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JCO Precis Oncol
JCO Precis Oncol
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JCO Precision Oncology
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Wolters Kluwer Health

38748970
PO.23.00722
10.1200/PO.23.00722
00102
Original Reports
Biomarkers
Using the Cell-Cycle Risk Score to Predict the Benefit of Androgen-Deprivation Therapy Added to Radiation Therapy in Patients With Newly Diagnosed Prostate Cancer
https://orcid.org/0000-0001-7765-4473
Tward Jonathan D. MD, PhD 1
https://orcid.org/0000-0003-1957-1068
Lenz Lauren MS 2
Gutin Alexander PhD 2
Clegg Wyatt MS 2
https://orcid.org/0000-0002-6502-1051
Kasten Chelsea R. PhD 2
Finch Robert MS, CGC 2
Cohen Todd MD 2
https://orcid.org/0000-0003-0563-3766
Michalski Jeff MD 3
https://orcid.org/0000-0002-7437-6591
Kishan Amar U. MD 4
1 University of Utah, Salt Lake City, UT
2 Myriad Genetics, Salt Lake City, UT
3 Wash U St Louis, St. Louis, MO
4 UCLA, Los Angeles, CA
Jonathan D. Tward, MD, PhD; e-mail: jonathan.tward@hci.utah.edu.
2024
15 5 2024
15 5 2024
8 e230072226 12 2023
7 3 2024
21 3 2024
© 2024 by American Society of Clinical Oncology
2024
American Society of Clinical Oncology
https://creativecommons.org/licenses/by-nc-nd/4.0/ Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: http://creativecommons.org/licenses/by-nc-nd/4.0/

PURPOSE

Guidelines recommend adding androgen-deprivation therapy (ADT) to radiation therapy (RT) in certain patients with localized prostate cancer. Individualized genomic testing may improve the prognostic accuracy of risk assessments. Herein, we describe a mathematical model of the benefit of adding ADT to RT as a function of the personalized clinical cell-cycle risk (CCR) score to inform 10-year metastasis risk.

METHODS

A model of absolute risk reduction (ARR) was built using a retrospective cohort of men tested with Prolaris who received RT alone (N = 467). The relative benefit of ADT added to RT to reduce distant metastasis was estimated at 41% on the basis of a meta-analysis of randomized trials. The ARR and number needed to treat (NNT) were computationally derived in patients clinically tested with Prolaris between January 1, 2020, and October 31, 2022 (N = 56,485). Risks were predicted using a cause-specific Cox proportional hazards model with CCR score predicting time to metastasis. A CCR score of 2.112 represents the validated multimodal treatment (MMT) threshold.

RESULTS

The ARR from ADT increased from almost zero at low CCR scores to 17.1% at CCR = 3.690 with the corresponding NNT = 6, indicating that adding ADT to RT would prevent metastasis within 10 years for one of every six treated individuals. In the clinical cohort, the average ARR was 0.86% in individuals under the MMT threshold (NNT = 116). The average ARR was 8.19% in individuals above the MMT threshold (NNT = 12). Broad ranges of ADT benefit were observed within National Comprehensive Cancer Network risk categories.

CONCLUSION

The precise and personalized risk estimate of metastasis provided by the CCR score can help inform patients and physicians when considering treatment intensification.

CCR score predicts ADT benefit in prostate cancer therapy.

OPEN-ACCESSTRUE
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pmcINTRODUCTION

Approximately one third of patients diagnosed with localized prostate cancer receive radiation therapy (RT) as their primary treatment.1 Numerous studies have shown that adding androgen-deprivation therapy (ADT) to prostate-directed RT improves metastasis-free survival at the population level.2-7 Preventing metastasis is crucial, as metastasis-free survival is a reliable surrogate for overall survival.8 Additionally, individuals with metastatic prostate cancer often report poor overall quality of life (QOL).9

CONTEXT

Key Objective

Can the combined clinical risk score be used to provide a personalized risk estimate for metastasis risk reduction of adding androgen-deprivation therapy (ADT) to radiation.

Knowledge Generated

The cell-cycle risk score combined with hazard ratio reductions from randomized trials can provide highly accurate risk reduction estimates.

Relevance

Patients can use this test to determine whether intensifying treatment with ADT fits their care goals.

Expert guidelines suggest combining ADT with RT for unfavorable intermediate- and high-risk localized prostate cancer to reduce metastasis and death risk.10-14 However, ADT can cause adverse effects such as hot flashes, fatigue, sexual dysfunction, bone loss, cognitive changes, and cardiovascular risks, even in short courses (<1 year).15 These effects can persist longer than the prescribed therapy duration, affecting QOL.16-18

Patients and physicians can use measures such as the hazard ratio (HR), relative risk, absolute risk reduction (ARR), and number needed to treat (NNT) to compare therapies.19 These metrics are often calculated for different patient cohorts in randomized clinical trials. However, the benefit may vary for individuals within each risk group, and treatment decisions require understanding the patient's individual risks, goals, preferences, and willingness to undergo various therapies. For example, only 53% of patients with unfavorable intermediate-risk prostate cancer who received RT between 2004 and 2016 added ADT,20 although randomized trial data showed improved outcomes as early as 2002.21

An accurate prognostic estimate of the baseline risk is necessary to determine an individual's ARR. The combined clinical cell-cycle risk (CCR) score, which includes clinical components and a molecular cell-cycle progression (CCP) component, can be used to estimate the 10-year risk of metastatic disease and prostate cancer–specific mortality.22-24 Retrospective analyses have also shown the usefulness of CCR in identifying patients who may benefit more from multimodal therapy with RT + ADT.25,26

Knowledge of personalized ARR and NNT for RT + ADT can help patients understand risks and benefits of using combined modality therapy over RT alone and aid in making treatment intensification decisions. This study describes the derivation of personalized ARR and NNT when adding ADT to RT in individuals with localized prostate cancer.

