy. Furthermore, PI-RADS four and five lesions are more often associated with higher-grade cancers. Once again, we have added another tool that improves overall patient outcome and reduces morbidity and costs.
Over the last several years our strategic approach to patients with elevated PSA and prostate cancer has lacked a clear and concise approach. With the emergence of these newer blood and urine assays (4K score, PHI, and PCA3), multiparametric MRI, and genomic biomarkers (MDx, Prolaris®, Oncotype and Decipher), we now have a clear-cut algorithmic approach in dealing with patients with elevated PSA and localized cancer. Given the diverse nature of this disease and plethora of treatment options, these tests allow us to individualize the approach for each patient. Furthermore, it has enhanced the physician-patient relationship and decision-making process in order to reduce morbidity and improve outcomes and quality of life.
R. Scott Owens, MD, is a urologist practicing at Urology of Central PA.