Prostate cancer is the most common noncutaneous cancer diagnosed in men and the second leading cause of cancer deaths in men; more than 26,000 men were estimated to die from the disease in the United States in 2016.1 Typically, prostate cancer is suspected following routine screening with a prostate-specific antigen (PSA) blood test and/or digital rectal examination. In either case, abnormal findings typically result in referral to a urologist who will likely recommend a prostate biopsy.2 It is estimated that approximately 700,000 to 1 million prostate biopsies are performed annually in the United States.3-5 Contemporary decision making with PSA testing has a low specificity and high false-positive rate for aggressive prostate cancer (defined as Gleason score ≥ 7 prostate cancer). The majority of these biopsies discover no cancer (approximately 50% of all biopsies performed) or an indolent, non–life-threatening, Gleason score 6 cancer (approximately 25% of all biopsies performed).6 Men who undergo an invasive prostate biopsy are subject to anxiety and associated complications that sometimes require hospitalization.7 Moreover, men found to have low-grade, Gleason score 6 prostate cancer are often treated aggressively with surgery or radiation, two-thirds of whom are confirmed to have indolent, low-grade disease.8 Thus, many of these men were unnecessarily subjected to complications such as incontinence and impotence. Morgan and colleagues9 and Wilt and colleagues10 have defined the overdiagnosis and overtreatment of nonclinically significant disease as low-value, high-cost care. Specifically, low-value care is defined as care for which the health benefits of an intervention are exceeded by its harms and costs.11 Low-value care is also defined as overuse, when care is provided in the absence of a clear medical basis.12
Overall, the current prostate cancer diagnostic and treatment paradigms represent a significant financial burden on the US healthcare system.13 The United States Preventive Services Task Force (USPSTF) has recommended against all PSA-based screening for prostate cancer,14 despite the fact that a mortality reduction exceeding 50% has been observed since PSA-based screening was introduced in the 1990s.15 The USPSTF concluded that the harms of overdiagnosis and overtreatment from PSA screening outweigh the mortality reduction benefits.
The 4Kscore® Test (BioReference Laboratories, Elmwood Park, NJ) was designed to address the dilemma presented by routine PSA screening. The 4Kscore Test is a blood-based diagnostic test that identifies a man’s risk for aggressive prostate cancer. A low 4Kscore Test result (< 7.5%) usually indicates that a prostate biopsy can be safely deferred. The 4Kscore Test is indicated for men who have never undergone a prostate biopsy (ie, biopsy naive) or have had a prior biopsy with no cancer detected. The 4Kscore Test is included in the National Comprehensive Cancer Network clinical practice guidelines for prostate cancer early detection.2
Voigt and associates3 conducted a meta-analysis on seven clinical studies of the 4Kscore Test conducted in Europe and suggested that, if applied to the US population, the 4Kscore Test would provide substantial cost savings based solely on its potential to reduce unnecessary biopsies. Parekh and associates6 conducted a multicenter, prospective study that validated the 4Kscore Test as a precise diagnostic test for US patients. Since then, the performance of the 4Kscore Test has been further validated in another US-based prospective, multicenter clinical study in the US Department of Veterans Affairs hospital system in a predominantly African American population.16 In a retrospective clinical utility study, the 4Kscore Test reduced overall prostate biopsies by almost 65%.17
In this study, we used clinical data from the 4Kscore Test US validation study,6 and created a budget impact model that is inclusive of all direct costs to patients during a 1-year time frame. The objectives of this study were (1) to evaluate the cost savings of the 4Kscore Test on the 1-year total costs for the detection of prostate cancer and follow-up treatment after diagnosis; and (2) to determine if using the 4Kscore Test prior to prostate biopsy can provide cost savings to the US healthcare system through reduced biopsies, overtreatments, and cost of complications resulting from overtreatment, while ensuring appropriate treatment for men who have aggressive prostate cancer.