METHODS

Data Sets

This study used two cohorts of male patients with prostate cancer who had undergone Prolaris testing (Myriad Genetics, Salt Lake City, UT), either clinically or through retrospective studies. The RT-alone cohort included 467 patients from two previously described and published, retrospective cohorts who were treated with RT alone as a single modality.25,26 The clinical cohort included 56,485 patients who underwent a clinical Prolaris biopsy test between January 1, 2020, and October 31, 2022. These patients were untreated at the time of biopsy used for testing, and their clinical follow-up, including treatment choices, is unknown. The test reports were limited to the first reported test per patient, with calculable disease-specific mortality and metastasis risk. Patients younger than 18 years at the time of testing were excluded. The clinical and molecular characteristics of the cohorts are summarized in Table 1. No demographic, clinical, or molecular data were missing from these cohorts.

TABLE 1. Clinical and Molecular Characteristics of Individuals With Prostate Cancer From the RT-Alone Cohort (N = 467) and the Clinical Cohort (N = 56,485)

Baseline Characteristic	RT-Alone Cohort (n = 467)	Clinical Cohort (n = 56,485)	
Patient age at diagnosis, years, median (IQR)	70 (64-76)	67 (62-72)	
Gleason score, No. (%)			
 <7	68 (14.6)	22,216 (39.3)	
 3 + 4	263 (56.3)	21,962 (38.9)	
 4 + 3	110 (23.6)	7,797 (13.8)	
 >7	26 (5.6)	4,510 (8.0)	
Percent positive scores, %, median (IQR)	33.3 (21.4-50.0)	25.0 (16.0-41.0)	
Clinical T stage, No. (%)			
 T1	285 (61.0)	50,437 (89.3)	
 T2	172 (36.8)	5,898 (10.4)	
 T3	10 (2.1)	150 (0.3)	
Diagnostic PSA, median (IQR)	7.0 (5.0-11.1)	6.2 (4.8-8.8)	
CAPRA, median (IQR)	4 (3-5)	3 (2-4)	
NCCN, No. (%)			
 Very low/low risk	0 (0)	19,013 (33.7)	
 Favorable intermediate risk	172 (36.8)	16,812 (29.8)	
 Unfavorable intermediate risk	254 (54.4)	14,453 (25.6)	
 High/very high risk	41 (8.8)	6,207 (11.0)	
CCP score, median (IQR)	0.3 (–0.2 to 0.8)	–0.5 (–1.0 to 0.0)	
CCR score, median (IQR)	1.617 (1.122-2.178)	0.771 (0.258-1.503)	
 Below MMT threshold, No. (%)	341 (73.0)	49,294 (87.3)	
 Above MMT threshold, No. (%)	126 (27.0)	7,191 (12.7)	
NOTE. There were no missing values for demographic, clinical, or molecular data.

Abbreviations: CAPRA, Cancer of the Prostate Risk Assessment; CCP, cell-cycle progression; CCR, cell-cycle risk; MMT, multimodal treatment; NCCN, National Comprehensive Cancer Network; PSA, prostate-specific antigen; RT, radiation therapy.

CCR Score

Prolaris testing was conducted at Myriad Genetics, Inc (Salt Lake City, UT) to generate the CCP score. This was done blinded to patient outcomes, as described previously.27-29 RNA extraction was performed using either miRNeasy (Qiagen, Redwood City, CA) or MagMAX (Thermo Fisher Scientific, Waltham, MA). The CCP score was calculated as the average expression of normalized CCP genes that were amplified using either TaqMan Low-Density Arrays (Applied Biosystems, Foster City, CA) or OpenArrays (Thermo Fisher Scientific). The CCR score was then calculated by combining the CCP molecular score with the University of California, San Francisco Cancer of the Prostate Risk Assessment score to produce the CCR score.30 The CCR score has been validated as a prognostic tool for determining risk of oncologic outcomes given active surveillance, single-mode therapy, or multimodal therapy.25,26

Statistical Methods

The ability of the CCR score to provide an estimate of the ARR from ADT added to RT was modeled on the basis of previous reports,31 as shown in Figure 1. First, the 10-year risk of metastasis with RT alone was modeled as a function of CCR score, rRT(CCR), in the RT-alone cohort (Fig 1A). The 10-year risk of metastasis in patients treated with RT + ADT was estimated by introducing a relative ADT benefit, HRADT, to the risk with RT alone according to a proportional hazards model (Fig 1B).rRT+ADT=1−(1−rRT)HRADT1

FIG 1. Overview of statistical methods to model ADT benefit as a function of CCR score. (A) Calculate risk of 10-year metastasis with RT alone. (B) Model risk of 10-year metastasis with RT + ADT. (C) Calculate absolute risk reduction because of ADT. ADT, androgen-deprivation therapy; CCR, cell-cycle risk; HR, hazard ratio; RT, radiation therapy.

