Eikesdal Hans P, Knappskog Stian, Aas Turid, Lønning Per E
Section of Oncology, Department of Clinical Science, University of Bergen , Bergen , Norway.
Acta Oncol. 2014 Oct;53(10):1347-55. doi: 10.3109/0284186X.2014.922215. Epub 2014 Jun 9.
Before the advent of neoadjuvant chemotherapy, radiotherapy and surgery alone were associated with a high risk of uncontrolled locoregional relapses in locally advanced breast cancer (LABC).
In the 1990s we initiated two neoadjuvant protocols, where patients with LABC were given either doxorubicin qW or 5-fluorouracil/mitomycin (FUMI) q3W to shrink the tumours prior to mastectomy and postoperative radiotherapy. Previously, we reported TP53 mutation status to predict a poor response to chemotherapy. Here, we present the long-term survival data, with a follow-up of 20 years in the doxorubicin (n = 90) and 15 years in the FUMI trial (n = 34).
Patients in the doxorubicin trial with TP53-mutated tumours experienced a shorter recurrence-free (RFS; 14 vs. 83 months, p < 0.001) and overall survival (OS; 35 vs. 90 months, p < 0.001) than patients with TP53 wt tumours. Similarily, TP53 mutations were associated with a shorter OS (22 vs. 80 months, p = 0.03) and a tendency to shorter RFS (17 vs. 33 months, p = 0.06) in patients treated with FUMI. Furthermore, axillary lymph node metastases predicted shorter OS, but only in patients treated with doxorubicin (49 vs. 142 months, p < 0.04). Applying multivariate analysis, TP53 mutations predicted inferior RFS (p < 0.001) as well as OS (p < 0.001), independently of axillary lymph node status. Isolated local recurrences, without simultaneous distant metastases, occurred in seven patients only in the two trials. Interestingly, chest wall radiation fibrosis predicted improved OS (p = 0.004).
TP53 inactivating mutations are associated with an inferior long-term prognosis in patients with LABC treated with conventional chemotherapy.
在新辅助化疗出现之前，单纯放疗和手术治疗局部晚期乳腺癌（LABC）时，局部区域复发失控的风险很高。
在20世纪90年代，我们启动了两项新辅助治疗方案，LABC患者接受阿霉素每周一次或5-氟尿嘧啶/丝裂霉素（FUMI）每三周一次治疗，以在乳房切除术和术后放疗前缩小肿瘤。此前，我们报道TP53突变状态可预测化疗反应不佳。在此，我们展示长期生存数据，阿霉素试验随访20年（n = 90），FUMI试验随访15年（n = 34）。
阿霉素试验中，TP53突变肿瘤患者的无复发生存期（RFS；14个月对83个月，p < 0.001）和总生存期（OS；35个月对90个月，p < 0.001）均短于TP53野生型肿瘤患者。同样，在接受FUMI治疗的患者中，TP53突变与较短的OS（22个月对80个月，p = 0.03）以及较短RFS的趋势（17个月对33个月，p = 0.06）相关。此外，腋窝淋巴结转移预示着较短的OS，但仅在接受阿霉素治疗的患者中出现（49个月对142个月，p < 0.04）。应用多因素分析，TP53突变预示着较差的RFS（p < 0.001）以及OS（p < 0.001），与腋窝淋巴结状态无关。仅在这两项试验中的7名患者出现了孤立的局部复发，无同时发生的远处转移。有趣的是，胸壁放射性纤维化预示着OS改善（p = 0.004）。
TP53失活突变与接受传统化疗的LABC患者较差的长期预后相关。