A decision tree and budget impact model was developed to test the hypothesis that the 4Kscore Test provides cost savings and clinical benefits to men suspected of having prostate cancer. These patients would otherwise undergo a prostate biopsy under the current standard of care (SOC). The model was applied to a theoretic cohort of 100,000 patients suspected of having prostate cancer based on a urologist’s evaluation. The patient characteristics of this cohort were assumed to be very similar to those described in the 4Kscore US validation study.6 This number of patients (100,000) is of the same magnitude as the total number of Medicare patients (154,600) who underwent prostate biopsies in the 2015 fiscal year, according to the National Summary Data File of the US Centers for Medicare & Medicaid Services.18
Model metrics (including costs and probabilities) were derived from the peer-reviewed literature and from the Medicare Provider Utilization and Payment Data (Figure 1, Table 1). On the 4Kscore arm of the decision tree, patients with a 4Kscore ≥ 7.5% would subsequently undergo a prostate biopsy. Those with a 4Kscore < 7.5% would be considered at low risk for aggressive prostate cancer based on the user guidelines from the 4Kscore Test developer (BioReference Laboratories, Elmwood Park, NJ), and, therefore, would not undergo a prostate biopsy. On the SOC arm, all patients would undergo a prostate biopsy. On both strategy arms, the patients’ biopsy results would lead to certain treatment or active surveillance paradigms typically used by urologists in the United States (Figure 2).
The probabilities of biopsy outcomes for the SOC arm and the 4Kscore arm, and the probabilities of the 4Kscore groups (4Kscore < 7.5% vs 4Kscore ≥ 7.5%), were derived from a multicenter prospective trial of the 4Kscore Test (Figure 1A-C).6
We conducted a thorough review of the published clinical and health economics studies regarding the likelihood of use for various treatment options available to patients diagnosed with Gleason score ≥ 6 prostate cancer.19,20 The current study used the recently published probabilities from Cooperberg and Carroll,19 which estimated a higher proportion of men who chose active surveillance versus other more invasive and more expensive treatments. Therefore, these analyses reflected the most current SOC treatment choices and probabilities (Figure 1B and C), and helped us avoid overestimation of the cost savings of the 4Kscore strategy versus SOC by accurately reflecting the growth in adoption of active surveillance for low- and intermediate-risk patients.
Base-case costs of the biopsy-related procedures, blood tests, and office visits were obtained from a literature review after cross-referencing the Medicare national fee schedule. Base-case costs of the prostate cancer treatments were obtained from Optum (Eden Prairie, MN) and were based on a large-scale Medicare patient database (Table 1). The Optum database used to estimate these costs included the reimbursement information of approximately 1.5 million Medicare patients of record between July 2013 and July 2015.21
We calculated the total costs for both SOC and the 4Kscore strategies, including all the direct costs of the 4Kscore Test (for the 4Kscore arm only), biopsy (where applicable), and any treatment costs attributable within 1 year of receiving the 4Kscore Test or undergoing the biopsy procedure. All costs are expressed in the 2016 value of US dollars. We then evaluated the budget impact on the US healthcare system by calculating the differences in the total costs and categorized costs between the SOC and the 4Kscore strategy. A set of one-way sensitivity analyses was performed using a tornado plot to evaluate the impacts of the key cost variables on the budget outcome, with increasing and decreasing the value of each cost variable by 25%.
All analyses were conducted with TreeAge Pro 2016 (Williamstown, MA) and Microsoft® Office Excel 2013 (Redmond, WA). We followed the International Society for Pharmacoeconomics and Outcomes Research (Lawrenceville, NJ) principles of good practice for budget impact analysis in designing the study and analyzing the study data.