HRADT is the HR for the benefit of ADT in the population, as modeled in The Meta-Analysis of Randomized Trials in Cancer of the Prostate, which used several prospectively randomized trials of RT alone compared with RT + ADT.32 In this meta-analysis, the overall reduction in distant metastasis was estimated to be 41%, with a 95% CI of 32 to 48 (HRADT, 0.59 [95% CI, 0.52 to 0.68]).32

The ARR of ADT added to RT was determined according to Equation 2 (Fig 1C).ARR=rRT−rRT+ADT2

Although there is no evidence of any dependence of the relative benefit of ADT (HRADT) on CCR scores, patients with higher CCR scores may benefit more from ADT than patients with low CCR scores. As a sensitivity analysis, a simple dependence of the relative benefit of ADT on CCR was introduced into the calculations as an interaction between the relative benefit of ADT and CCR (Appendix Fig A1).

CIs for the estimated rRT+ADT and ARR were generated through simulations. To do so, the risk for a given CCR score was randomly generated from a normal distribution centered at log(–log(rRT)) with the standard deviation equal to the SE of log(–log(rRT)). HRADT was randomly generated from a normal distribution centered at log(HRADT) with the standard deviation derived from the width of the CI on the log scale. The sampled rRT and HRADT were subsequently used to generate rRT+ADT, as described in Equation 1. When this simulation is repeated many times for each CCR score, the values at the 2.5th and 97.5th quantiles can be taken as 95% CIs for the estimated value of rRT+ADT for that CCR score. The difference between the randomly sampled rRT and rRT+ADT values, calculated using the randomly sampled rRT value, is the ARR. The 2.5th and 97.5th quantiles of the simulated distribution (composed of three million simulations) for the ARR for each CCR score were smoothed using Loess regression and taken as the 95% CIs for the absolute reduction in risk because of treatment with ADT for that CCR score.

The NNT was calculated as one divided by the ARR and rounded to the nearest whole number.

The distribution of CCR scores in the clinical cohort was used to approximate the distribution of CCR scores in the general population of patients with prostate cancer. The rRT, rRT+ADT, and ARR were calculated for each patient in the clinical cohort.

Ethics Approval Statement

The analysis described in this manuscript was performed using deidentified data obtained from previously institutional review board (IRB)–approved protocols and during the course of routine health care operations. Only aggregate data are presented in the manuscript. Therefore, this analysis did not meet the US Health and Human Services definition of research on human subjects (HHS 46.102) and did not require IRB approval.

RESULTS

The 10-year risk of metastasis with RT alone (rRT) was calculated in the RT-alone cohort (N = 467). Patients in the RT-alone cohort had a distribution of CCR scores with a fifth percentile of 0.543 and a 95th percentile of 3.072 (corresponding 10-year risk of metastasis with single-mode RT = 1.2% and 28.7%) and included the National Comprehensive Cancer Network (NCCN) favorable intermediate-risk, unfavorable intermediate-risk, and high-risk patients. More than a quarter (27.0%) of patients had CCR scores above the multimodal treatment (MMT) threshold (Table 1).

The risk of metastasis with RT + ADT (rRT+ADT) was calculated using rRT, and a relative benefit from ADT of 32%, 41%, and 48%, corresponding to the estimate and 95% confidence limits of HRADT published in Kishan et al32 (Fig 2). The estimated risk of metastasis with RT + ADT, assuming a relative benefit from ADT of 41%, is shown with simulated CIs in Figure 3. The corresponding ARR and NNT values are shown in Figure 4. The absolute reduction in the risk of metastasis from ADT was low at low CCR scores and increased to 17.1% at CCR = 3.690 (Fig 4). At very high CCR scores, the CIs for the estimated risk with RT alone became wider, making it difficult to accurately estimate the risk reduction with RT + ADT. Consequently, the risk and ARR were plotted for CCR scores below the 99th percentile of clinically tested patients (CCR ≤3.690). For patients with CCR scores above the 99th percentile (CCR >3.690), the risk of metastasis with RT alone is high enough to always warrant the use of multimodal treatment (Appendix Fig A2). Therefore, a personalized ARR estimate is not expected to provide clinically meaningful treatment guidance for patients with very high CCR scores.

FIG 2. Risk of metastasis as a function of CCR score in the RT-alone cohort compared with the mathematically derived risk with RT + ADT under different assumptions of relative benefit of ADT: 32%, 41%, and 48%. The vertical dashed line represents the multimodal treatment threshold at CCR = 2.112. The x-axis shows the range of CCR scores observed in 99% of clinically tested patients. ADT, androgen-deprivation therapy; CCR, cell-cycle risk; RT, radiation therapy.

FIG 3. Risk of metastasis as a function of CCR score in the RT-alone cohort compared with the mathematically derived risk with RT + ADT assuming a 41% relative benefit of ADT. The 95% CIs were simulated for the derived risk with RT + ADT. The dashed vertical line represents the multimodal treatment threshold at CCR = 2.112. The x-axis shows the range of CCR scores observed in 99% of clinically tested patients. ADT, androgen-deprivation therapy; CCR, cell-cycle risk; RT, radiation therapy.

FIG 4. The computationally derived absolute risk reduction from ADT added to RT with corresponding NNT as a function of CCR score, assuming a relative benefit of ADT of 41%, with simulated 95% CIs. The dashed vertical line represents the multimodal treatment threshold at CCR = 2.112. The x-axis shows the range of CCR scores observed in 99% of clinically tested patients. ADT, androgen-deprivation therapy; CCR, cell-cycle risk; NNT, number needed to treat; RT, radiation therapy.

The 10-year risk of metastasis with RT alone (rRT) at the MMT threshold (CCR = 2.112) was 9.2% (95% CI, 5.4 to 15.3). Assuming a relative benefit of ADT of 41%, the risk at the MMT threshold given RT + ADT (rRT+ADT) was 5.5% (95% CI, 3.2 to 9.5), corresponding to an ARR from ADT of 3.7% (95% CI, 2.1 to 6.2; NNT = 27; 95% CI, 16 to 48; Fig 4).

