Patel Krishnan R, Nguyen Paul L, Proudfoot James A, Liu Yang, Pra Alan Dal, Spratt Daniel E, Pollack Alan, Sandler Howard M, Efstathiou Jason A, Lawton Colleen, Simko Jeffry P, Rosenthal Seth A, Zeitzer Kenneth L, Mendez Lucas C, Hartford Alan C, Hall William A, Desai Anand B, Pugh Stephanie L, Davicioni Elai, Tran Phuoc T, Feng Felix Y
Radiation Oncology Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
Brigham and Women's Hospital, Boston, MA, USA.
Eur Urol Oncol. 2024 Nov 13. doi: 10.1016/j.euo.2024.10.017.
Long-term (LT) androgen deprivation therapy (ADT) has been found to be beneficial to patients with high-risk prostate cancer (PCa). However, administration of LT-ADT to all patients with high-risk PCa may lead to overtreatment. Enhanced risk stratification using genomic classifiers (such as the recently developed prostate subtyping classifier [PSC]) might be useful. This study aims to characterize the prognostic and predictive ability of the PSC in patients with high-risk PCa undergoing radiotherapy long-term (LT; 24-28 mo) versus short-term (ST; 4 mo) ADT.
Biopsy samples from three randomized, phase 3 trials-NRG/RTOG 9202, 9413, and 9902-were classified as either PSC basal or luminal. The prognostic and predictive values of PSC for each oncologic endpoint (biochemical failure [BF], distant metastasis [DM], metastasis-free survival [MFS], PCa-specific mortality [PCSM], overall survival [OS]) and other cause-mortality (OCM) were assessed with Cox proportional hazards (MFS, OCM, and OS), Fine-Gray (BF, DM, and PCSM), and restricted mean survival time (RMST) models.
On a multivariable analysis, the basal subtype was found to have a worse prognosis for MFS (hazard ratio [HR] 1.8 [1.3-2.5], p < 0.001), PCSM (subdistribution HR 2.4 [95% confidence interval {CI} 1.4-4.1], p = 0.001), and OS (HR 1.8 [1.3-2.6], p < 0.001). Ten-year PCSM was 15% better for the luminal subtype than for the basal subtype (11% [95% CI 6-15%] vs 26% [95% CI 17-35%]). A significant interaction between ADT duration (LT vs ST) and PSC subtype (basal vs luminal) was observed for PCSM (p = 0.008), leading to the observation that 10-yr PCSM was improved with LT-ADT only in patients with basal-type tumors (5% [95% CI 0-11%] vs 42% [29-56%], p < 0.001). Improvements in 10-yr RMST with LT-ADT were greater for basal tumors for oncologic endpoints with the exception of OCM.
PSC is both a prognostic and a predictive biomarker for patients who benefit from LT-ADT. PSC subtypes may be used to personalize ADT recommendations for patients with high-risk PCa, pending further validation in a prospective study.
In this study, we tried to understand the usefulness of a new genomic test in patients with high-risk, nonmetastatic prostate cancer who underwent radiation therapy and hormonal therapy (HT). We found that this test can help determine a patient's prognosis (eg, a patient's chance of having the cancer return) and, more importantly, personalize treatment decisions by understanding which patients may benefit from long-term HT. This has the potential to save many patients who may not benefit from prolonged HT from "overtreatment" or the unnecessary side effects of such treatment.
长期雄激素剥夺治疗（ADT）已被证实对高危前列腺癌（PCa）患者有益。然而，对所有高危PCa患者进行长期ADT治疗可能会导致过度治疗。使用基因组分类器（如最近开发的前列腺亚型分类器[PSC]）加强风险分层可能会有所帮助。本研究旨在描述PSC在接受长期（LT；24 - 28个月）与短期（ST；4个月）ADT放疗的高危PCa患者中的预后和预测能力。
来自三项随机3期试验（NRG/RTOG 9202、9413和9902）的活检样本被分类为PSC基底型或管腔型。使用Cox比例风险模型（MFS、OCM和OS）、Fine - Gray模型（BF、DM和PCSM）和受限平均生存时间（RMST）模型评估PSC对每个肿瘤学终点（生化复发[BF]、远处转移[DM]、无转移生存期[MFS]、前列腺癌特异性死亡率[PCSM]、总生存期[OS]）和其他原因死亡率（OCM）的预后和预测价值。
在多变量分析中，发现基底型亚型在MFS（风险比[HR] 1.8 [1.3 - 2.5]，p < 0.001）、PCSM（亚分布HR 2.4 [95%置信区间{CI} 1.4 - 4.1]，p = 0.001）和OS（HR 1.8 [1.3 - 2.6]，p < 0.001）方面预后较差。管腔型亚型的10年PCSM比基底型亚型好15%（11% [95% CI 6 - 15%]对26% [95% CI 17 - 35%]）。对于PCSM，观察到ADT持续时间（LT与ST）和PSC亚型（基底型与管腔型）之间存在显著交互作用（p = 0.008），这导致观察到仅在基底型肿瘤患者中，长期ADT可改善10年PCSM（5% [95% CI 0 - 11%]对(42% [29 - 56%]，p < 0.001）。除OCM外，对于肿瘤学终点，基底型肿瘤在长期ADT下10年RMST的改善更大。
PSC既是接受长期ADT治疗患者的预后生物标志物，也是预测生物标志物。在进一步的前瞻性研究验证之前，PSC亚型可用于为高危PCa患者制定个性化的ADT建议。
在本研究中，我们试图了解一种新的基因组检测在接受放疗和激素治疗（HT）的高危、非转移性前列腺癌患者中的有用性。我们发现这种检测有助于确定患者的预后（例如，癌症复发的可能性），更重要的是，通过了解哪些患者可能从长期HT中获益来个性化治疗决策。这有可能使许多可能无法从延长HT中获益的患者避免“过度治疗”或此类治疗的不必要副作用。