The line items associated with the cost savings of the 4Kscore strategy versus SOC over a 1-year time horizon are shown in Table 2. In the base-case analysis, the 1-year time horizon costs associated with a theoretic cohort of 100,000 patients receiving a prostate biopsy according to SOC was $1.086 billion. On the 4Kscore Test arm, only patients with a 4Kscore ≥ 7.5% would undergo a biopsy procedure and follow-up treatment, leading to a cost reduction of more than $169 million (–15.6%) compared with the SOC arm. The savings stem from the fact that the 4Kscore Test would prevent 36% of the biopsy procedures; this category alone accounted for saving $87.2 million (38% of the total savings). Using the 4Kscore strategy, the number of negative biopsy results would be reduced by 51% from 55,000 to 26,880. The number of Gleason score 6 biopsy outcomes would be reduced by 27%—or 6360—from 23,000 to 16,640. The postbiopsy cost savings for patients who would otherwise be diagnosed with Gleason score 6 disease contributed $102 million in savings (45% of the total savings). The average cost to detect and treat each high-grade cancer case was reduced by $4587 in the 4Kscore strategy arm compared with the SOC arm ($49,373 for SOC vs $44,786 for the 4Kscore strategy).
The one-way sensitivity analyses using a tornado plot (Figure 2) demonstrated that the cost savings of the 4Kscore strategy are robust when the cost variables fluctuate by ± 25%. The model results were most sensitive to the biopsy cost and the cost of radical prostatectomy. For instance, if the biopsy cost is increased by 25%, the maximum expected cost saving of the 4Kscore strategy versus SOC would reach $1912 per patient.
The predictive performance of the 4Kscore Test and its proprietary combination of kallikrein biomarkers has been extensively studied in 12 clinical studies of more than 20,000 patients and reported in several peer-reviewed publications. 6,25-27 These previous studies have consistently demonstrated that the 4Kscore Test, if performed prior to proceeding with a prostate biopsy, can significantly reduce the number of unnecessary biopsies and overtreatment of indolent disease. In this study, based on a cohort of 100,000 men suspected of having clinically significant prostate cancer requiring a prostate biopsy, the 4Kscore Test has resulted in an average net savings of $169 million ($1694 per patient) during the 1-year period after the first urologist visit. All of these men would have undergone a prostate biopsy under SOC. Thus, the savings associated with reducing unnecessary biopsies and treatments will recover nearly three times the upfront cost of the 4Kscore Test. The data also demonstrated that 86% of the cost savings resulted from men who, if biopsied, would either be cancer free or diagnosed with indolent Gleason score 6 disease, and could have avoided the biopsy altogether.
According to the National Summary Data File of the US Centers for Medicare & Medicaid Services, 154,600 Medicare patients in the 2015 fiscal year underwent prostate biopsies.18 At the cost savings of $1694 per patient, adoption of the 4Kscore strategy could potentially save the Medicare system $262 million annually.
The cost of some medical procedures, such as a prostate biopsy, has decreased in recent years, whereas other costs, such as those of radical prostatectomy and radiotherapy, have remained stable or increased due to regional differences in reimbursement. The utilization of magnetic resonance imaging (MRI) and active surveillance has also increased in recent years. In the base-case analysis, the model reflects 2016 Medicare reimbursement rates for prostate biopsy and the recent trends in prostate cancer treatment selection. These considerations ensured that cost savings were not overestimated. In addition, to account for the uncertainty and changing trends in treatments and costs, a series of one-way sensitivity analyses across a broad range (± 25%) of costs was also used. The results of the sensitivity analyses support the robustness of the estimated savings in these analyses.
In a blinded, prospective clinical trial of the 4Kscore in a US population of 1012 men suspected of having clinically significant prostate cancer, the 4Kscore Test had 30% to 58% biopsy reduction potential, with very few aggressive prostate cancer diagnoses delayed (< 2% of all patients when utilizing a 4Kscore cutpoint of 7.5%).6 In particular, no biopsies of patients with Gleason score 8-10 cancers were delayed, and the delayed diagnoses of men with Gleason score 7 cancer were not clinically significant in most cases; the majority were likely to be managed by active surveillance rather than aggressive treatment. Furthermore, men with a 4Kscore < 7.5% are at very low risk for developing adverse long-term outcomes. In a large-scale case-control study, Stattin and colleagues27 showed that men with an elevated PSA level, but without a diagnosis of prostate cancer and a 4Kscore < 7.5%, are unlikely to develop distant prostate cancer metastases up to 20 years later. Thus, men suspected of having prostate cancer but who have a 4Kscore < 7.5% can be monitored, knowing that their risk of distant prostate cancer metastases 20 years later is < 2%.
