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Supplements Improving Risk Stratification among Veterans Diagnosed With Prostate Cancer: Impact of the 17-Gene Genomic Prostate Score Assay
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Improving Risk Stratification Among Veterans Diagnosed With Prostate Cancer: Impact of the 17-Gene Genomic Prostate Score Assay
Julie A. Lynch, PhD, RN, MBA; Megan P. Rothney, PhD; Raoul R. Salup, MD, FACS; Cesar E. Ercole, MD; Sharad C. Mathur, MD; David A. Duchene, MD, FACS; Joseph W. Basler, PhD, MD; Javier Hernandez, MD; Michael A. Liss, MD, MAS, FACS; Michael P. Porter, M

Improving Risk Stratification Among Veterans Diagnosed With Prostate Cancer: Impact of the 17-Gene Genomic Prostate Score Assay

Julie A. Lynch, PhD, RN, MBA; Megan P. Rothney, PhD; Raoul R. Salup, MD, FACS; Cesar E. Ercole, MD; Sharad C. Mathur, MD; David A. Duchene, MD, FACS; Joseph W. Basler, PhD, MD; Javier Hernandez, MD; Michael A. Liss, MD, MAS, FACS; Michael P. Porter, M
Background: Active surveillance (AS) has been widely implemented within Veterans Affairs’ medical centers (VAMCs) as a standard of care for low-risk prostate cancer (PCa). Patient characteristics such as age, race, and Agent Orange (AO) exposure may influence advisability of AS in veterans. The 17-gene assay may improve risk stratification and management selection.
Objectives: To compare management strategies for PCa at 6 VAMCs before and after introduction of the Oncotype DX Genomic Prostate Score (GPS) assay.
Study Design: We reviewed records of patients diagnosed with PCa between 2013 and 2014 to identify management patterns in an untested cohort. From 2015 to 2016, these patients received GPS testing in a prospective study. Charts from 6 months post biopsy were reviewed for both cohorts to compare management received in the untested and tested cohorts.
Subjects: Men who just received their diagnosis and have National Comprehensive Cancer Network (NCCN) very low-, low-, and select cases of intermediate-risk PCa.
Results: Patient characteristics were generally similar in the untested and tested cohorts. AS utilization was 12% higher in the tested cohort compared with the untested cohort. In men younger than 60 years, utilization of AS in tested men was 33% higher than in untested men. AS in tested men was higher across all NCCN risk groups and races, particular in low-risk men (72% vs 90% for untested vs tested, respectively). Tested veterans exposed to AO received less AS than untested veterans. Tested nonexposed veterans received 19% more AS than untested veterans. Median GPS results did not significantly differ as a factor of race or AO exposure.
Conclusions: Men who receive GPS testing are more likely to utilize AS within the year post diagnosis, regardless of age, race, and NCCN risk group. Median GPS was similar across racial groups and AO exposure groups, suggesting similar biology across these groups. The GPS assay may be a useful tool to refine risk assessment of PCa and increase rates of AS among clinically and biologically low-risk patients, which is in line with guideline-based care.
Am J Manag Care. 2018;24:-S0
Prostate cancer (PCa) represents a significant management challenge for the Department of Veterans Affairs (VA). Between 12,000 and 14,000 veterans are diagnosed with PCa within the VA every year.1 The majority of these patients have low-risk PCa, a clinically indolent form of cancer that is of questionable clinical relevance.2 Clinical practice guidelines recommend active surveillance (AS) as the management strategy of choice for men diagnosed with very low- and low-risk PCa.3 Despite a growing consensus on the appropriateness of AS for very low- and low-risk PCa, there is wide variation in AS utilization nationally and within VA medical centers (VAMCs).4-6 Aggregate AS increased sharply between 2010 and 2013 but still accounted for management in just 40% of patients with PCa.7

Lack of confidence in conventional risk assessment tools may contribute to the limited use of AS. Traditional PCa metrics, such as prostate specific antigen (PSA) levels, biopsy Gleason score, tumor stage, burden of disease (the percentage of positive biopsy cores), and nomograms that integrate these factors are of great value but subject to significant limitations.8-10 A substantial number of men diagnosed with PCa following biopsy experience upgrading or downgrading of their Gleason score based on surgical pathology.11 Disparity between biopsy and surgical Gleason grading poses a major challenge because some patients with apparently indolent disease may harbor occult aggressive cancer that poses a small but finite risk of metastasis.12 Conversely, some patients with apparently aggressive cancer may have an indolent disease that is not likely to pose a threat to their quality and length of life, but they proceed with invasive treatment for cancer that has little benefit.11 Integrated classification systems, such as the National Comprehensive Cancer Network’s (NCCN) risk grouping, perform better than solitary clinical metrics but remain limited in scope (ie, risk and ability to predict outcomes).13

Approximately 7% of veterans in VAMCs may have been exposed to Agent Orange (AO).1 A total of 26% of veterans with PCa are black men.1 Black race has been clearly linked to worse outcomes in PCa.14-16 However, an observational cohort analysis of 1270 patients with PCa within the VA demonstrated that in this equal-access healthcare system, PCa mortality in black and white patients was similar.17 An association between AO exposure and PCa is controversial but a topic of ongoing research.18,19