Risk estimates were also calculated for the clinical cohort (N = 56,485). The distribution of CCR scores had a fifth percentile of –0.351 and 95th percentile of 2.787, spanning all NCCN risk categories. Most patients in the clinical cohort had CCR scores at or below the MMT threshold (87.3%), whereas only 12.7% had CCR scores above the MMT threshold (Table 1). The 10-year risk of metastasis assuming RT alone was calculated for each patient in the clinical cohort. The risk of metastasis was summarized for the entire cohort and each NCCN risk group in Appendix Table A1. In NCCN unfavorable intermediate-risk patients, the fifth and 95th percentiles of individualized risk of metastasis with RT alone were 1.3% and 19.6%, respectively. The fifth and 95th percentiles of risk in NCCN high-risk patients were 2.6% and 66.2%, respectively. These distributions indicated that the risk of metastasis varied greatly, even within population-based risk groups (Appendix Fig A2). The 10-year risk of metastasis given RT + ADT was estimated for each patient, and the personalized ARR from ADT added to RT was calculated. Assuming a relative benefit of 41% for ADT, the average ARR below the MMT threshold was 0.86% (NNT = 116), whereas the average ARR above the MMT threshold was 8.19% (NNT = 12). A summary of the average ARRs and corresponding NNT values assuming relative benefits of 32%, 41%, and 48% are shown by the MMT threshold status in Table 2. Summaries of the average ARR and NNT values by NCCN category are shown in Appendix Table A2.

TABLE 2. Mean, fifth, and 95th Percentiles of the Distribution of ARR From ADT Added to RT in the Clinical Cohort for Patients Above and Below the MMT Threshold, Assuming Different Relative Benefits of ADT (32%, 41%, and 48%), and With Corresponding NNT

Relative Benefit	Below MMT Threshold, Mean (fifth percentile-95th percentile)	Above MMT Threshold, Mean (fifth percentile-95th percentile)	
ARR, %	NNT	ARR, %	NNT	
Thirty-two percent relative benefit of ADT	0.67 (0.12-2.06)	149 (833-49)	6.25 (3.05-13.22)	16 (33-8)	
Forty-one percent relative benefit of ADT	0.86 (0.16-2.64)	116 (625-38)	8.19 (3.92-17.94)	12 (26-6)	
Forty-eight percent relative benefit of ADT	1.01 (0.18-3.10)	99 (556-32)	9.75 (4.61-21.78)	10 (22-5)	
Abbreviations: ADT, androgen-deprivation therapy; ARR, absolute risk reduction; MMT, multimodal treatment; NNT, number needed to treat; RT, radiation therapy.

In the sensitivity analysis, the dependence of the relative benefit of ADT on CCR was introduced into the calculations as an interaction between the relative benefit of ADT and CCR. The maximal interaction strength was calculated assuming a patient's relative benefit from ADT was 0 at the lowest possible CCR score while maintaining the overall HRADT value at 0.59. HRADT as a function of the CCR score was then calculated with the maximal interaction strength and 50% maximal interaction strength (Appendix Fig A3). For higher CCR scores, the rRT+ADT values calculated with these RT + ADT interaction strengths were lower than those calculated in the absence of an interaction. For lower CCR scores, there was no substantial difference when RT + ADT interactions were included in the calculation (Appendix Fig A4). Although the interaction resulted in more extreme differences in ARR and NNT by MMT threshold status, the outcomes were not significantly different from conservatively assuming no interaction between the relative benefit of ADT and CCR score (Appendix Fig A5 and Table A3).

DISCUSSION

As personalized risk estimators become more widely available, it is unclear how patient-level precision medicine approaches can be reconciled with population-level therapeutic options. This study modeled the personalized ARR of adding ADT to RT for prostate cancer using a relative risk reduction from prospective randomized trials. The CCR score provided personalized risk information and our model showed that those with scores above the Prolaris MMT threshold benefit more from combined treatment. The model revealed that adding ADT to RT would prevent metastasis within 10 years for one in 12 individuals with above-threshold scores, whereas only one in 116 individuals with below-threshold scores would benefit from the treatment.

We drew upon the meta-analysis by Kishan et al,32 which demonstrated that adding ADT to RT reduces metastasis risk regardless of NCCN risk group, age, and radiotherapy dose. Although the magnitude of the benefit varies, they recommended shared decision making between doctors and patients because of ADT's potential toxicity. To address this critical need, we quantified how adding ADT to RT reduces the risk of metastasis in individual patients by applying the meta-analysis results32 to personalized risk estimates derived from the CCR score, which combines molecular and clinical prognostic information.22-26,29,30,33-35 The results of the current study revealed that the CCR score can inform personalized ARR because of treatment with ADT, with a substantially reduced 10-year risk of metastasis predicted in those above the Prolaris MMT threshold. This methodology can be applied to any validated nomogram or biomarker that produces an individual risk estimate for metastasis. However, nomogram or biomarker risk estimates must be calibrated exclusively for a population treated with RT and without ADT.

