Celecoxib With Neoadjuvant Chemotherapy for Breast Cancer Might Worsen Outcomes Differentially by COX-2 Expression and ER Status: Exploratory Analysis of the REMAGUS02 Trial
Celecoxib With Neoadjuvant Chemotherapy for Breast Cancer Might Worsen Outcomes Differentially by COX-2 Expression and ER Status: Exploratory Analysis of the REMAGUS02 Trial
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DOI：
10.1200/jco.18.00636
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发表时间：
2019-03-10
影响因子：
45.3
通讯作者：
Reyal, Fabien
中科院分区：
文献类型：
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作者：
Hamy, Anne-Sophie;Tury, Sandrine;Reyal, Fabien
目的乳腺癌中存在环氧合酶 2 (COX-2) 基因（也称为前列腺素内过氧化物合酶 2 (PTGS2)）的过度表达，但其是否影响抗氧化药物的反应仍不清楚。我们研究了 PTGS2 表达、新辅助化疗 (NAC) 期间塞来昔布的使用以及无事件生存期 (EFS) 和总生存期 (OS) 之间的关系。 材料和方法我们分析了 REMAGUS02（ISRCTN 注册号 10059974）试验中 156 名患有人表皮生长因子受体 2 阴性乳腺癌患者的队列，并进行了预处理 PTGS2 表达数据。患者接受序贯 NAC 治疗（表阿霉素加环磷酰胺，然后多西他赛联合或不联合塞来昔布）。在乳腺癌细胞系上进行了实验验证。癌症和白血病 B 组 (CALGB) 30801（ClinicalTrials.gov 标识符：NCT01041781）试验在肺癌患者中测试了联合或不联合塞来昔布的化疗，作为独立的验证队列。 结果 94.5 个月的随访后，塞来昔布组的 EFS 显着较低（风险比 [HR]，1.7；95% CI，1 至 2.88； P = .046)。检测到 PTGS2 表达与塞来昔布使用之间存在显着交互作用（P 交互作用 = .01）。在 PTGS2 低组 (n = 100) 中，塞来昔布组的 EFS 低于标准治疗组（HR，3.01；95% CI，1.45 至 6.24；P = 0.002）。塞来昔布的使用是不良 EFS、远处无复发生存和 OS 的独立预测因子。除了多西他赛之外，塞来昔布增强了 PTGS2-low 细胞系的细胞活力，但不增强 PTGS2-high 细胞系的细胞活力。在 CALGB 30801 中，接受塞来昔布治疗的尿前列腺素 E2 代谢物低的患者观察到无进展生存期较差的趋势（HR = 1.57；95% CI，0.87 至 2.84；P = .13）。 结论化疗期间使用塞来昔布对乳腺癌患者的生存产生不利影响，并且在 PTGS2-low 患者中效果更明显 和/或雌激素受体阴性肿瘤。对于正在接受 NAC 的乳腺癌患者，在使用多西紫杉醇期间，最好避免使用 COX-2 抑制剂。
PURPOSEThe overexpression of cyclooxygenase 2 (COX-2) gene, also known as prostaglandin-endoperoxide synthase 2 (PTGS2), occurs in breast cancer, but whether it affects response to anticox drugs remains unclear. We investigated the relationships between PTGS2 expression, celecoxib use during neoadjuvant chemotherapy (NAC), and both event-free survival (EFS) and overall survival (OS).MATERIALS AND METHODSWe analyzed a cohort of 156 patients with human epidermal growth factor receptor 2-negative breast cancer from the REMAGUS02 (ISRCTN Registry No. 10059974) trial with pretreatment PTGS2 expression data. Patients were treated by sequential NAC (epirubicin plus cyclophosphamide followed by docetaxel with or without celecoxib). Experimental validation was performed on breast cancer cell lines. The Cancer and Leukemia Group B (CALGB) 30801 (ClinicalTrials.gov identifier: NCT01041781) trial that tested chemotherapy with or without celecoxib in patients with lung cancer served as an independent validation cohort.RESULTSAfter 94.5 months of follow-up, EFS was significantly lower in the celecoxib group (hazard ratio [HR], 1.7; 95% CI, 1 to 2.88; P = .046). A significant interaction between PTGS2 expression and celecoxib use was detected (P-interaction = .01). In the PTGS2-low group (n = 100), EFS was lower in the celecoxib arm (HR, 3.01; 95% CI, 1.45 to 6.24; P = .002) than in the standard treatment arm. Celecoxib use was an independent predictor of poor EFS, distant relapse-free survival, and OS.Celecoxib in addition to docetaxel enhanced cell viability in PTGS2-low cell lines but not in PTGS2-high cell lines. In CALGB 30801, a trend toward poorer progression-free survival was observed in the patients with low urinary metabolite of prostaglandin E2 who received celecoxib (HR = 1.57; 95% CI, 0.87 to 2.84; P = .13).CONCLUSIONCelecoxib use during chemotherapy adversely affected survival in patients with breast cancer, and the effect was more marked in PTGS2-low and/or estrogen receptor-negative tumors. COX-2 inhibitors should preferably be avoided during docetaxel use in patients with breast cancer who are undergoing NAC.