Since the USPSTF 2012 recommendation against routine prostate cancer screening based on PSA testing, there has been no medical consensus as to how to screen and identify men with aggressive prostate cancer. However, since the USPSTF recommendations were released, several diagnostic tests have been introduced to stratify men by prostate cancer risk. The 4Kscore Test has been extensively studied, with clinical research spanning over a decade in more than 20,000 men,6,25-27 and has been included in urologists’ guidelines both in the United States2 and Europe.28 Performing the 4Kscore Test prior to a prostate biopsy provides a noninvasive alternative method for accurate prediction of risk for aggressive prostate cancer and can significantly reduce unnecessary prostate biopsies. Use of the 4Kscore risk stratification helps to address the concerns of overdiagnoses and overtreatment of indolent prostate cancer associated with contemporary PSA-based prostate cancer screening. These benefits will accrue not only in terms of the improved quality of care (ie, high-value care) for patients, but also as significant cost savings for prostate cancer early detection programs.
This study provides the analyses on the 1-year saving of the SOC versus 4Kscore strategy and lays the groundwork for future studies that investigate the long-term cost-effectiveness impact of the 4Kscore, with consideration of patients’ costs and health-based quality of life over many years.
Actual data collected from a large-scale, multicenter clinical study in the United States were used to precisely estimate the probability input variables for the budget analysis model. The data from large databases of actual Medicare patients were also used to estimate many of the cost input variables for the model, and these data were obtained through one of the largest healthcare service organizations in the United States.
The most recent literature and data evidence was referenced to account for recent cost and treatment trends, such as changing treatment options (ie, active surveillance) and decreasing costs of prostate biopsy. Therefore, overestimation of biopsy costs and treatment costs was avoided, resulting in a robust, up-to-date cost savings estimation.
The reference used in calculating the treatment costs16 did not include probabilities of combined treatments (such as radiotherapy following radical prostatectomy). However, because the probabilities of treatment options estimated in the referred article were obtained from an actual payer database and reflect the most current trends in prostate cancer treatment, these data remain the most valid and up-to-date among all sources. In addition, the combined treatments are mostly applied to very aggressive cancers, which is a category of patients associated with very similar costs in both arms of the model. Therefore, the omission of combined treatments in the model did not significantly bias the cost savings estimation.
The analysis did not include patients who would typically have undergone prostate biopsies under the SOC, but instead were treated with procedures of unconfirmed diagnostic sensitivity (ie, MRI) performed by the urologist to avoid biopsy. Although MRI costs were included if performed in conjunction with a prostate biopsy, they could not be captured if the MRI results precluded a prostate biopsy. Inclusion of the costs of these MRI procedures would further increase the savings in the 4Kscore arm.
The budget impact model did not include indirect costs, such as patients’ time cost due to medical procedures and complications resulting from these procedures. Again, this would further increase the savings in the 4Kscore arm.
Early detection of prostate cancer results in curative treatment for the majority of men. This is a direct result of the effectiveness of PSA screening programs and the development of effective treatment modalities. The downside of these mortality reductions that stem from PSA testing is the number of men who undergo unnecessary biopsy procedures and overtreatment of indolent prostate cancer. The 4Kscore Test was designed and validated to significantly improve the specificity of detecting aggressive prostate cancer in men in whom a suspicion for clinically significant prostate cancer exists. Furthermore, the use of the 4Kscore Test to guide prostate biopsy decisions significantly reduces costs to the healthcare system compared with the SOC, while improving the quality of patient care. This study has demonstrated the 4Kscore Test provides improved quality of care by avoiding unnecessary prostate biopsies and consequent downstream treatments, complications and costs.
We thank Stacy Loeb, MD, MSc, David Okrongly, PhD, Jay Newmark, MD, Grannum Sant, MD, and Christina Higgins, PhD, for reviewing the manuscript. We also thank Whitney Pratt, BBA, at Optum (Eden Prairie, MN) for providing estimates of the costs variables used in the analytic model of this study.