Additionally, personalized risk estimates can address inherent issues with population-based risk cohorts used in guidelines or clinical trial criteria. These cohorts represent a broad spectrum of actual risks, with patients who may experience vastly different levels of ARR. For example, data from Radiation Therapy Oncology Group (RTOG) 0126 evaluated dose escalation using RT alone in patients with D'Amico/NCCN-classified intermediate-risk disease.36,37 At the trial population level, patients enrolled in RTOG 0126 had a 95% CI for the 10-year risk of metastasis between 3% and 9%.38 Validated personalized risk estimators on the basis of CCR scores of those with unfavorable intermediate-risk disease in our clinically tested cohort placed the median individual risk at 4.6%, within the RTOG 0126 range. However, individuals categorized as having unfavorable intermediate disease had patient-level estimated risks that varied between 0.2% and 67.9% when the CCR score was used as a personalized risk estimator, and high-risk individuals varied from 0.5% to >99% (Appendix Table A1). Assuming a 41% relative ADT benefit, the average ARR was 2.63% in unfavorable intermediate-risk individuals and 7.06% in high-risk individuals, corresponding to respective NNTs of 38 and 14 (Appendix Table A2). These results suggest that those who are recommended to receive RT + ADT on the basis of current guidelines39 may experience a range of benefits from RT + ADT, thereby highlighting the importance of considering individual risk factors when making treatment decisions.

Using this method, patients can learn their personalized ARR from adding ADT to RT. This ARR can also be reported as an NNT, representing the number of patients needed to treat with ADT to prevent metastasis for one patient. Expert physicians treating genitourinary malignancies and the general public lack a consistent individual threshold for adding ADT to RT, assuming they were choosing for themselves. Some would accept the therapy with a 1% ARR at 10 years, whereas others would require a benefit of at least 10% before accepting RT + ADT over RT alone.40 Most people would need an ARR of more than 4%,40 which is close to the risk reduction at the MMT threshold proposed in previous studies using the CCR score.25,26,40 In this study, individuals below the MMT threshold had an average ARR of only 0.86%, whereas those above the threshold had an average ARR of 8.19%. The average ARR observed in those above the MMT threshold was even higher than the 7.06% average ARR observed in the NCCN high-risk subset of the cohort, demonstrating the utility of the CCR score in predicting the benefit of adding ADT to RT.

Our study's strength lies in estimating personalized risks using the biomarker (CCR score) in patients treated with RT alone, and determining ARR from adding ADT to RT on the basis of evidence from prospectively randomized trials. The limitations are that the risk estimates with RT alone were derived from retrospective data sets,25,26 although the RT-alone cohort used to build the estimates had similar clinical characteristics and produced similar risk estimates to the prospective RTOG 0126 cohort.36,41 Only 8.8% of the RT-alone cohort had NCCN high-risk or very high-risk prostate cancer; therefore, decisions to limit ADT in this subgroup should be approached with caution. The retrospective data set also produced wide CIs for the top 1% of clinically observed CCR scores. Additionally, the analysis assumes that the relationship between CCR score and ADT responsiveness is constant. It is possible that the benefit of ADT varies with the value of the biomarker. However, this effect was modeled by including the interaction between ADT and CCR, which indicates that biomarker-dependent effects on estimates of the relative benefit of ADT would be insubstantial (Appendix Table A3). Finally, the impact of race or ancestry on estimates of the risk and benefit of ADT was not explored in our data set or the meta-analysis used to estimate the relative benefit of ADT used in this study.32 It is unclear how the score’s performance may vary across different demographic groups, which may limit its utility and accuracy. However, the CCP score has been tested in African American populations, where it demonstrated that African American men have similar prostate cancer outcomes to non-African American patients after accounting for CCP and clinicopathologic variables.22 External validation using additional independent data sets could continue to refine the model and potentially be able to account for the effect different patient populations, treatment settings, and health care systems.

The CCR score provides a precise and personalized risk estimate of metastasis, calibrated in a population treated with RT alone. Therefore, a patient and their physician considering RT for localized prostate cancer would know precisely how intensifying treatment with ADT might affect oncologic outcomes when weighed against its toxicities. By understanding the ARR and NNT for their case, patients can make a risk-based assessment compatible with their personal goals, instead of a strictly guideline-concordant recommendation predicated on expert physician judgment.

PRIOR PRESENTATION

SUPPORT

DATA SHARING STATEMENT

The data analyzed during the current study are not publicly available because of patient privacy but are available from the corresponding author on reasonable request.

AUTHOR CONTRIBUTIONS

Conception and design: Jonathan D. Tward, Lauren Lenz, Alexander Gutin, Wyatt Clegg, Chelsea R. Kasten, Robert Finch, Amar U. Kishan

Provision of study materials or patients: Jonathan D. Tward

Collection and assembly of data: Lauren Lenz, Alexander Gutin, Wyatt Clegg, Chelsea R. Kasten, Robert Finch, Todd Cohen, Jeff Michalski

Data analysis and interpretation: Jonathan D. Tward, Lauren Lenz, Alexander Gutin, Wyatt Clegg, Chelsea R. Kasten, Robert Finch, Todd Cohen, Jeff Michalski, Amar U. Kishan

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

APPENDIX

FIG A1. Overview of statistical methods to model ADT benefit as a function of CCR score. (A) Calculate risk of 10-year metastasis with RT alone. (B) Model risk of 10-year metastasis with RT + ADT, including an interaction between the benefit of ADT and CCR score. (C) Calculate absolute risk reduction because of ADT. ADT, androgen-deprivation therapy; CCR, cell-cycle risk; HR, hazard ratio; RT, radiation therapy.

FIG A2. Predicted 10-year risk of metastasis given RT alone for patients in the clinical cohort by NCCN risk category. CCR, cell-cycle risk; NCCN, National Comprehensive Cancer Network; RT, radiation therapy.

