Reference: “Twenty-year Risk of Prostate Cancer Death by Midlife Prostate-specific Antigen and a Panel of Four Kallikrein Markers in a Large Population-based Cohort of Healthy Men” Authors: Daniel D Sjoberg, Andrew J Vickers, Melissa Assel, Anders Dahlin, Bing Ying Poon, David Ulmert, Hans Lilja. 2018. Eur Urol
A landmark study recently reported in European Urology reports that using the 4Kscore in men with an elevated PSA can clearly identify those with a low risk of dying from prostate cancer up to 20 years after the test result.
The study’s conclusion that ”men with elevated PSA but low scores from the four-kallikrein panel [4Kscore test] can be monitored rather than being subject to biopsy”  provides patients and physicians with reassurance that conservative management and monitoring can spare them the discomfort and possible side effects of an avoidable prostate biopsy.
Shortcomings of PSA-Only Screening for Prostate Cancer
More than 20 years after PSA testing became a widespread screening tool for prostate cancer, the test and its usefulness are the subject of controversy. Since its introduction in the early 1990’s, PSA screening has helped lower the risk of prostate cancer death by over 50%, but some health experts and doctors believe this improvement has come at a very high cost to both individual men and society as a whole.
Because PSA has a low specificity for prostate cancer it can be elevated in benign conditions such as benign prostatic hyperplasia (BPH) and infection of the prostate. In addition, it does not differentiate low-grade, indolent cancer from the aggressive prostate cancers that are likely to metastasize and lead to death. Under current protocols, an abnormal PSA or DRE (digital rectal exam) is often followed by a prostate biopsy to determine whether prostate cancer is present and if aggressive therapy is warranted. Approximately 75% of prostate biopsies will be negative for cancer or find indolent disease.
Citing unnecessary anxiety and side effects for individual men and high costs of overdiagnosis and overtreatment for the general population, the US Preventative Services Task Force has issued guidelines questioning the utility of PSA as a test that leads to prostate biopsy. They recognize the decision to be screened for prostate cancer is a complex one, and recommend individualized decision making in appropriate men.
The 4Kscore addresses the concerns of the Task Force of reducing prostate biopsies in low risk men, and has been validated in numerous studies in the US and Europe. The Malmo study by Sjoberg et al. was designed to investigate its ability to predict long term risk of dying from prostate cancer, in a large cohort of healthy, unscreened men.
Malmo Study Population & Four Kallikrein Marker Results
Between 1991 and 1996, a study on diet and cancer enrolled 11,506 men from Malmo, Sweden born between 1925 and 1945. Upon enrollment, the men provided a sample of anticoagulated blood plasma, which was cryopreserved. Follow-up data on study participants were collected through December 31, 2014. The large population of healthy men and the extensive monitoring period provided a baseline to test the effectiveness of 4Kscore for determining risk of dying from prostate cancer in men with an elevated PSA. Previous prospective studies in Europe and the U.S. validated the accuracy of the 4Kscore test when compared against results from biopsy, and the Malmo study demonstrated that it can also provide important information about long term clinical risk of dying from prostate cancer. The previously published Vasterbotten study (Stattin, et al. 2015) similarly demonstrated that 4Kscore can categorize risk of developing metastatic prostate cancer. 
For the study, blood from 4251 program participants (291 prostate cancer deaths, 1223 with prostate cancer diagnoses, and 3028 control subjects) was measured for four kallikrein markers:
• Total PSA
• Free PSA
• Intact PSA
Results were then assessed using the 4Kscore Test. The study concluded that in men with a PSA ≥ 2.0 ng/ml, the 4Kscore increases the predictive discrimination for 15-20 year risk of prostate cancer death. According to the study, “the 15 year risk of prostate cancer death more than doubles to 7.7% among those with a baseline PSA ≥ 2.0 ng/mL. Among these men, 46% had a four-kallikrein panel risk score of < 7.5%, with low 10 and 15 year risks of prostate cancer death (0.55% and 1.7% respectively).” Study authors concluded that the kallikrein marker-based statistical model “reclassified many men with modestly elevated PSA to have a low long-term risk of prostate cancer death. Men with elevated PSA but low scores from the four-kallikrein panel can be monitored rather than being subject to biopsy.”
Significance Of Malmo Study Findings
According to Dr. Steve Zappala of OPKO Health, the company offering the 4Kscore Test in the U.S., the majority of men diagnosed with prostate cancer do not die of the disease. These men are far more likely to die of other causes and generally do not require aggressive treatments like a radical prostatectomy (surgical removal of the prostate). While PSA readings > 2.0 ng/mL at age 50 to 60 are very frequently detected in men who later died of prostate cancer, this abnormal reading is not specific enough to warrant biopsy of every patient. At least half of these abnormal PSAs reflect antigen levels elevated by some other cause, including the presence of indolent prostate cancer.  Using the 4Kscore to provide the risk of aggressive prostate cancer in these men allows for more informed decisions about the need for a prostate biopsy, which may be avoided in low risk men.
The cohort study from Malmo, Sweden provided a large population that was monitored for death due to prostate cancer over a lengthy period. The 4Kscore Test accurately categorized men at high risk of prostate cancer death, who would benefit from early biopsy and treatment, and men with a low risk, who could safely be monitored without a prostate biopsy.
Dr. Zappala urges physicians and urologists to embrace these study findings and recommend the 4Kscore Test to any patient with abnormal PSA readings. He emphasizes, “these [study] results will support the reduction of prostate biopsy rates and overdiagnosis of indolent disease, but still maintain sensitivity for identifying those high-risk patients at an earlier and likely curable stage.”
1. Sjoberg, et al. “Twenty-year Risk of Prostate Cancer Death by Midlife Prostate-specific Antigen and a Panel of Four Kallikrein Markers in a Large Population-based Cohort of Healthy Men.” European Urology. https://doi.org/10.1016/j.eururo.2018.02.016.
2. Parekh, et al. “A Multi-institutional Prospective Trial in the USA Confirms that the 4Kscore Accurately Identifies Men with High-grade Prostate Cancer.” European Urology. http://dx.doi.org/10.1016/j.eururo.2014.10.021.
3. Draft Recommendation Statement: Prostate Cancer: Screening. U.S. Preventive Services Task Force. May 2018.
4. Stattin, et al. “Improving the Specificity of Screening for Lethal Prostate Cancer Using Prostate-specific Antigen and a Panel of Kallikrein Markers: A Nested Case-Control Study.” European Urology. http://dx.doi.org/10.1016/j.eururo.2015.01.009.
5. Sjoberg, et al. “Twenty-year Risk of Prostate Cancer Death by Midlife Prostate-specific Antigen and a Panel of Four Kallikrein Markers in a Large Population-based Cohort of Healthy Men.” European Urology. https://doi.org/10.1016/j.eururo.2018.02.016.