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Impact of Decipher Biopsy Testing on Clinical Outcomes in Localized Prostate Cancer in a Prospective Statewide Collaborative - Full-Text Article

BACKGROUND: Decipher Biopsy is a commercially available gene expression classifier used in risk stratification of newly diagnosed prostate cancer (PCa). Currently, there are no prospective data evaluating its clinical utility. We seek to assess the clinical utility of Decipher Biopsy in localized PCa patients.

METHODS: A multi-institutional study of 855 men who underwent Decipher Biopsy testing between February 2015 and October 2019. All patients were tracked through the prospective Michigan Urological Surgery Improvement Collaborative and linked to the Decipher Genomics Resource Information Database (GRID® ; NCT02609269). Patient matching was performed by an independent third-party (ArborMetrix Inc.) using two or more unique identifiers. Cumulative incidence curves for time to treatment (TTT) and time to failure (TTF) were constructed using Kaplan–Meier estimates. Multivariable Cox proportional hazard models were used to evaluate the independent association of high-risk Decipher scores with the conversion from AS to radical therapy and treatment failure (biochemical failure or receipt of salvage therapy).

RESULTS AND LIMITATIONS: Eight hundred fifty-five patients underwent Decipher Biopsy testing during the study period. Of the 855 men, 264 proceeded to AS (31%), and 454 (53%) received radical therapy. In men electing AS, after adjusting for NCCN risk group, age, PSA, prostate volume, body mass index, and percent positive cores, a high-risk Decipher score was independently associated with shorter TTT (HR 2.51, 95% CI 1.52–4.13 p < 0.001). Similarly, in patients that underwent radical therapy, a high-risk Decipher score was independently associated with TTF (HR 2.98, 95% CI 1.22–7.29, p = 0.01) on multivariable analysis. Follow-up time was a limitation.

CONCLUSION: In a prospective statewide registry, high-risk Decipher Biopsy score was strongly and independently associated with conversion from AS to definitive treatment and treatment failure. These real-world data support the clinical utility of Decipher Biopsy. An ongoing phase 3 randomized trial (NCT04396808) will provide level 1 evidence of the clinical impact of Decipher biopsy testing.

INTRODUCTION

Long-term data support the safety of active surveillance (AS) for men with low-risk, and well-selected favorable intermediate-risk prostate cancer.1-3 However, some men on AS experience disease progression and metastasis, and there remains variability in the use of AS.4 Much of this variability is potentially related to concerns of disease progression and lack of confidence in clinical and pathologic tools given the documented clinical heterogeneity within traditional National Comprehensive Cancer Network (NCCN) or Cancer of the Prostate Risk Assessment (CAPRA) risk groups.5,6 Strategies to improve risk stratification of these patients include the use of clinical nomograms, multiparametric MRI, and tissue-based gene expression classifiers.7,8

There are several commercially available gene expression classifiers intended to provide additional prognostic information to men with newly diagnosed prostate cancer. All of these tests measure expression of a specific set of genes using tissue from prostate needle cores.9-11 While each of these tests has robust analytical validity, the majority of the published data are retrospective studies using archival specimens. Additionally, in the case of Decipher, while there is a substantial body of data using prostatectomy specimens to predict metastasis, there are less prospective outcomes data evaluating the performance of Decipher Biopsy in men with newly diagnosed prostate cancer.12-16 Given the increasing use of genomic classifiers in men considering AS, there is a critical need to understand both the performance of a given assay and its potential impact on clinical care.17 In this study, we performed a retrospective analysis using a large prospective statewide collaborative registry to better understand the real-world clinical utility of Decipher Biopsy in men initially managed with either AS or who receive definitive therapy with surgery or radiotherapy.

METHODS

Study cohort Michigan Urological Surgery Improvement Collaborative (MUSIC) is a statewide collaborative with prospective data collection funded by Blue Cross Blue Shield of Michigan. It is composed of 44 practices and includes over 90% of practicing Urologists in the state of Michigan.18 All practices have either an exemption or approval from the local internal review board to participate in the collaborative. Each MUSIC practice employs data abstractors with standardized training who prospectively collect patient information, including demographics, clinical variables, treatment, and additional variables.