FIG A3. Patient benefit from ADT (HRADT) according to CCR score with no interaction (β = 0), 50% maximum interaction strength (β = 0.1199929), and maximum interaction strength (β = 0.2399858). ADT, androgen-deprivation therapy; CCR, cell-cycle risk; HR, hazard ratio.

FIG A4. Risk of metastasis with simulated 95% CIs as a function of CCR score for different interaction strengths and assuming a relative benefit of ADT of 41%. The dashed vertical line represents the multimodal treatment threshold at CCR = 2.112. The x-axis shows the range of CCR scores observed in 99% of clinically tested patients. (A) RT ± ADT with no interaction. (B) RT ± ADT assuming a 50% of maximum interaction. (C) RT ± ADT with maximum interaction. ADT, androgen-deprivation therapy; CCR, cell-cycle risk; RT, radiation therapy.

FIG A5. Absolute risk reduction from ADT added to RT as a function of CCR score for different interaction strengths and assuming a relative benefit of ADT of 41%, shown with simulated 95% CIs and corresponding NNT values. The dashed vertical line represents the multimodal treatment threshold at CCR = 2.112. The x-axis shows the range of CCR scores observed in 99% of clinically tested patients. (A) RT ± ADT with no interaction. (B) RT ± ADT assuming a 50% of maximum interaction. (C) RT ± ADT with maximum interaction. ADT, androgen-deprivation therapy; ARR, absolute risk reduction; CCR, cell-cycle risk; NNT, number needed to treat; RT, radiation therapy.

TABLE A1. Distributions of Estimated 10-Year Risk of Metastasis Given RT Alone in the Clinical Cohort, Summarized by NCCN Risk Group and in the Full Cohort

NCCN Risk Group	No.	Min, %	Fifth Quantile, %	25th Quantile, %	Median, %	75th Quantile, %	95th Quantile, %	Max, %	
Low	19,013	0.1	0.3	0.5	0.7	1.1	2.1	28.3	
Favorable intermediate	16,812	0.2	0.6	1.0	1.5	2.3	4.3	29.5	
Unfavorable intermediate	14,453	0.2	1.3	2.6	4.6	8.6	19.6	67.9	
High	6,207	0.5	2.6	6.9	13.8	28.9	66.2	>99	
Overall cohort	56,485	0.1	0.4	0.9	1.7	4.3	20.8	>99	
Abbreviations: NCCN, National Comprehensive Cancer Network; RT, radiation therapy.

TABLE A2. Mean, Fifth, and 95th Percentiles of the Distribution of ARR From ADT Added to RT in the Clinical Cohort for Patients Separated by NCCN Category, Assuming Different Relative Benefits of ADT (32%, 41%, and 48%), and With Corresponding NNT

Relative Benefit	ARR, %	NNT, Persons	
Thirty-two percent relative benefit of ADT			
 Low	0.28 (0.09-0.66)	357 (1,111-152)	
 Favorable intermediate	0.59 (0.19-1.34)	169 (526-75)	
 Unfavorable intermediate	2.04 (0.42-5.82)	49 (238-17)	
 High	5.37 (0.81-13.44)	19 (123-7)	
Forty-one percent relative benefit of ADT			
 Low	0.36 (0.12-0.84)	278 (833-119)	
 Favorable intermediate	0.76 (0.24-1.73)	132 (417-58)	
 Unfavorable intermediate	2.63 (0.54-7.54)	38 (185-13)	
 High	7.06 (1.04-18.07)	14 (96-6)	
Forty-eight percent relative benefit of ADT			
 Low	0.43 (0.14-0.99)	233 (714-101)	
 Favorable intermediate	0.89 (0.29-2.02)	112 (335-50)	
 Unfavorable intermediate	3.09 (0.63-8.89)	32 (159-11)	
 High	8.43 (1.22-22.23)	12 (82-4)	
Abbreviations: ADT, androgen-deprivation therapy; ARR, absolute risk reduction; NCCN, National Comprehensive Cancer Network; NNT, number needed to treat; RT, radiation therapy.

TABLE A3. Mean ARR From ADT and Corresponding NNT for Patients Above and Below the MMT Threshold Assuming Different Overall Relative Benefits of ADT (32%, 41%, and 48%) and Interaction Strengths Between CCR and ADT Benefit (no interaction, 50% of the maximum interaction, and maximum interaction)

Relative Benefit	Below MMT Threshold	Above MMT Threshold	
ARR, %	NNT	ARR, %	NNT	
Thirty-two percent relative benefit of ADT					
 No interaction between CCR and ADT benefit	0.67	149	6.25	16	
 50% of maximum interaction between CCR and ADT benefit	0.71	141	8.79	11	
 Maximum interaction between CCR and ADT benefit	0.74	135	11.06	9	
Forty-one percent relative benefit of ADT					
 No interaction between CCR and ADT benefit	0.86	116	8.19	12	
 50% of maximum interaction between CCR and ADT benefit	0.90	111	11.30	9	
 Maximum interaction between CCR and ADT benefit	0.94	107	13.92	7	
Forty-eight percent relative benefit of ADT					
 No interaction between CCR and ADT benefit	1.01	99	9.75	10	
 50% of maximum interaction between CCR and ADT benefit	1.06	94	13.24	8	
 Maximum interaction between CCR and ADT benefit	1.09	92	15.98	6	
Abbreviations: ADT, androgen-deprivation therapy; ARR, absolute risk reduction; CCR, cell-cycle risk; MMT, multimodal treatment; NNT, number needed to treat; RT, radiation therapy.

