Background

Circulating biomarkers of bone metabolism are significantly associated with overall survival (OS) in men with advanced prostate cancer. In the SWOG S1216 phase III trial, we showed that elevated bone biomarkers are significantly associated with an increased risk of death in hormone-sensitive prostate cancer (HSPC) regardless of the status of bone metastases, identifying three risk groups with differential OS outcomes based on bone biomarker status. Here we report the association of bone biomarkers with OS in men with HSPC and documented skeletal metastases as part of a planned subset analysis of S1216.

Methods

Bone resorption [C-telopeptide (CTx); Pyridinoline (PYD)] and bone formation markers [C-terminal collagen propeptide (CICP); bone alkaline phosphatase (BAP)] were assessed in blood from men with bone metastatic HSPC. Patients were randomly divided into training (n = 238) and validation (n = 475) sets. In the training set, recursive partitioning that maximizes discrimination of OS was used to identify the dichotomous cut-point for each biomarker and for a combination of biomarker split points to define prognostic groups. In the validation set, Cox proportional hazards models were used to assess the impact of biomarkers on OS, adjusted for patient and tumor characteristics.

Results

Of 1279 men, 713 had both baseline bone metastases and evaluable bone biomarkers. Patient characteristics were similar between the overall population and the subset with bone metastases. Elevated levels of CICP, CTX, and PYD were strongly prognostic for OS. Hazard ratios (95% CI) for OS adjusted for treatment arm and baseline clinical variables were: BAP–1.31 (0.93, 1.84), p = 0.12; CICP–1.58 (1.09, 2.29), p < 0.02; CTx – 1.55 (1.12, 2.15), p = 0.008; and PYD–1.66 (1.27, 2.217), p = 0.0002. There was no evidence of interaction between elevated biomarkers and treatment (all p > 0.2). Recursive partitioning algorithms identified four groups of patients with differential OS outcomes based on bone biomarkers, adjusted for baseline clinical variables, with median OS ranging from 2.3 years (highest risk group) to 7.5 years (lowest risk group).

Conclusions

In this planned S1216 subset analysis of men with HSPC and bone metastases, elevated serum markers of bone metabolism were significantly associated with worse OS. Bone biomarker levels alone and in combination with patient and tumor characteristics identify unique subsets of men with differential OS outcomes.

ClinicalTrials.gov Identifier

NCT01809691

中文翻译：

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患有骨转移激素敏感前列腺癌 (HSPC) 的男性骨代谢和总体生存率的标志物：SWOG S1216 的子集分析，SWOG S1216 是一项雄激素剥夺（联合或不联合奥特罗奈）的 III 期试验

背景

骨代谢的循环生物标志物与晚期前列腺癌男性的总生存期 (OS) 显着相关。在 SWOG S1216 III 期试验中，我们表明，无论骨转移状态如何，骨生物标志物升高与激素敏感型前列腺癌 (HSPC) 死亡风险增加显着相关，根据不同的 OS 结果确定了三个风险组骨生物标志物状态。在这里，我们报告了骨生物标志物与 HSPC 男性 OS 的关联，并记录了骨骼转移，作为计划的 S1216 子集分析的一部分。

方法

骨吸收[C-端肽(CTx)；吡啶啉(PYD)]和骨形成标志物[C端胶原前肽(CICP)；骨碱性磷酸酶（BAP）]在患有骨转移性 HSPC 的男性血液中进行了评估。患者被随机分为训练组 ( n  = 238) 和验证组 ( n  = 475)。在训练集中，使用最大化 OS 区分度的递归分区来确定每个生物标志物的二分切点以及生物标志物分割点的组合来定义预后组。在验证集中，Cox 比例风险模型用于评估生物标志物对 OS 的影响，并根据患者和肿瘤特征进行调整。

结果

在 1279 名男性中，713 人同时患有基线骨转移和可评估的骨生物标志物。总体人群和患有骨转移的亚群之间的患者特征相似。CICP、CTX 和 PYD 水平升高对 OS 有很强的预测作用。根据治疗组和基线临床变量调整后的 OS 风险比 (95% CI) 为：BAP–1.31 (0.93, 1.84)，p  = 0.12；CICP–1.58 (1.09, 2.29)，p  < 0.02；CTx – 1.55 (1.12, 2.15)，p  = 0.008；和 PYD–1.66 (1.27, 2.217)，p  = 0.0002。没有证据表明生物标志物升高与治疗之间存在相互作用（所有p  > 0.2）。递归分区算法根据骨生物标志物确定了四组具有不同 OS 结果的患者，并根据基线临床变量进行调整，中位 OS 范围从 2.3 年（最高风险组）到 7.5 年（最低风险组）。

结论

在这项计划对 HSPC 和骨转移男性进行的 S1216 子集分析中，骨代谢血清标志物升高与 OS 较差显着相关。单独的骨生物标志物水平以及与患者和肿瘤特征相结合可以识别具有不同 OS 结果的独特男性亚群。

ClinicalTrials.gov 标识符

NCT01809691