Abstract：
BACKGROUND: Salvage radiation therapy (SRT) is a mainstay of treatment for biochemical relapse following radical prostatectomy; however, few studies have examined genomic biomarkers in this context.
OBJECTIVE: We characterized the prognostic impact of previously identified deleterious molecular phenotypes-loss of PTEN, ERG expression, and TP53 mutation-for patients undergoing SRT.
METHODS: We leveraged an institutional database of 320 SRT patients with available tissue and follow-up. Tissue microarrays were used for genetically validated immunohistochemistry assays.
METHODS: All men underwent SRT with or without androgen deprivation therapy OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariable and multivariable Cox-proportional hazard models assessed the association of molecular phenotypes with biochemical recurrence-free (bRFS) and metastasis-free (MFS) survival after SRT.
CONCLUSIONS: Loss of PTEN (n = 123, 43%) and ERG expression (n = 118, 39%) were common in this cohort, while p53 overexpression (signifying TP53 missense mutation) was infrequent (n = 21, 7%). In univariable analyses, any loss of PTEN portended worse bRFS (hazard ratio [HR] 1.86; 95% confidence interval 1.36-2.57) and MFS (HR 1.89; 1.21-2.94), with homogeneous PTEN loss being associated with the highest risk of MFS (HR 2.47; 1.54-3.95). Similarly, p53 overexpression predicted worse bRFS (HR 1.95; 1.14-3.32) and MFS (HR 2.79; 1.50-5.19). ERG expression was associated with worse MFS only (HR 1.6; 1.03-2.48). On the multivariable analysis adjusting for known prognostic features, homogeneous PTEN loss remained predictive of adverse bRFS (HR 1.82; 1.12-2.96) and MFS (HR 2.08; 1.06-4.86). The study is limited by its retrospective and single-institution design.
CONCLUSIONS: PTEN loss by immunohistochemistry is an independent adverse prognostic factor for bRFS and MFS in prostate cancer patients treated with SRT. Future trials will determine the optimal approach to treating SRT patients with adverse molecular prognostic features.
RESULTS: Loss of the PTEN tumor suppressor protein is associated with worse outcomes after salvage radiotherapy, independent of other clinical or pathologic patient characteristics.
OBJECTIVE: We characterized the prognostic impact of previously identified deleterious molecular phenotypes-loss of PTEN, ERG expression, and TP53 mutation-for patients undergoing SRT.
METHODS: We leveraged an institutional database of 320 SRT patients with available tissue and follow-up. Tissue microarrays were used for genetically validated immunohistochemistry assays.
METHODS: All men underwent SRT with or without androgen deprivation therapy OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariable and multivariable Cox-proportional hazard models assessed the association of molecular phenotypes with biochemical recurrence-free (bRFS) and metastasis-free (MFS) survival after SRT.
CONCLUSIONS: Loss of PTEN (n = 123, 43%) and ERG expression (n = 118, 39%) were common in this cohort, while p53 overexpression (signifying TP53 missense mutation) was infrequent (n = 21, 7%). In univariable analyses, any loss of PTEN portended worse bRFS (hazard ratio [HR] 1.86; 95% confidence interval 1.36-2.57) and MFS (HR 1.89; 1.21-2.94), with homogeneous PTEN loss being associated with the highest risk of MFS (HR 2.47; 1.54-3.95). Similarly, p53 overexpression predicted worse bRFS (HR 1.95; 1.14-3.32) and MFS (HR 2.79; 1.50-5.19). ERG expression was associated with worse MFS only (HR 1.6; 1.03-2.48). On the multivariable analysis adjusting for known prognostic features, homogeneous PTEN loss remained predictive of adverse bRFS (HR 1.82; 1.12-2.96) and MFS (HR 2.08; 1.06-4.86). The study is limited by its retrospective and single-institution design.
CONCLUSIONS: PTEN loss by immunohistochemistry is an independent adverse prognostic factor for bRFS and MFS in prostate cancer patients treated with SRT. Future trials will determine the optimal approach to treating SRT patients with adverse molecular prognostic features.
