LETTER Adjuvant vs. salvage Radiation Therapy after Radical Prostatectomy: Role of Decipher® in the Era of Personalized Medicine Ali Nowroozi1,2, Amirali Karimi1,2, Sanam Alilou1,2, Erfan Amini1* Prostate cancer (PCa) is the most common and the second cause of cancer-related deaths among men, with in-creasing incidence and burden, nationally and globally.(1,2) Radical prostatectomy (RP) has substantially influ- enced PCa management, providing excellent results in treating the patients.(3) However, likelihood of biochemical recurrence (BCR) remains high, especially in patients with adverse pathological features and these patients should receive postoperative adjuvant radiation therapy (ART) according to the guidelines. There are some uncertainties about receiving immediate ART after RP in men with adverse pathological features versus salvage radiation therapy (SRT) after BCR. Unlike ART, SRT provides time for urinary and sexual recov- ery, though it might be associated with undertreatment and risk of disease progression in a subset of patients. In the era of personalized medicine, molecular diagnosis has the potential to distinguish patients with higher risk of progression and metastasis who may benefit from ART. Decipher® (GenomeDx Biosciences) is a semi-quantitative genomic classifier (GC) with the potential to predict the risk of PCa metastasis after RP in men at high risk of recurrence. The test is based on gene-expression microar- ray analysis of 22 RNA biomarkers and produces scores ranging between 0 and 1. Results are also classified into low-risk, intermediate-risk, and high-risk groups (for scores < 0.45, between 0.45 and 0.6, and > 0.6, respectively). (3) The probability of recurrence at 10 years after RP has been reported to be 2.6% and 13.6% in men with low risk and high risk Decipher scores respectively.(3) Analyzing data from the Leuven and GRID cohorts also revealed that for every 10% growth in Decipher test score, 10-year metastasis odds increased 53% and 31%, respectively(4) Decipher has been found to be predictive of 5-year Prostate cancer-specific mortality (PCSM) rate. Mortality rates among men with low and intermediate Decipher scores were found to be 0%, compared to 9.4% for high-risk patients.(5) In a Recent meta-analysis,(6)10-year incidence of metastasis based on Decipher score in low-risk, intermediate-risk and high-risk patients were 5.5%, 15.0% and 26.7%, respectively. The National Comprehensive Cancer Network (NCCN) classifies intermediate-risk PCa patients into two favora- ble and unfavorable intermediate risk groups (FIR and UIR respectively). Although regression-free survival is statistically comparable between FIR and low risk (LR) groups, odds of adverse pathology in FIR patients is significantly higher compared to very low (VL) and LR men.(7) Therefore, it is yet to be determined whether wait- and-see followed by SRT is beneficial in the FIR group. Herlemann et al.(8) conducted a retrospective study on 647 patients who were classified as VL/LR (427, 66%) or FIR (220, 34%) risk groups. RP was their initial treatment and Decipher analysis was performed to assess if this genomic test can predict the presence of adverse pathology. FIR patients with low or intermediate risk Decipher scores demonstrated statistically same odds for harboring ad- verse pathology as NCCN VL/LR groups; however, adverse pathology was observed at significantly higher rates in Decipher high risk FIR patients compared to VL/LR groups (OR = 6.8, p < 0.001). One study in patients with low risk disease based on Decipher testing (score<0.4) showed that receiving SRT compared to ART is not associated with decline in 5-year metastasis free survival; however, ART decreased 5-year metastasis rate from 23% to 6% in patients with scores ≥ 0.4.(9) In order to better identify the appropriate treatment for each patient, Dalela et al.