Between February 2015 and October 2019, 855 patients from 25 different sites in the MUSIC collaborative with clinically localized prostate cancer underwent testing with the Decipher Prostate Biopsy assay (Decipher Biosciences) during their routine clinical care. Decipher data were obtained through the Decipher prospective Genomics Resource Information Database (GRID® ; NCT02609269), a prospective registry, which was cross-referenced with the MUSIC registry based on two or more identifiers (medical record number, patient name, date of birth, treatment date, and biopsy date) using an independent third-party (Arbormetrix Inc.). Patients were eligible for inclusion in the study if they underwent Decipher Biopsy testing for localized prostate cancer and could be matched with the Decipher GRID registry. Importantly, the biopsy used for Decipher Biopsy testing is termed the index biopsy, while the biopsy resulting in the diagnosis of prostate cancer is referred to as the diagnostic biopsy. For 750/855 (88%) of patients these were the same biopsy.

Patients included in the time on AS analysis were required to have met two criteria, as per established MUSIC protocols: (1) clinicians have explicitly stated in the medical record that AS is their primary management strategy, and (2) patients must not have received any definitive treatment within 6 months of diagnosis.19 Patients managed by watchful waiting (as specified by their treating physician) were excluded.

Decipher Biopsy Decipher Biopsy testing was performed as previously described.20 Briefly, Decipher testing utilizes a microarray platform to perform wholetranscriptome RNA expression analysis. Scores are derived from the expression of 22 genes. Decipher scores are a continuous variable reported on a scale of 0 to 1. These scores are then stratified to three risk categories: low (<0.45), intermediate (≥0.45–< 0.6), and high (≥0.6). In this study, Decipher scores were analyzed as an ordinal variable based on predefined risk categories (low, intermediate, and high) and also as a continuous variable. Use of both methods allows evaluation of Decipher scores associations across risk categories, and for every 0.1 increase in score.

Endpoints The primary endpoints for analysis were determined a priori. For men on AS, the primary endpoint was time to treatment (TTT), which was defined as time from Decipher Biopsy testing until radical therapy (i.e., radical prostatectomy or radiotherapy). For men that underwent radical therapy, the primary endpoint was time to treatment failure (TTF), defined from date of treatment completion until biochemical failure or receipt of salvage therapy. Treatment failure for patients undergoing prostatectomy was defined as PSA ≥0.2 ng/ml. For patients who received radiotherapy, treatment failure was defined in accordance with the Phoenix definition of biochemical failure (PSA rise of ≥2 ng/ml above the nadir).21 Salvage therapy included any form of oncologic therapy used for a patient with a detectable PSA after radical therapy, including salvage hormone therapy, radiotherapy, or other ablative therapies (e.g., cryotherapy) for prostate cancer.

Patients who received initial cryotherapy or androgen deprivation therapy alone were classified as “other” in our treatment stratification. Patients under this treatment class were included in our analysis to compare Decipher Biopsy scores to clinicopathologic variables; however, these patients were excluded from our time to event analyses. Patients who underwent definitive treatment without PSA follow-up data were also excluded from primary endpoint analyses.

Sensitivity analysis TTT for patients initially managed with AS was also analyzed where time zero was the date of initial diagnostic biopsy rather than at time of initial Decipher biopsy (index biopsy).

Statistical analysis Patient characteristics were compared between those with low/ intermediate Decipher scores and those with high Decipher scores based on previous analyses.22 Median Decipher scores were compared across NCCN risk groups, CAPRA risk groups, and Grade Groups using Wilcoxon tests, and violin plots were constructed. One minus Kaplan–Meier method was utilized for time-to-event analysis to generate cumulative incidence curves for duration on AS (TTT) and TTF. Multivariable Cox proportional hazards regression was performed to evaluate the association of Decipher scores with time on AS and time to failure following radical therapy. Variables included in multivariable models were selected a priori based on published literature23 and included age, NCCN risk category, Log PSA, Log prostate volume, body mass index, percent positive cores, and Decipher score. The TTF model additionally included treatment modality (i.e., RP vs. radiotherapy). Statistical analyses were performed in R version 3.6.2 (R Foundation, Vienna, Austria).24 All statistical tests were two-sided using a 5% significance level.

