Nielsen Kirsten Vang, Ejlertsen Bent, Møller Susanne, Jørgensen Jan Trøst, Knoop Ann, Knudsen Helle, Mouridsen Henning T
Dako A/S, Glostrup, Denmark.
Acta Oncol. 2008;47(4):725-34. doi: 10.1080/02841860801995396.
BACKGROUND: Previous analyses of TOP2A and HER2 in the Danish Breast Cancer Coopererative Group (DBCG) trial 89D suggested that TOP2A amplifications and possible also deletions are predictive markers for the effect of adjuvant epirubicin in patients with primary breast cancer. We present an updated and extended statistical analysis, requested for IVD-labeling of TOP2A testing. MATERIAL AND METHODS: In the DBCG trial 89D 980 Danish patients were randomly assigned to nine cycles of intravenous CMF (cyclophosphamide, methotrexate, and fluorouracil) or CEF (cyclophosphamide, epirubicin, and fluorouracil). Archival tumor tissue was collected retrospectively from 806 of these patients in a prospectively designed, biological sub-study, and was successfully analyzed for TOP2A aberrations and HER2 status in 773 samples (96%). Recurrence-free survival (RFS) was the primary endpoint. RESULTS: TOP2A aberrations (amplifications and deletions) were significantly associated with shorter RFS (p<0.0001) and overall survival (OS) (p<0.0001). Deleted cases had worse prognosis than amplified cases. In a Cox proportional hazard model TOP2A was an independent prognostic marker for RFS and OS. Patients with amplifications had a 61% reduction in the risk of an event (p=0.002) and a 51% reduction in the risk of death (p=0.01) if allocated to CEF compared to 6% and 10% in TOP2A normal patients. A similar but non-significant trend (p=0.08) was shown in patients with TOP2A deletions. Clear statistical evidence of a differential benefit, favoring CEF among patients with TOP2A aberrations was found for RFS (p=0.02 for interaction) but not for OS (p=0.14 for interaction). CONCLUSION: In conclusion, this updated analysis of TOP2A aberrations in DBCG trial 89D suggests a differential benefit of adjuvant chemotherapy in patients with primary breast cancer, favoring treatment with epirubicin in patients with TOP2A amplifications, and perhaps deletions. Additional studies are needed to clarify the exact importance of TOP2A deletions on outcome, but deletions have proven to be associated with a very poor prognosis.
背景：丹麦乳腺癌协作组（DBCG）89D试验中既往对TOP2A和HER2的分析表明，TOP2A扩增以及可能存在的缺失是原发性乳腺癌患者辅助性表柔比星疗效的预测标志物。我们进行了一项更新且扩展的统计分析，这是为TOP2A检测的体外诊断（IVD）标签要求而开展的。 材料与方法：在DBCG 89D试验中，980名丹麦患者被随机分配接受9个周期的静脉注射CMF（环磷酰胺、甲氨蝶呤和氟尿嘧啶）或CEF（环磷酰胺、表柔比星和氟尿嘧啶）治疗。在一项前瞻性设计的生物学子研究中，对其中806名患者的存档肿瘤组织进行了回顾性收集，773份样本（96%）成功分析了TOP2A异常和HER2状态。无复发生存期（RFS）是主要终点。 结果：TOP2A异常（扩增和缺失）与较短的RFS（p<0.0001）和总生存期（OS）（p<0.0001）显著相关。缺失病例的预后比扩增病例更差。在Cox比例风险模型中，TOP2A是RFS和OS的独立预后标志物。与TOP2A正常的患者相比，扩增患者若被分配至CEF组，事件风险降低61%（p=0.002），死亡风险降低51%（p=0.01），而TOP2A正常患者的这两个风险分别为6%和10%。TOP2A缺失的患者显示出类似但不显著的趋势（p=0.08）。对于RFS，发现了明确的统计学证据表明存在差异获益，即TOP2A异常的患者中CEF更具优势（交互作用p=0.02），但对于OS则未发现（交互作用p=0.14）。 结论：总之，对DBCG 89D试验中TOP2A异常的这项更新分析表明，原发性乳腺癌患者辅助化疗存在差异获益，TOP2A扩增以及可能存在缺失的患者接受表柔比星治疗更具优势。需要进一步研究以阐明TOP2A缺失对预后的确切重要性，但已证实缺失与非常差的预后相关。
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