Mathiesen Randi R, Borgen Elin, Renolen Anne, Løkkevik Erik, Nesland Jahn M, Anker Gun, Ostenstad Bjørn, Lundgren Steinar, Risberg Terje, Mjaaland Ingvil, Kvalheim Gunnar, Lønning Per Eystein, Naume Bjørn
Breast Cancer Res. 2012 Aug 14;14(4):R117. doi: 10.1186/bcr3242.
Presence of disseminated tumor cells (DTCs) in bone marrow (BM) and circulating tumor cells (CTC) in peripheral blood (PB) predicts reduced survival in early breast cancer. The aim of this study was to determine the presence of and alterations in DTC- and CTC-status in locally advanced breast cancer patients undergoing neoadjuvant chemotherapy (NACT) and to evaluate their prognostic impact.
Bone marrow and peripheral blood were collected before NACT (BM1: n = 231/PB1: n = 219), at surgery (BM2: n = 69/PB2: n = 71), and after 12 months from start of NACT (BM3: n = 162/PB3: n = 141). Patients were included from 1997 to 2003 and followed until 2009 (or ten years follow-up). DTC- and CTC-status were determined by morphological evaluation of immunocytochemically detected cytokeratin-positive cells. The prognostic significance of DTCs/CTCs was assessed by univariate and multivariate Cox-regression analyses.
Before NACT, DTCs and CTCs were detected in 21.2% and 4.9% of the patients, respectively. At surgery, 15.9% and 1.4% had DTC- and CTC-presence, compared to 26.5% and 4.3% at 12 months from start of NACT. Of patients for whom DTC results both before NACT and at 12 months were available, concordant results were observed in 68%, and 14 out of 65 had positive DTC-status at both time points. Presence of ≥ 1 DTC 12 months from start of NACT, but not at other time points, predicted reduced disease-free survival (DFS; HR 2.3, p = 0.003), breast cancer-specific survival (BCSS; HR 3.0, p < 0.001) and overall survival (OS; HR 2.8, p < 0.001). Before NACT, presence of ≥ 3 DTCs was also associated with unfavorable outcome, and reduced BCSS was observed for CTC-positive patients (HR 2.2, p = 0.046). In multivariate analysis, DTC status (</≥ 1 DTC) at 12 months after start of NACT remained as a prognostic factor for both DFS (HR 2.2, p = 0.005), BCSS (HR 2.6, p = 0.002) and OS (HR 2.6, p = 0.002). The survival for patients with change in DTC-status was determined by the DTC-status at 12 months.
Presence of DTCs after NACT indicated high risk for relapse and death, irrespective of the DTC-status before treatment. The results supports the potential use of DTC analysis as a monitoring tool during follow up, for selection of patients to secondary treatment intervention within clinical trials.
骨髓中播散肿瘤细胞（DTCs）和外周血中循环肿瘤细胞（CTCs）的存在预示着早期乳腺癌患者生存率降低。本研究的目的是确定接受新辅助化疗（NACT）的局部晚期乳腺癌患者中DTC和CTC状态的存在及变化，并评估其预后影响。
在NACT前（BM1：n = 231/PB1：n = 219）、手术时（BM2：n = 69/PB2：n = 71）以及NACT开始后12个月（BM3：n = 162/PB3：n = 141）采集骨髓和外周血。患者纳入时间为1997年至2003年，并随访至2009年（或十年随访）。通过免疫细胞化学检测细胞角蛋白阳性细胞的形态学评估来确定DTC和CTC状态。通过单因素和多因素Cox回归分析评估DTCs/CTCs的预后意义。
NACT前，分别在21.2%和4.9%的患者中检测到DTCs和CTCs。手术时，15.9%和1.4%的患者存在DTC和CTC，而在NACT开始后12个月时分别为26.5%和4.3%。对于NACT前和12个月时均有DTC结果的患者，68%观察到结果一致，65例中有14例在两个时间点DTC状态均为阳性。NACT开始后12个月时存在≥1个DTC，但在其他时间点不存在，预示无病生存期（DFS；HR 2.3，p = 0.003）、乳腺癌特异性生存期（BCSS；HR 3.0，p < 0.001）和总生存期（OS；HR 2.8，p < 0.001）降低。NACT前，≥3个DTC的存在也与不良预后相关，CTC阳性患者的BCSS降低（HR 2.2，p = 0.046）。在多因素分析中，NACT开始后12个月时的DTC状态（</≥1个DTC）仍然是DFS（HR 2.2，p = 0.005）、BCSS（HR 2.6，p = 0.002）和OS（HR 2.6，p = 0.002）的预后因素。DTC状态发生变化的患者的生存期由12个月时的DTC状态决定。
NACT后DTC的存在表明复发和死亡风险高，与治疗前的DTC状态无关。结果支持DTC分析作为随访期间监测工具的潜在用途，用于在临床试验中选择接受二次治疗干预的患者。
