Mahon K L, Qu W, Devaney J, Paul C, Castillo L, Wykes R J, Chatfield M D, Boyer M J, Stockler M R, Marx G, Gurney H, Mallesara G, Molloy P L, Horvath L G, Clark S J
1] Chris O'Brien Lifehouse, Missenden Rd, Camperdown, New South Wales, 2050, Australia [2] Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, New South Wales, 2010, Australia [3] Sydney Medical School, University of Sydney, Camperdown, New South Wales, 2050, Australia.
Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, New South Wales, 2010, Australia.
Br J Cancer. 2014 Oct 28;111(9):1802-9. doi: 10.1038/bjc.2014.463. Epub 2014 Aug 21.
Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS).
Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay.
The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007).
We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted.
在大多数前列腺癌（PC）中，谷胱甘肽S-转移酶1（GSTP1）失活与CpG岛启动子高甲基化有关。本研究评估了血浆DNA中循环甲基化GSTP1（mGSTP1）水平是否与化疗反应和总生存期（OS）相关。
前瞻性收集了75例去势抵抗性PC（CRPC）男性的I期探索性队列和II期独立验证队列（n = 51）的血浆样本。使用灵敏的甲基化特异性PCR测定法测量游离DNA中的mGSTP1水平。
I期队列发现，可检测到的基线mGSTP1 DNA与较差的OS相关（HR，4.2；95%CI 2.1 - 8.2；P < 0.0001）。第1周期后mGSTP1 DNA水平降低与PSA反应相关（P = 0.008）。在II期队列中，基线mGSTP1 DNA比3个月后的PSA变化更能预测OS（P = 0.02）。化疗1周期后血浆mGSTP1检测不到与PSA反应相关（P = 0.007）。
我们确定血浆mGSTP1 DNA是CRPC男性的潜在预后标志物以及化疗的潜在替代治疗疗效标志物，并在独立的II期队列中证实了这些发现。现在有必要对血浆DNA中的mGSTP1水平进行前瞻性III期评估。
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