RESULTS: Loss of the PTEN tumor suppressor protein is associated with worse outcomes after salvage radiotherapy, independent of other clinical or pathologic patient characteristics.
摘要：
背景：挽救性放射治疗（SRT）是根治性前列腺切除术后生化复发的主要治疗方法；然而，很少有研究在这种情况下检查基因组生物标志物。
目的：我们表征了先前发现的PTEN的有害分子表型缺失对预后的影响，ERG表达式,和TP53突变-适用于接受SRT的患者。
方法：我们利用了320名SRT患者的机构数据库，并提供了组织和随访。组织微阵列用于遗传验证的免疫组织化学测定。
方法：所有男性均接受有或没有雄激素剥夺治疗的SRT，结果测量和统计学分析：单变量和多变量Cox比例风险模型评估了分子表型与生化无复发（bRFS）和无转移（MFS）生存的关联。
结论：PTEN缺失（n=123，43%）和ERG表达（n=118，39%）在该队列中是常见的，而p53过表达（表示TP53错义突变）很少见（n=21，7％）。在单变量分析中，PTEN的任何损失预示bRFS（危险比[HR]1.86;95％置信区间1.36-2.57）和MFS（HR1.89;1.21-2.94）更差，同质PTEN丢失与MFS的最高风险相关(HR2.47;1.54-3.95)。同样，p53过表达预测bRFS(HR1.95;1.14-3.32)和MFS(HR2.79;1.50-5.19)更差。ERG表达仅与较差的MFS相关(HR1.6;1.03-2.48)。关于调整已知预后特征的多变量分析，同质PTEN丢失仍可预测不良bRFS(HR1.82;1.12-2.96)和MFS(HR2.08;1.06-4.86).这项研究受到其回顾性和单一机构设计的限制。
结论：在接受SRT治疗的前列腺癌患者中，免疫组织化学PTEN丢失是bRFS和MFS的独立不良预后因素。未来的试验将确定治疗具有不良分子预后特征的SRT患者的最佳方法。
结果：PTEN肿瘤抑制蛋白的丢失与挽救性放疗后的不良预后相关，独立于其他临床或病理患者特征。
目的：我们表征了先前发现的PTEN的有害分子表型缺失对预后的影响，ERG表达式,和TP53突变-适用于接受SRT的患者。
方法：我们利用了320名SRT患者的机构数据库，并提供了组织和随访。组织微阵列用于遗传验证的免疫组织化学测定。
方法：所有男性均接受有或没有雄激素剥夺治疗的SRT，结果测量和统计学分析：单变量和多变量Cox比例风险模型评估了分子表型与生化无复发（bRFS）和无转移（MFS）生存的关联。
结论：PTEN缺失（n=123，43%）和ERG表达（n=118，39%）在该队列中是常见的，而p53过表达（表示TP53错义突变）很少见（n=21，7％）。在单变量分析中，PTEN的任何损失预示bRFS（危险比[HR]1.86;95％置信区间1.36-2.57）和MFS（HR1.89;1.21-2.94）更差，同质PTEN丢失与MFS的最高风险相关(HR2.47;1.54-3.95)。同样，p53过表达预测bRFS(HR1.95;1.14-3.32)和MFS(HR2.79;1.50-5.19)更差。ERG表达仅与较差的MFS相关(HR1.6;1.03-2.48)。关于调整已知预后特征的多变量分析，同质PTEN丢失仍可预测不良bRFS(HR1.82;1.12-2.96)和MFS(HR2.08;1.06-4.86).这项研究受到其回顾性和单一机构设计的限制。
结论：在接受SRT治疗的前列腺癌患者中，免疫组织化学PTEN丢失是bRFS和MFS的独立不良预后因素。未来的试验将确定治疗具有不良分子预后特征的SRT患者的最佳方法。
结果：PTEN肿瘤抑制蛋白的丢失与挽救性放疗后的不良预后相关，独立于其他临床或病理患者特征。