(10) proposed a novel scoring sys- tem (ranging 0-4) by merging genomic and histopathology data. Based on their nomogram, when patients with high Decipher scores and aggressive disease characteristics (overall score ≥ 2) received ART rather than SRT, an absolute decrease of 17.3% and 32% in clinical recurrence was noted, 5 and 10 years following RP, respectively. While proposing radiotherapy is aimed for PCa relapse prevention, short- and long-term side effects and complica- tions must be taken into account. Treatment-associated cost is also a salient criterion to consider in decision-mak- ing. In comparison with 100% adjuvant radiotherapy, Decipher engenders more QALYs and is more effective whilst being more cost-effective. Due to imperfect implementation of the guidelines (which suggest ART for all patients with adverse pathologic features), and subsequent diminished use of ART, Decipher-based treatment happens to be the superior side in QALY and outcomes of the patients, but more expensive than usual care. The incremental cost-effectiveness ratio (ICER) of GC-based care is $90,833 per QALY, which is within reasonable thresholds ($100,000 to $150,000).(11) Decipher has shown to be capable of predicting disease recurrence, metastasis and PCSM in multiple studies and 1Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran. 2School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. *Correspondence: Associate Professor of Urology, Department of Urology, Uro-Oncology Research Center, Tehran University of Medical Sciences. Tehran, Iran. Tel. +98 21 66903063, Fax: +98 21 66903063, . E-mail address: amini.erfan@gmail.com; e-amini@sina.tums.ac.ir Received October 2020 & Accepted November 2020 Urology Journal/Vol 18 No. 3/ May-June 2021/ pp. 349-350. [DOI: 10.22037/uj.v16i7.6526] has the potential to predict subgroup of patients who might benefit from ART after RP; however, further investigations are required to prove Decipher’s role in clinical outcome improvement in patients receiving De- cipher-based treatment compared with those receiving usual care. REFERENCES 1. Pishgar, F., et al., Global, Regional and National Burden of Prostate Cancer, 1990 to 2015: Results from the Global Burden of Disease Study 2015. J Urol, 2018. 199: p. 1224-32. 2. Basiri, A., et al., Incidence, Gleason Score and Ethnicity Pattern of Prostate Cancer in the Multi-ethnicity Country of Iran During 2008- 2010. Urol J, 2020. 3. Glass, A.G., et al., Validation of a Genomic Classifier for Predicting Post-Prostatectomy Recurrence in a Community Based Health Care Setting. J Urol, 2016. 195: p. 1748-53. 4. Van den Broeck, T., et al., Validation of the Decipher Test for Predicting Distant Metastatic Recurrence in Men with High-risk Nonmetastatic Prostate Cancer 10 Years After Surgery. Eur Urol Oncol, 2019. 2: p. 589-96. 5. Nguyen, P.L., et al., Ability of a Genomic Classifier to Predict Metastasis and Prostate Cancer-specific Mortality after Radiation or Surgery based on Needle Biopsy Specimens. Eur Urol, 2017. 72: p. 845-52. 6. Spratt, D.E., et al., Individual Patient-Level Meta-Analysis of the Performance of the Decipher Genomic Classifier in High- Risk Men After Prostatectomy to Predict Development of Metastatic Disease. J Clin Oncol, 2017. 35: p. 1991-8. 7. Aghazadeh, M.A., et al., National Comprehensive Cancer Network(R) Favorable Intermediate Risk Prostate Cancer-Is Active Surveillance Appropriate? J Urol, 2018. 199: p. 1196-201. 8. Herlemann, A., et al., Decipher identifies men with otherwise clinically favorable- intermediate risk disease who may not be good candidates for active surveillance. Prostate Cancer Prostatic Dis, 2019. 9. Den, R.B., et al., Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy. J Clin Oncol, 2015. 33: p. 944-51. 10. Dalela, D., et al., Genomic Classifier Augments the Role of Pathological Features in Identifying Optimal Candidates for Adjuvant Radiation Therapy in Patients With Prostate Cancer: Development and Internal Validation of a Multivariable Prognostic Model. J Clin Oncol, 2017. 35: p. 1982-90. 11. Lobo, J.M., et al., Cost-effectiveness of the Decipher Genomic Classifier to Guide Individualized Decisions for Early Radiation Therapy After Prostatectomy for Prostate Cancer. Clin Genitourin Cancer, 2017. 15: p. e299-e309. Letter 350