RESULTS

Patient characteristics The 855 patients in this cohort had a median age of 66 years (IQR 60–72 years). Patient characteristics are given in Table 1, and a breakdown of patient characteristics by Decipher risk category is given in Supplementary Table 1. A total of 641 (75%) patients were self-reported white and 112 (13%) were self-reported black race. At the time of diagnosis, the median PSA level was 5.9 ng/ml (IQR 4.4–8.9 ng/ml), and 83% of patients had cT1 or T2a disease at diagnosis. Also, 60% of patients had either Grade Group 1 or 2 disease at diagnosis. Of the 105 patients (12%) who were diagnosed with prostate cancer prior to their index Decipher biopsy, the median time from diagnostic biopsy to their index Decipher biopsy was 15.7 months (IQR 11.7–32.4 months). An analysis of all men diagnosed with prostate cancer in MUSIC during our study period, stratified by receipt of Decipher Biopsy testing, demonstrates men undergoing Decipher Biopsy testing were more likely to have intermediate-risk disease (p < 0.001; Supplementary Table 2).

Initial management was AS in 264 individuals (30.9%), RP in 236 (27.6%), and RT in 218 (25.5%). There were also 55 patients treated with primary ADT alone, 25 patients who underwent primary cryotherapy, and 66 patients classified as “other” who had no treatment recorded. For the patients initially managed on AS, 116 (44%) underwent subsequent primary treatment at a median of 15.2 months (IQR 8.0–22.5). For patients who stayed on AS, the median follow-up was 25.2 months (IQR 12.7–34.1). For patients who underwent RP (inclusive of those who were managed by AS prior to RP), pathologic characteristics are given in Supplementary Table 3. A total of 58 patients (18%) experienced treatment failure following RP, and the median time to failure was 6.4 months (IQR 4.3–9.6) after RP. Additionally, 10 (3.7%) patients experienced treatment failure following RT, and the median time to failure was 13.3 (IQR 4.0–22.0) months. Patients who underwent definitive treatment with no subsequent BCR had a median follow-up of 15.8 months (IQR 8.4–22.7).

Screen_Shot_2021-11-08_at_1.44.50_PM.png
AS active surveillance, BMI body mass index, EBRT external beam radiation therapy, IQR interquartile range, NCCN National Comprehensive Cancer Network, PSA prostate-specific antigen, RP radical prostatectomy.

Correlation of Decipher with clinical variables Decipher scores were assessed within biopsy Grade Group strata, and there was substantial variability of Decipher scores within each Grade Group (Fig. 1A). Overall, increasing Decipher score was correlated with increasing Grade Group (p < 0.001). This variability within standard clinical risk stratification categories was also observed when comparing Decipher scores according to NCCN risk group (p < 0.001, Fig. 1B) and CAPRA risk groups (p < 0.001, Fig. 1C).

Clinical utility of Decipher in active surveillance To assess the impact of Decipher score on length of time on AS, patients initially managed on AS were stratified according to Decipher risk category. A total of 241 patients were included in this analysis, with 23 patients being excluded due to incomplete follow-up data. In the cumulative incidence analysis, men with high-risk Decipher scores spent significantly less time on AS (median 13.6 months, IQR 3.5–24.9) than men with Decipher low/intermediate risk scores (median 33.0 months; p < 0.001) (Fig. 2). A repeat analysis assessing the differences between individual Decipher Biopsy risk groups (low, intermediate, and high) yields similar results (Supplementary Fig. 1). At the time of data collection greater than 25% of patients with Decipher low/ intermediate scores remained on AS, making the IQR unable to be reported. To evaluate patients initially managed on AS, we assessed grade group reclassification on subsequent biopsies for patients with NCCN low and favorable intermediate risk prostate cancer stratified by Decipher Biopsy risk (Supplementary Table 4). Among NCCN low-risk patients, reclassification was observed in 20/58 (34%) of patients with lower Decipher scores compared to 3/8 (38%) with high Decipher scores. Among NCCN favorable intermediate risk patients, reclassification was observed in 11/43 (26%) of patients with lower Decipher scores compared to 2/7 (29%) with high Decipher scores.

When analyzing Decipher scores as an ordinal variable on multivariable analysis, high-risk Decipher scores were associated with a significantly greater likelihood of undergoing definitive treatment (HR 2.51, 95% CI 1.52–4.13; p < 0.001, Table 2). Similar findings were observed when analyzing Decipher scores as a continuous variable (HR 1.20 per 0.1 unit score increase, 95% CI 1.07–1.35; p = 0.002, Supplementary Table 5).