Presented at the American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 2-6, 2023.

Supported by Myriad Genetic Laboratories, Salt Lake City, UT, who funded the analyses.

Jonathan D. Tward

Honoraria: Bayer

Consulting or Advisory Role: Myriad Genetics, Blue Earth Diagnostics, Janssen Scientific Affairs, Merck, Bayer, Boston Scientific, Myovant Sciences, Lantheus Medical Imaging

Research Funding: Bayer (Inst), Myriad Genetics (Inst)

Expert Testimony: Expert Consulting Services

Travel, Accommodations, Expenses: Myriad Genetics, Bayer

Lauren Lenz

Employment: Myriad Genetics

Stock and Other Ownership Interests: Myriad Genetics

Alexander Gutin

Employment: Myriad Genetics

Stock and Other Ownership Interests: Myriad Genetics

Consulting or Advisory Role: DermTech

Wyatt Clegg

Employment: Myriad Genetics Genetic Laboratories, Inc

Stock and Other Ownership Interests: Myriad Genetics Medical Laboratories, Inc

Chelsea R. Kasten

Employment: Myriad Genetics

Stock and Other Ownership Interests: Myriad Genetics

Consulting or Advisory Role: Roche

Travel, Accommodations, Expenses: Myriad Genetics

Robert Finch

Employment: Myriad Genetic Laboratories

Stock and Other Ownership Interests: Myriad Genetic Laboratories

Travel, Accommodations, Expenses: Myriad Genetic Laboratories

Todd Cohen

Employment: Blue Earth Diagnostics, Myovant Sciences

Stock and Other Ownership Interests: Lilly, Nov Nordisk

Consulting or Advisory Role: Myriad Genetics

Jeff Michalski

Leadership: American Society of Therapeutic Radiation Oncology

Travel, Accommodations, Expenses: American Society of Therapeutic Radiation Oncology

Open Payments Link: https://openpaymentsdata.cms.gov/physician/221723

Amar U. Kishan

Stock and Other Ownership Interests: ViewRay

Honoraria: Varian Medical Systems, ViewRay, Boston Scientific, Janssen Oncology

Consulting or Advisory Role: Janssen, Boston Scientific

Research Funding: ViewRay, Janssen Oncology (Inst), Point Biopharma (Inst)

No other potential conflicts of interest were reported.
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REFERENCES