The development and clinical implementation of molecular testing is one means by which physicians may provide additional risk assessment based on an individual’s tumor biology.20 The NCCN guidelines on PCa have cited molecular diagnostics as an option to aid in management decisions.10 One such molecular marker for use in the PCa biopsy space is the Oncotype DX Genomic Prostate Score assay (Genomic Health; Redwood City, CA).21,22 This assay uses a proprietary algorithm that measures the expression of 12 cancer-specific genes and 5 reference genes to yield a Genomic Prostate Score (GPS) result, which ranges from 0 to 100, with higher scores implying a more aggressive tumor phenotype. The GPS result is integrated with the patient’s NCCN clinical risk group to provide a refined estimate for the likelihood of favorable pathology, defined as a pathological Gleason score less than 3+4 and pT2 disease (tumor confined to the prostate).23 The GPS assay has been validated as an independent predictor of adverse pathology (AP) in clinical studies, one of which was conducted at 2 military hospitals and included 81 black patients, representing 20% of the total cohort.21,22 Subgroup analyses demonstrated that the GPS assay was an independent predictor of AP and biochemical recurrence in both Caucasian and African American men.21

Given the racial diversity, potential for exposure to AO, and the high prevalence of competing comorbidities among veterans with PCa, it is important to study genomic testing specifically within VAMCs before considering widespread adoption of this technology. To our knowledge, studies of molecular diagnostics in veterans with PCa have been limited.

In this supplement, we analyze treatment patterns across 6 VAMCs before and after introduction of the GPS assay. We hypothesized that incorporation of the GPS assay would lead to a significant increase in aggregate utilization of AS in veterans who received the test compared with a historical cohort that did not have molecular profiling of their tumors.

Methods

Study Design

This was a 2-part study with retrospective and prospective components. Through retrospective chart review, we studied management patterns for men with NCCN very low-, low-, and intermediate-risk PCa who did not receive molecular profiling and were managed at 1 of 6 VAMCs. In a prospective clinical trial at these same VAMCs, veterans with clinically similar PCa were offered GPS testing. Those who agreed to participate reviewed the test results with their urologists and incorporated the information into their management decision making.

Facility Selection

We identified 6 VAMCs from a geographically diverse sampling of the country. We conducted a historical review of data from VA Central Cancer Registry (VACCR) and VA Corporate Data Warehouse (CDW) to ensure that these sites had a high volume of veterans diagnosed with low-risk PCa and that they offered all standard-of-care management options for PCa.1

Patient Selection

Patients with newly diagnosed NCCN very low-, low-, or select intermediate-risk PCa were included in the study. To be eligible, men with intermediate-risk PCa were required to have a biopsy Gleason score of 3+3, with a PSA level between 10 and 20 ng/mL or a biopsy Gleason score of 3+4 with 3 or fewer positive biopsy cores and 33% or less positive cores for tumor and a PSA level less than 20 ng/mL.

Men who had yet to make a management decision and for whom biopsy tissue was available for analysis were eligible to participate in the prospective cohort. Physicians at each site offered enrollment to all eligible patients. Patients in the prospective cohort were enrolled between March 2015 and February 2016.

The retrospective cohort was identified by screening patients with PCa managed at 1 of the 6 VAMCs between January 2014 and March 2015. All clinically eligible patients (using the same criteria as the prospective study) were included in the untested cohort. Approximately 200 patients were expected to be included in each cohort (tested and untested), with no single physician providing more than 35 patients to each cohort.

Regulatory Approvals

The Institutional Review Board and the VA Research and Development Committee at each VAMC approved the conduct of the study. We obtained informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization from veterans in the tested cohort. For the untested cohort, we obtained HIPAA authorization and a waiver of informed consent.

Data Collection

The primary sources of data were the VA’s electronic health records (EHRs): the VACCR1 and the VA CDW. Demographic information (eg, age, race) and exposure to AO were obtained from patient registration in the CDW. Clinical characteristics, such as clinical stage, NCCN risk group, and management decisions were obtained from review of the EHRs. Pathology reports were accessed to determine the presence of cancer and the biopsy Gleason score.

Management decisions for both cohorts were determined by reviewing the record from 6 months after the initial diagnostic biopsy. AS was recorded as the management strategy if a chart note indicated that this was the treatment decision or if no other treatment for PCa was recorded. Urologists also completed questionnaires capturing their treatment recommendations before and after reviewing the assay results with patients.

All chart abstractions were conducted centrally at the Bedford VA. Prior to conducting the chart review for this study, the 2 nurse abstractors independently reviewed identical records in groups of 5 until they achieved greater than 90% observed agreement across all questions. The pair of nurse-abstractors then proceeded to review charts independently for the study.

Data Analysis

We conducted univariate descriptive analyses to describe the demographic and clinical characteristics, distribution of GPS results, and the management decisions in the retrospective and prospective cohorts. We conducted bivariate analyses to compare the untested and tested populations. Independent variables included age, race, AO exposure, Gleason score, cancer stage, NCCN risk group, and GPS result. Outcome variables were genomic testing and management choice. For statistical comparisons, we used the χ2 test for categorical variables, paired t test for means of continuous variables, and 1-way analysis of variance when there were more than 2 levels for the independent variable. All statistical analyses were conducted using SAS 9.4 (SAS, Cary, NC).

Results

Two hundred male veterans were included in the untested cohort and 219 were enrolled in the prospective study (Figure 1). Of the prospectively enrolled veterans, 29 were ineligible for the final analysis. Reasons for exclusion included insufficient tissue for genomic analysis (25 patients), lost to follow-up (2 patients), incorrect assignment of NCCN risk group (1 patient), and withdrawal of patient consent (1 patient). All results presented included 200 untested patients and 190 tested patients.

Clinical characteristics, including age, race, and AO exposure, were similar between the untested and tested patients (Table 1). The untested cohort included more NCCN intermediate-risk patients than the tested cohort (46% vs 35%); this was driven by the greater number of patients with a Gleason score of 3+4 in the untested cohort (37% vs 26%).

 
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