Association of Decipher scores and time to treatment failure after radical therapy To assess the performance of Decipher scores in predicting treatment failure, we analyzed a total of 479 evaluable patients who underwent definitive treatment either initially or after a period of AS and had complete follow-up data. These patients were stratified into two categories: Decipher low/intermediate-risk and Decipher high-risk using the locked Decipher cut-points. Patients with high-risk Decipher scores had significantly shorter TTF than lower Decipher score patients (p = 0.007, Fig. 3). Similar results for TTF were demonstrated on repeat analysis assessing differences between low, intermediate, and high-risk Decipher Biopsy groups (Supplementary Fig. 2).

This finding held true on multivariable analysis, when Decipher scores were analyzed as an ordinal variable with a HR of 2.98 (95% CI 1.22–7.29, p = 0.01, Table 2). Similar results were observed when analyzing Decipher scores as a continuous variable, HR 1.26 (95% CI 1.02–1.544, p = 0.026, Supplementary Table 5).

DISCUSSION

Decipher initially received Molecular Diagnostic Services (MolDx) approval for Centers for Medicare and Medicaid Services coverage for use as a post-RP test to help with postoperative decision making. More recently, the Decipher Biopsy pretreatment test

PCAN_Nov_2.png
Fig. 1 Correlation of decipher biopsy with clinical variables. Violin plots showing the median and distribution of Decipher Biopsy scores for each pathologic grade group (A), NCCN risk strata (B), and CAPRA risk strata (C) (red dash line notates high-risk Decipher score cutpoint; blue dash line notates intermediate-risk Decipher score cutpoint). CAPRA Cancer of the Prostate Risk Assessment, NCCN National Comprehensive Cancer Network, Int. Fav favorable-intermediate risk, Int. Unfav. unfavorable-intermediate risk (Color figure online).

PCAN_Nov_3.png
Fig. 2 Cumulative Incidence plot comparing patients with high-risk Decipher scores to those with low/intermediate Decipher scores to analyze time to treatment failure from index biopsy

has been evaluated in multiple studies.16,25,26 These studies range from showing disease reclassification, change in management, and improved prognostication and discrimination in men with low-, intermediate-, and high-risk disease. Due to the accumulation of data across these risk strata, Decipher Biopsy recently received MolDx approval for localized prostate cancer in cases where the test may impact clinical decision-making. Despite prospective data supporting clinical utility in the post-RP setting, there are limited data describing utility in the biopsy setting. To date, there have been no prospective studies evaluating the use of Decipher Biopsy on common oncologic endpoints for early-stage disease. These intermediate endpoints (e.g., TTT and TTF), although unlikely to be formal statistical surrogate endpoints for overall survival, are clinically relevant as they trigger subsequent therapy.

PCAN_November.png
Decipher scores analyzed as ordinal variable. BMI body mass index, HR hazard ratio, NCCN National Comprehensive Cancer Network, Ordinal NCCN risk strata low, favorable intermediate, unfavorable intermediate, high, PSA prostate-specific antigen.

The present study addresses a current knowledge gap in the field of gene expression biomarkers. To date, there are multiple retrospective studies demonstrating that Decipher, Oncotype Dx, and Prolaris are prognostic in men with favorable-risk disease pretreatment. However, this is the first study performed on purely prospectively collected data analyzing Decipher in men on AS and following radical therapy, studying the performance in the intended use population. Our data reveal that men with high Decipher scores are more likely to receive radical therapy sooner by more than 1.5 years, and that men with high Decipher scores are over two-fold more likely to experience treatment failure after radical therapy. These data are consistent with prior retrospective studies supporting the prognostic performance of Decipher in newly diagnosed prostate cancer. Cooperberg et al. retrospectively analyzed 408 patients with low-risk prostate cancer using the Decipher microarray platform, which allows simultaneous assessment of a large number of molecular signatures.6 They demonstrated that the only independent predictor of biochemical recurrence after adjusting for CAPRA and PSA density was the average genomic risk score.

Recently, Lonergan et al. reported a retrospective analysis of men with early-stage prostate cancer managed by AS who had undergone either Decipher, Prolaris, or Oncotype DX testing. They pooled all patients together regardless of test used and dichotomized outcomes according to the high-risk vs. lower-risk threshold provided on the test report of each assay. On multivariable analysis, they demonstrated that high genomic risk score was independently associated with biopsy reclassification from GG1 to GG2 or higher at initial surveillance biopsy (HR 2.81, 95% CI 1.21–6.52) and 1–3 years after the initial biopsy (HR 2.02, 95% CI 1.16–3.54). Furthermore, a high genomic risk score was independently associated with reclassification at first surveillance biopsy to GG3 or higher cancer (HR 6.77, 95% CI 1.58–29.08). It is unclear whether grouping of various test thresholds provides a consistent risk estimate across these platforms.27 Notably, multiparametric MRI did not significantly predict for any of these endpoints.22

PCAN_fig_3.png
Fig. 3 Cumulative Incidence plot comparing patients with high-risk Decipher scores to those with low/intermediate Decipher score to analyze time to treatment failure from index biopsy.

