Genito Urinary Cancer Research Group, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester, UK; Department of Urology, Salford Royal NHS Foundation Trust, Manchester, UK.
Genito Urinary Cancer Research Group, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester, UK.
Eur Urol Focus. 2019 Sep;5(5):831-841. doi: 10.1016/j.euf.2018.04.006. Epub 2018 Apr 24.
Docetaxel chemotherapy is a standard of care for metastatic castrate-resistant prostate cancer (mCRPC): 40-50% of patients achieve a biochemical response. However, there is a lack of response predictive biomarkers.
To assess lactate dehydrogenase (LDH) as a docetaxel response biomarker in mCRPC and to examine the association of LDH with genomic alterations in primary diagnostic biopsies.
DESIGN, SETTING, AND PARTICIPANTS: Clinical and associated primary tumour-targeted next-generation sequencing data from matched training (n=150) and test (n=120) cohorts of progressive mCRPC patients receiving docetaxel therapy were analysed. Data were correlated with large-scale prostate cancer genomic datasets.
Prostate-specific antigen (PSA) response, radiographic response, biochemical progression-free survival (PFS), overall survival (OS), genomic analysis of primary biopsies, and genomic datasets (Memorial Sloan Kettering Cancer Center [MSKCC] and SU2C/PCF).
Serum LDH ≥450U/l is a reliable prognostic biomarker (area under the curve: 0.757 [standard deviation 0.054, 95% confidence interval [CI] 0.650-0.864, p<0.001]) in progressive mCRPC, predicting PFS at 3 mo. Patients with LDH ≥450U/l were poorer PSA responders, with shorter PFS (213 vs 372 d, hazard ratio [HR] 1.876, 95% CI 1.289-2.7300) and OS (362 vs 563 d, HR 1.630, 95% CI 1.127-2.357). High LDH is an independent surrogate marker for survival following docetaxel and predicts a poor radiological response (p=0.043). Of the 14 patients with LDH ≥450U/l available for next-generation sequencing, nine (64.3%) were more likely to have DNA repair gene mutation(s) (BRCA1/2, ATM, CHEK2, Fanconi anaemia gene) in their primary biopsy. Cross correlation with MSKCC and SU2C/PCF databases revealed a positive correlation between LDHA, PARP1 (r=0.667, p<0.01), and other DNA repair genes.
Genomic abnormalities of LDHA and DNA repair in primary biopsies link to high pretreatment LDH and poor response to docetaxel in mCRPC.
The presence of mutations of the lactate dehydrogenase and DNA repair pathways are associated with aggressive prostate cancer and poor response to chemotherapy later in the disease.
多西紫杉醇化疗是转移性去势抵抗性前列腺癌（mCRPC）的标准治疗方法：40-50%的患者实现生化缓解。然而，缺乏反应预测生物标志物。
评估乳酸脱氢酶（LDH）作为 mCRPC 中多西紫杉醇反应的生物标志物，并研究 LDH 与原发性诊断活检中基因组改变的关系。
设计、设置和参与者：分析了接受多西紫杉醇治疗的进行性 mCRPC 患者的匹配训练（n=150）和测试（n=120）队列的临床和相关原发性肿瘤靶向下一代测序数据。数据与大规模前列腺癌基因组数据集相关联。
血清 LDH≥450U/l 是进展性 mCRPC 的可靠预后生物标志物（曲线下面积：0.757 [标准偏差 0.054，95%置信区间 [CI] 0.650-0.864，p<0.001]），预测 3 个月时的无进展生存期（PFS）。LDH≥450U/l 的患者 PSA 反应较差，PFS 更短（213 与 372 天，风险比 [HR] 1.876，95%CI 1.289-2.7300）和 OS（362 与 563 天，HR 1.630，95%CI 1.127-2.357）。高 LDH 是多西紫杉醇后生存的独立替代标志物，并预测影像学反应不佳（p=0.043）。在可进行下一代测序的 14 名 LDH≥450U/l 的患者中，有 9 名（64.3%）在原发性活检中更有可能存在 DNA 修复基因突变（BRCA1/2、ATM、CHEK2、范可尼贫血基因）。与 MSKCC 和 SU2C/PCF 数据库的交叉相关性显示，LDHA 和 PARP1（r=0.667，p<0.01）和其他 DNA 修复基因之间存在正相关。
原发性活检中 LDHA 和 DNA 修复的基因组异常与 mCRPC 中高预处理 LDH 和对多西紫杉醇反应不良相关。
乳酸脱氢酶和 DNA 修复途径的突变与侵袭性前列腺癌有关，并且在疾病后期对化疗的反应较差。
