Westbrook Jules A, Cairns David A, Peng Jianhe, Speirs Valerie, Hanby Andrew M, Holen Ingunn, Wood Steven L, Ottewell Penelope D, Marshall Helen, Banks Rosamonde E, Selby Peter J, Coleman Robert E, Brown Janet E
Affiliations of authors:Academic Unit of Clinical Oncology, University of Sheffield , Sheffield , UK (JAW*, IH, PDO, REC, JEB*); Cancer Research UK Leeds Centre (JAW, DAC, JP, SLW, REB, PJS, JEB), Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research (DAC*, HM), and Clinical and Biomedical Proteomics Group (JAW, DAC, JP, SLW, REB, PJS, JEB) and Pathology and Tumor Biology (VS, AMH), Leeds Institute of Cancer and Pathology, University of Leeds , UK ; Department of Oncology and Metabolism, University of Sheffield, Sheffield , UK (SLW*).
J Natl Cancer Inst. 2016 Jan 12;108(4). doi: 10.1093/jnci/djv360. Print 2016 Apr.
Bone is the predominant site of metastasis from breast cancer, and recent trials have demonstrated that adjuvant bisphosphonate therapy can reduce bone metastasis development and improve survival. There is an unmet need for prognostic and predictive biomarkers so that therapy can be appropriately targeted.
Potential biomarkers for bone metastasis were identified using proteomic comparison of bone-metastatic, lung-metastatic, and nonmetastatic variants of human breast cancer MDA-MB-231 cells. Clinical validation was performed using immunohistochemical staining of tumor tissue microarrays from patients in a large randomized trial of adjuvant zoledronic acid (zoledronate) (AZURE-ISRCTN79831382). We used Cox proportional hazards regression, the Kaplan-Meier estimate of the survival function, and the log-rank test to investigate associations between protein expression, clinical variables, and time to distant recurrence events. All statistical tests were two-sided.
Two novel biomarker candidates, macrophage-capping protein (CAPG) and PDZ domain-containing protein GIPC1 (GIPC1), were identified for clinical validation. Cox regression analysis of AZURE training and validation sets showed that control patients (no zoledronate) were more likely to develop first distant recurrence in bone (hazard ratio [HR] = 4.5, 95% confidence interval [CI] = 2.1 to 9.8, P < .001) and die (HR for overall survival = 1.8, 95% CI = 1.01 to 3.24, P = .045) if both proteins were highly expressed in the primary tumor. In patients with high expression of both proteins, zoledronate had a substantial effect, leading to 10-fold hazard ratio reduction (compared with control) for first distant recurrence in bone (P = .008).
The composite biomarker, CAPG and GIPC1 in primary breast tumors, predicted disease outcomes and benefit from zoledronate and may facilitate patient selection for adjuvant bisphosphonate treatment.
骨是乳腺癌转移的主要部位，近期试验表明辅助性双膦酸盐治疗可减少骨转移的发生并提高生存率。目前对预后和预测性生物标志物存在未满足的需求，以便能够合理地靶向治疗。
通过对人乳腺癌MDA-MB-231细胞的骨转移、肺转移和非转移变体进行蛋白质组学比较，确定骨转移的潜在生物标志物。使用来自辅助性唑来膦酸（唑来膦酸盐）大型随机试验（AZURE-ISRCTN79831382）患者的肿瘤组织微阵列进行免疫组织化学染色，进行临床验证。我们使用Cox比例风险回归、生存函数的Kaplan-Meier估计以及对数秩检验来研究蛋白质表达、临床变量与远处复发事件时间之间的关联。所有统计检验均为双侧检验。
鉴定出两种新型生物标志物候选物，即巨噬细胞封闭蛋白（CAPG）和含PDZ结构域的蛋白GIPC1（GIPC1）用于临床验证。对AZURE训练集和验证集进行Cox回归分析表明，如果这两种蛋白在原发性肿瘤中高表达，对照患者（未使用唑来膦酸盐）更有可能在骨中发生首次远处复发（风险比[HR]=4.5，95%置信区间[CI]=2.1至9.8，P<.001）以及死亡（总生存HR=1.8，95%CI=1.01至3.24，P=.045）。在两种蛋白均高表达的患者中，唑来膦酸盐具有显著效果，使骨中首次远处复发的风险比降低10倍（与对照相比）（P=.008）。
原发性乳腺肿瘤中的复合生物标志物CAPG和GIPC1可预测疾病结局以及从唑来膦酸盐治疗中获益的情况，并可能有助于辅助性双膦酸盐治疗的患者选择。
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