Another key study assessing the performance of molecular classifiers in men with newly diagnosed favorable risk prostate cancer is the post hoc analysis from the Prostate Cancer Active Surveillance Study.28 This prospective observational cohort retrospectively evaluated tissue from initial prostate biopsy specimens and determined Oncotype Dx risk scores to measure its association with adverse surgical pathology. While this study included only 101 men, it demonstrated that the Oncotype Dx score was independently associated with time to development of adverse pathology when accounting only for GG. However, when also adjusting for PSA density the classifier did not reach statistical significance (HR 1.17 (95% CI 1.00–1.43), p = 0.06). This is in contrast to the current study that included nearly every prognostic variable for time on AS reported recently by Cooperberg et al., where Decipher score remained independently prognostic.23

Our group previously demonstrated that the use of gene expression classifiers are associated with patient and provider decision-making.27 The current data provide evidence of an association between baseline molecular classifier risk and duration of AS. Combined with prior studies, these data suggest that men with early-stage prostate cancer with a high Decipher score are more likely to rapidly transition off of AS and are more likely to recur after radical therapy. With growing understanding that early reclassification on AS is predominantly due to undersampling on initial diagnostic biopsy, these findings merit thoughtful assessment of risk prior to proceeding with AS in Decipher high-risk patients and further support the importance of early confirmatory testing.1

This study has limitations. The length of follow-up is relevant for the endpoints analyzed, but longer follow-up is needed to assess the impact of Decipher score on endpoints, such as time to metastasis. In addition, the data relating Decipher score to the duration on AS are insufficient to demonstrate a causal relationship, given the nature of this study. Also, we can not account for the influence receipt of ADT has on lower rates of TTF in patients who received radiation for definitive treatment. Collectively, however, this does not explain the independent association of Decipher scores and TTF. There is variability in how molecular classifiers are used among providers, and data on the cause of withdrawal from AS (e.g., due to progression vs. patient anxiety) are not collected in MUSIC. Despite these limitations, this prospectively tracked, multi-institutional cohort allows for an improved understanding of Decipher testing in everyday clinical practice.

CONCLUSION

In men with newly diagnosed prostate cancer, Decipher Biopsy score is independently associated with time on AS and TTF after radical therapy. The ongoing G-MAJOR clinical trial (NCT04396808) is assessing the use of molecular classifier testing in a prospective randomized trial in favorable risk prostate cancer to further establish the clinical utility of these tests.

Randy A. Vince Jr.,1,7 Ralph Jiang,2,7 Ji Qi,1 Jeffrey J. Tosoian,1 Rebecca Takele,3 Felix Y. Feng,4 Susan Linsell,1 Anna Johnson,1 Sughand Shetty,5 Patrick Hurley,5 David C. Miller,1 Arvin George,1 Khurshid Ghani,1 Fionna Sun,5 Mariana Seymore,1 Robert T. Dess,6 William C. Jackson,6 Matthew Schipper,2,6 Daniel E. Spratt,6,7 and Todd M. Morgan1,7

  1. Department of Urology, University of Michigan, Ann Arbor, MI, USA.
  2. Department of Biostatics, University of Michigan, Ann Arbor, MI, USA.
  3. Edward Via College of Osteopathic Medicine, Blacksburg, VA, USA.
  4. Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA.
  5. Oakland University William Beaumont School of Medicine, Auburn Hills, MI, USA.
  6. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
  7. These authors contributed equally: Randy A. Vince Jr., Ralph Jiang, Daniel E. Spratt, Todd M. Morgan

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Prostate Cancer and Prostatic Diseases; https://doi.org/10.1038/s41391-021-00428-y
Received: 23 March 2021 Revised: 4 June 2021 Accepted: 29 June 2021


Read an Editorial on this Article: Real-World Clinical Utility of Decipher Biopsy Testing in Localized Prostate Cancer