Biochemical markers of bone turnover in metastatic prostate cancer

描述（由申请人提供）：骨转移在前列腺癌患者中很常见，是发病率的常见来源，包括骨痛或骨折。对这些患者的骨转移的评估一直采用影像学方法。然而，骨显像不是高度特异性的，不能检测到骨退化的区域，这是骨转移的一个常见特征。此外，许多临床反应以PSA下降和健康改善为特征的患者在骨显像扫描中可能没有立即相应的改善。因此，血液中骨代谢的生化标记物已被探索作为骨转换的指标，因为它们具有作为预后和/或预测变量的潜力。作为nci赞助的基质金属蛋白酶抑制剂在伴有骨骼转移的激素难治性前列腺癌患者中的随机II期试验的一部分，我们的研究小组前瞻性地评估了69名患者的骨转换血清标志物，并将结果与患者预后相关联。我们发现血清中骨形成的几个基线标志物（骨钙素，前胶原n端前肽：PINP和PIIINP，总碱性磷酸盐）和吸收（n端肽，吡啶啉，脱氧吡啶啉）具有统计学意义的预后价值。在前列腺癌患者中使用内皮素- a拮抗剂阿特拉森的试验数据显示，总碱性磷酸盐和骨碱性磷酸盐水平显著预测进展时间。我们将通过最近启动的西南肿瘤组随机III期试验（S0421），在转移激素难治性前列腺癌患者中，多西他赛/泼尼松加或不加内皮素- a拮抗剂阿特拉森（n=706），在一个类似的、更大的患者队列中前瞻性验证这些令人鼓舞的初步结果。假设是，从转移激素难治性前列腺癌患者收集的血清中收集的骨代谢标记物的基线水平将具有预后价值，而这些相同标记物的连续水平将预测使用骨靶向药物（如阿特拉森坦）治疗后的增强反应和生存率。该假设将通过以下具体目标进行验证：1)测量基线和连续收集SWOG 0421患者血清中骨形成（前胶原I氨基末端前肽：PINP，总磷酸盐和骨碱性磷酸盐）和吸收（N-端肽，脱氧吡啶啉）的选定标记物水平，SWOG 0421是一项随机III期试验，多西他赛/泼尼松加或不加阿特拉森坦治疗激素难治性前列腺癌伴骨骼转移患者；2)将这些标志物研究的结果与肿瘤反应、无进展生存期和总生存期相关联，以检测预后（基线或治疗前血清）和/或预测（系列血清）价值；3)根据基线骨标志物和其他临床及疾病相关因素确定预后组，并评估骨标志物的变化是否可以替代这种情况下的生存。

DESCRIPTION (provided by applicant): Bone metastasis is common in patients with prostate cancer and is a frequent source of morbidity, including bone pain or fracture. Assessment of skeletal bone metastases in these patients has been with imaging modalities. However, bone scintigraphy is not highly specific and fails to detect areas of bone degradation, a feature common to bony metastases. In addition, many patients with a clinical response to therapy characterized by a declining PSA and improved well-being may not have an immediate corresponding improvement in the bone scintigraphy scan. Thus, biochemical markers of bone metabolism in blood have been explored as indicators of bone turnover for their potential as prognostic and/or predictive variables. As part of a randomized NCI-sponsored phase II trial of a matrix metalloproteinase inhibitor in patients with hormone refractory prostate cancer with skeletal metastases, our group prospectively evaluated serum markers of bone turnover from 69 patients and correlated the results with patient outcome. We found that several baseline markers of bone formation (osteocalcin, procollagen N-terminal propeptides: PINP & PIIINP, total alkaline phosphates) and resorption (N-telopeptide, pyridinoline, deoxypyridinoline) in serum had statistically significant prognostic value. Data from trials employing the endothelin-A antagonist Atrasentan in prostate cancer patients showed that levels of total and bone alkaline phosphates significantly predicted time to progression. We will prospectively validate these encouraging preliminary results in a similar, larger, patient cohort through the recently initiated randomized phase III Southwest Oncology Group trial (S0421) of docetaxel/prednisone with or without the endothelin-A antagonist Atrasentan (n=706) in patients with metastatic hormone refractory prostate cancer. The hypothesis is that baseline levels of bone metabolism markers in sera collected from patients with metastatic hormone refractory prostate cancer will be of prognostic value, while serial levels of these same markers will predict enhanced response and survival following therapy with a bone-targeted agent such as Atrasentan. This hypothesis will be tested through the following specific aims: 1) measure levels of selected markers of bone formation (procollagen I amino-terminal propeptides: PINP, total and bone alkaline phosphates) and resorption (N- telopeptide, deoxypyridinoline) in sera collected at baseline and serially from patients enrolled in SWOG 0421, a randomized phase III trial of docetaxel/prednisone with or without Atrasentan in patients with hormone refractory prostate cancer with skeletal metastases; 2) correlate the results of these marker studies with tumor response, progression-free survival, and overall survival to detect prognostic (baseline or pre-treatment sera) and/or predictive (serial sera) value; 3) identify prognostic groups based on baseline bone markers and other clinical and disease-related factors, and to evaluate whether change in a bone marker is a surrogate for survival in this setting.