Department of Veterinary Disease Biology, Faculty of Life Sciences, University of Copenhagen, Frederiksberg, Denmark.
Breast Cancer Res Treat. 2012 Feb;132(1):225-34. doi: 10.1007/s10549-011-1896-1. Epub 2011 Dec 9.
HER2 amplification, TOP2A aberrations, and absence of tissue inhibitor of metalloproteinase (TIMP-1) expression in breast carcinomas have been shown to be associated with incremental benefit from anthracycline-containing adjuvant chemotherapy, and this study was undertaken to validate these findings in a similar, but independent, randomized clinical trial. TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to cyclophosphamide, epirubicin, and fluorouracil (CEF) or cyclophosphamide, methotrexate, and fluorouracil (CMF) in the MA.5 trial. Ninety-eight (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. Forty-four percentage was classified as HT responsive (HER2 amplified and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT-responsive patients, CEF was superior to CMF with an improved RFS (adjusted HR, 0.64; 95% CI, 0.42-0.97), but this was not significant for OS (adjusted HR, 0.66; 95% CI, 0.42-1.04). A significant HT profile versus treatment interaction was detected for OS (P = 0.03). In 2T-responsive patients, CEF seemed to improve RFS compared to CMF (adjusted HR, 0.67; 95% CI, 0.43-1.03) and improved OS (adjusted HR, 0.58; 95% CI, 0.36-0.93). A significant 2T profile versus treatment interaction was detected for OS (P = 0.01). With this study, we validate a more substantial reduction in mortality by CEF compared to CMF in patients with an HT- or 2T-responsive profile; however, we could not show a similarly significant reduction in RFS events, where a benefit of CEF over CMF was found irrespective of TIMP-1 status. Further studies are necessary before the HT and 2T profiles may be used to direct the use of anthracyclines.
在乳腺癌中，HER2 扩增、TOP2A 异常和组织金属蛋白酶抑制剂 (TIMP-1) 表达缺失与蒽环类辅助化疗的增量获益相关，本研究旨在在类似但独立的随机临床试验中验证这些发现。在 MA.5 试验中，对 716 例已知 HER2 和 TOP2A 状态的绝经前高危患者的 403 例存档肿瘤组织进行了 TIMP-1 的免疫组织化学检查，这些患者被随机分配至环磷酰胺、表柔比星和氟尿嘧啶 (CEF) 或环磷酰胺、甲氨蝶呤和氟尿嘧啶 (CMF) 组。98 例（24%）患者的肿瘤细胞无 TIMP-1 染色，27%患者的 HER2 扩增，18%患者的 TOP2A 异常。44%的患者被归类为 HT 反应性（HER2 扩增和/或 TIMP-1 阴性），37%的患者为 2T 反应性（TOP2A 异常和/或 TIMP-1 阴性）。根据 TIMP-1，CEF 与 CMF 的治疗效果没有差异。在 HT 反应性患者中，CEF 优于 CMF，RFS 改善（调整后的 HR，0.64；95%CI，0.42-0.97），但 OS 无显著改善（调整后的 HR，0.66；95%CI，0.42-1.04）。OS 存在显著的 HT 谱与治疗相互作用（P = 0.03）。在 2T 反应性患者中，CEF 似乎比 CMF 改善了 RFS（调整后的 HR，0.67；95%CI，0.43-1.03）和 OS（调整后的 HR，0.58；95%CI，0.36-0.93）。OS 存在显著的 2T 谱与治疗相互作用（P = 0.01）。通过这项研究，我们验证了在 HT 或 2T 反应性患者中，CEF 与 CMF 相比可显著降低死亡率；然而，我们无法显示 RFS 事件的同样显著降低，在这些事件中，CEF 优于 CMF，而不论 TIMP-1 状态如何。在 HT 和 2T 谱可用于指导蒽环类药物的使用之前，还需要进一步的研究。
