Personalized Prediction of Multimodal Treatment Benefit Using Genomic Testing
By: Jonathan Tward, MD, PhD, Huntsman Cancer Institute, University of Utah, Salt Lake City; Lauren Lenz, MS, Myriad Genetics, Inc., Salt Lake City, Utah; Alexander Gutin, PhD, Myriad Genetics, Inc., Salt Lake City, Utah; Wyatt Clegg, MS, Myriad Genetics, Inc., Salt Lake City, Utah; Chelsea R. Kasten, PhD, Myriad Genetics, Inc., Salt Lake City, Utah; Jeff Jasper, PhD, Myriad Genetics, Inc., Salt Lake City, Utah; Rob Finch, MS, CGC, Myriad Genetics, Inc., Salt Lake City, Utah; Todd Cohen, MD, Myriad Genetics, Inc., Salt Lake City, Utah | Posted on: 19 Sep 2023
Preventing metastasis is a critical goal of treatment in men diagnosed with prostate cancer. Clinical practice guidelines support adding androgen deprivation therapy (ADT) to radiation therapy (RT) in patients with unfavorable intermediate-risk or high-risk localized prostate cancer to reduce the risk of metastasis.1-3 These treatment guidelines are based on clinical trials that have shown treatment benefits for guideline-based cohorts of higher-risk patients.1-3 However, ADT is associated with a broad range of adverse effects4 that may impact a patient’s willingness to endure RT+ADT. The risks and benefits of treatment using RT+ADT can be evaluated by individual patients and their providers to develop a treatment plan. A systematic meta-analysis including individual patient data from 10,853 clinical trial participants found that addition of ADT to RT significantly improved metastasis-free survival in men with localized prostate cancer and that the treatment effects of ADT were not affected by RT dose, clinical risk group, or age.5 Therefore, tools are critically needed to predict the personalized absolute reduction in risk of metastasis from ADT added to RT while minimizing exposure to potential ADT side effects in patients who may not experience meaningful treatment benefit.
Genomic tests like Prolaris provide individualized information that may inform treatment decisions and improve the prognostic accuracy of risk assessment based on clinical disease markers alone.1-3 Prolaris provides a continuous clinical cell-cycle risk (CCR) score, which combines the clinical University of California, San Francisco’s Cancer of the Prostate Risk Assessment (CAPRA) with molecular markers of cell-cycle progression designed to determine cancer aggressiveness. The CCR score can inform the individual risk of developing metastatic disease and prostate cancer–specific mortality within 10 years in men with localized prostate cancer who have not received prior intervention.6-8 The CCR score includes validated thresholds to identify patients who are candidates for active surveillance, single-mode treatment, and multimodal treatment. Retrospective data have validated the Prolaris CCR score of 2.112 as a prognostic threshold for identifying patients who may be candidates for single-mode treatment rather than multimodal treatment.7,8 However, the value of the continuous CCR score for predicting individual absolute risk reduction from ADT added to RT had not been evaluated prior to this work.9
Our recent work has built upon a previous absolute risk reduction model,10 updated to determine the benefit of ADT added to RT5 for 10-year risk of metastasis as a function of the continuous Prolaris CCR score.9 The updated model was built using a retrospective cohort of men tested with Prolaris who received RT alone (N=467), and assumed a 41% relative reduction in risk of distant metastasis from ADT added to RT as estimated in a meta-analysis of ADT benefit.5 The updated model was then used to computationally derive absolute risk reduction and number needed to treat (NNT) for a set of commercially tested patients with CCR scores representative of the general population (N=56,485).9,10 The included patients were broadly representative of National Comprehensive Cancer Network risk categories and clinicopathological features.9
The addition of ADT to RT shifted the estimated 10-year risk of metastasis (Figure 1) and produced a broad range of absolute risk reduction and NNT across CCR scores (Figure 2). At the lowest end of the recommended multimodal treatment range, the absolute risk reduction from ADT added to RT was 3.7%, with the corresponding NNT =27 indicating that ADT added to RT would prevent metastasis within 10 years for 1 of every 27 treated men. The absolute risk reduction from ADT peaked at 19.2% near a CCR score of 4, corresponding to NNT =5. In the commercial cohort, the average absolute risk reduction was 0.86% in men under the CCR multimodal treatment threshold, corresponding to NNT =116. The average absolute risk reduction was 8.19% in men above the CCR multimodal treatment threshold, corresponding to NNT =12. These data reinforce that men under the multimodal treatment threshold, which comprised 87.3% of men in the commercial cohort,9 are unlikely to derive meaningful treatment benefit from adding ADT to RT.
Selecting cancer treatment modality involves understanding the patient’s goals and preferences, as well as weighing the risks of ADT4 against its benefits. Although RT+ADT is known to benefit patients and is recommended based on risk category,1-3,5 a balance of population-based risk knowledge against personalized risk estimates is needed. These recent data demonstrate that the personalized risk information provided by the CCR score can be used to inform individualized absolute risk reduction and NNT across a broad spectrum of actual risk,9 making it a useful tool for shared treatment decision-making between physicians and patients.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology—Prostate Cancer. Version 1.2023. Accessed June 22, 2023. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
- European Association of Urology. EAU Guidelines: Prostate Cancer. 2023. Accessed June 22, 2023. https://uroweb.org/guidelines/prostate-cancer/chapter/introduction
- Parker C, Castro E, Fizazi K, et al. Prostate cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(9):1119-1134.
- Nguyen PL, Alibhai SM, Basaria S, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol. 2015;67(5):825-836.
- 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. 2022;23(2):304-316.
- 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. 2019;75(3):515-522.
- 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. 2022;113(1):66-76.
- 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. 2021;19(4):296-304.e293.
- Tward JD, Lenz L, Gutin A, Clegg W, Finch R, Cohen T. Predicting absolute benefit in risk of metastasis of androgen deprivation therapy added to radiation therapy in patients with newly diagnosed prostate cancer using Prolaris. J Clin Oncol. 2023;41(16_suppl):5030.
- 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. 2019;(3):1-10.