1. Scherzer ND , DiBiase ZS , Srivastav SK , et al : Regional differences in the treatment of localized prostate cancer: An analysis of surgery and radiation utilization in the United States. Adv Radiat Oncol 4 :331-336, 2019 31011678
2. Bolla M , Maingon P , Carrie C , et al : Short androgen suppression and radiation dose escalation for intermediate- and high-risk localized prostate cancer: Results of EORTC trial 22991. J Clin Oncol 34 :1748-1756, 2016 26976418
3. Bolla M , Van Tienhoven G , Warde P , et al : External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 11 :1066-1073, 2010 20933466
4. Denham JW , Steigler A , Lamb DS , et al : Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial. Lancet Oncol 12 :451-459, 2011 21440505
5. Jones CU , Hunt D , McGowan DG , et al : Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med 365 :107-118, 2011 21751904
6. Nabid A , Carrier N , Vigneault E , et al : Androgen deprivation therapy and radiotherapy in intermediate-risk prostate cancer: A randomised phase III trial. Eur J Cancer 143 :64-74, 2021 33279855
7. Roach M , Bae K , Speight J , et al : Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: Long-term results of RTOG 8610. J Clin Oncol 26 :585-591, 2008 18172188
8. Xie W , Regan MM , Buyse M , et al : Metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer. J Clin Oncol 35 :3097-3104, 2017 28796587
9. Holm M , Doveson S , Lindqvist O , et al : Quality of life in men with metastatic prostate cancer in their final years before death—A retrospective analysis of prospective data. BMC Palliat Care 17 :126, 2018 30509249
10. Shill DK , Roobol MJ , Ehdaie B , et al : Active surveillance for prostate cancer. Transl Androl Urol 10 :2809-2819, 2021 34295763
11. Mottet N , van den Bergh RCN , Briers E , et al : EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate cancer-2020 update. Part 1: Screening, diagnosis, and local treatment with curative intent. Eur Urol 79 :243-262, 2021 33172724
12. Mottet N , Conford P , van den Bergh RCN , et al : EAU-ESTRO-ESUR-SIOG Guidelines on prostate cancer. Presented at the EAU Annual Congress Amsterdam, EAU Guidelines Office, Arnhem, the Netherlands, July 17-26, 2020
13. Bekelman JE , Rumble RB , Chen RC , et al : Clinically localized prostate cancer: ASCO Clinical Practice Guideline endorsement of an American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology guideline. J Clin Oncol 36 :3251-3258, 2018 30183466
14. Parker C , Castro E , Fizazi K , et al : Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 31 :1119-1134, 2020 32593798
15. Nguyen PL , Alibhai SM , Basaria S , et al : Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol 67 :825-836, 2015 25097095
16. Gay HA , Michalski JM , Hamstra DA , et al : Neoadjuvant androgen deprivation therapy leads to immediate impairment of vitality/hormonal and sexual quality of life: Results of a multicenter prospective study. Urology 82 :1363-1368, 2013 24139340
17. Gay HA , Sanda MG , Liu J , et al : External beam radiation therapy or brachytherapy with or without short-course neoadjuvant androgen deprivation therapy: Results of a multicenter, prospective study of quality of life. Int J Radiat Oncol Biol Phys 98 :304-317, 2017 28463150
18. Movsas B , Rodgers JP , Elshaikh MA , et al : Dose-escalated radiation alone or in combination with short-term total androgen suppression for intermediate-risk prostate cancer: Patient-reported outcomes from NRG/Radiation Therapy Oncology Group 0815 randomized trial. J Clin Oncol 41 :3217-3224, 2023 37104723
19. Laupacis A , Sackett DL , Roberts RS : An assessment of clinically useful measures of the consequences of treatment. N Engl J Med 318 :1728-1733, 1988 3374545
20. Agrawal V , Ma X , Hu JC , et al : Trends in androgen deprivation use in men with intermediate-risk prostate cancer who underwent radiation therapy. Adv Radiat Oncol 7 :100904, 2022 35814856
21. Bolla M , Collette L , Blank L , et al : Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): A phase III randomised trial. Lancet 360 :103-106, 2002 12126818
22. Canter DJ , Reid J , Latsis M , et al : Comparison of the prognostic utility of the cell cycle progression score for predicting clinical outcomes in African American and non-African American men with localized prostate cancer. Eur Urol 75 :515-522, 2019 30391079
23. Canter DJ , Freedland S , Rajamani S , et al : Analysis of the prognostic utility of the cell cycle progression (CCP) score generated from needle biopsy in men treated with definitive therapy. Prostate Cancer Prostatic Dis 23 :102-107, 2020 31243337
24. Cuzick J , Stone S , Fisher G , et al : Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort. Br J Cancer 113 :382-389, 2015 26103570
25. Tward JD , Schlomm T , Bardot S , et al : Personalizing localized prostate cancer: Validation of a combined clinical cell-cycle risk (CCR) score threshold for prognosticating benefit from multimodality therapy. Clin Genitourin Cancer 19 :296-304.e3, 2021 33608228
26. Tward J , Lenz L , Flake DD II , et al : The clinical cell-cycle risk (CCR) score is associated with metastasis after radiation therapy and provides guidance on when to forgo combined androgen deprivation therapy with dose-escalated radiation. Int J Radiat Oncol Biol Phys 113 :66-76, 2022 34610388
27. Cuzick J , Swanson GP , Fisher G , et al : Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: A retrospective study. Lancet Oncol 12 :245-255, 2011 21310658
28. Cuzick JM , Stone S , Lenz L , et al : Validation of the cell cycle progression score to differentiate indolent from aggressive prostate cancer in men diagnosed through transurethral resection of the prostate biopsy. Cancer Rep (Hoboken) 5 :e1535, 2022 34423592
29. Julia E MBW , Reid J , Brown K , et al : Analytical validation of a cell cycle progression signature used as a prognostic marker in prostate cancer. J Mol Biomarkers Diagn 6 :1-5, 2015
30. Brawer MK , Cooperberg MR , Freedland SJ , et al : Development and validation of a mutivariate model combining cell cycle progression score with CAPRA to predict prostate cancer mortality in a conservatively managed cohort. J Clin Oncol 31 , 2013 (suppl 6; abstr 67)
31. Soliman H , Flake DD , Magliocco A , et al : Predicting expected absolute chemotherapy treatment benefit in women with early-stage breast cancer using EndoPredict, an integrated 12-gene clinicomolecular assay. JCO Precis Oncol 10.1200/PO.18.00361
32. Kishan AU , Sun Y , Hartman H , et al : Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: An individual patient data meta-analysis. Lancet Oncol 23 :304-316, 2022 35051385
33. Kaul S , Wojno KJ , Stone S , et al : Clinical outcomes in men with prostate cancer who selected active surveillance using a clinical cell-cycle risk score. Per Med 16 :491-499, 2019 31483217
34. Koch MO , Cho JS , Kaimakliotis HZ , et al : Use of the cell cycle progression (CCP) score for predicting systemic disease and response to radiation of biochemical recurrence. Cancer Biomark 17 :83-88, 2016 27314296
35. Lin DW , Crawford ED , Keane T , et al : Identification of men with low-risk biopsy-confirmed prostate cancer as candidates for active surveillance. Urol Oncol 36 :310.e7-310.e13, 2018
36. Michalski JM , Moughan J , Purdy J , et al : Effect of standard vs dose-escalated radiation therapy for patients with intermediate-risk prostate cancer: The NRG Oncology RTOG 0126 randomized clinical trial. JAMA Oncol 4 :e180039, 2018 29543933
37. D'Amico AV , Whittington R , Malkowicz SB , et al : Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 280 :969-974, 1998 9749478
38. Michalski JM , Moughan J , Purdy JA , et al : Long-term outcomes of NRG/RTOG 0126, a randomized trial of high dose (79.2 Gy) vs. standard dose (70.2 Gy) radiation therapy (RT) for men with localized prostate cancer. Int J Radiat Oncol Biol Phys 117 :S4-S5, 2023
39. NCCN Clinical Practice Guidelines in Oncology—Prostate cancer, version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
40. Spratt DE , Tward JD : Absolute versus relative benefit of androgen deprivation therapy for prostate cancer: Moving beyond the hazard ratio to personalize therapy. Int J Radiat Oncol Biol Phys 108 :899-902, 2020 32928598
41. Hall WA , Deshmukh S , Bruner DW , et al : Quality of life implications of dose-escalated external beam radiation for localized prostate cancer: Results of a prospective randomized phase 3 clinical trial, NRG/RTOG 0126. Int J Radiat Oncol Biol Phys 112 :83-92, 2022 34919884
