Krogh Merete, Christensen Ib, Bouwhuis Marna, Johansen Julia S, Nørgaard Peter, Schmidt Henrik, Hansson Johan, Suciu Stefan, Eggermont Alexander M M, Bastholt Lars
aDepartment of Oncology, Odense University Hospital, Odense C bThe Finsen Laboratory, Rigshospitalet, and Biotech Research and Innovation Centre, University of Copenhagen, København Departments of cOncology dMedicine ePathology, Herlev University Hospital, Herlev fAarhus University Hospital, Aarhus, Denmark gDepartment of Surgical Oncology, Erasmus University Medical Center-Daniel Den Hoed Cancer Center, Rotterdam, The Netherlands hKarolinska Institute, Stockholm, Sweden iEORTC Headquarters, Brussels, Belgium jGustave Roussy Cancer Institute, Villejuif, France.
Melanoma Res. 2016 Aug;26(4):367-76. doi: 10.1097/CMR.0000000000000237.
This study investigates the prognostic and predictive value of YKL-40 in stage IIB-III melanoma patients who were randomized to adjuvant interferon α-2b (IFN) or observation. Serum YKL-40 was determined postoperatively in patients from the Nordic IFN Trial (n=602), EORTC 18952 (n=246), and EORTC 18991 (n=386) (EORTC, European Organisation for Research and Treatment of Cancer). YKL-40 protein expression was determined in 300 tissue sections of primary melanoma or lymph node metastases from 204 Danish patients from the Nordic IFN Trial. Multivariate Cox analysis (including sex, age, stage, ulceration, YKL-40) showed that elevated baseline YKL-40 level was associated with shorter overall survival (OS) in observation groups from the Nordic IFN Trial and EORTC 18952 [hazard ratio (HR)=1.33; 95% confidence interval (CI) 1.01-1.74; P=0.04], but not in the interferon groups (1-year IFN: HR=0.97; 95% CI 0.76-1.25; P=0.83; 2-years IFN: HR=1.06; 95% CI 0.83-1.34; P=0.64). During follow-up, increases in YKL-40 were significantly associated with shorter OS, but not with recurrence-free survival in univariate analysis. YKL-40 expression was stronger in tumor-associated macrophages than melanoma cells in primary melanoma. High YKL-40 expression in macrophages in lymph node metastases was associated with shorter OS in the observation group (HR=2.76; 95% CI: 1.13-6.76, P=0.02), but not in the interferon-treated groups. YKL-40 was an independent prognostic biomarker of OS in melanoma patients stage IIB-III. High serum YKL-40 in poor-prognosis patients may originate from macrophages in the tumor microenvironment and the melanoma cells. Furthermore, we hypothesize that elevated serum YKL-40 after surgery may predict the efficacy of adjuvant IFN treatment.
本研究调查了YKL-40在随机接受辅助性α-2b干扰素（IFN）治疗或观察的IIB-III期黑色素瘤患者中的预后和预测价值。在北欧IFN试验（n=602）、欧洲癌症研究与治疗组织（EORTC）18952试验（n=246）和EORTC 18991试验（n=386）的患者术后测定血清YKL-40。在来自北欧IFN试验的204例丹麦患者的300个原发性黑色素瘤或淋巴结转移灶组织切片中测定YKL-40蛋白表达。多变量Cox分析（包括性别、年龄、分期、溃疡、YKL-40）显示，北欧IFN试验和EORTC 18952试验观察组中，基线YKL-40水平升高与总生存期（OS）缩短相关[风险比（HR）=1.33；95%置信区间（CI）1.01-1.74；P=0.04]，但在干扰素治疗组中并非如此（1年IFN治疗：HR=0.97；95%CI 0.76-1.25；P=0.83；2年IFN治疗：HR=1.06；95%CI 0.83-1.34；P=0.64）。在随访期间，YKL-40升高与OS缩短显著相关，但在单变量分析中与无复发生存期无关。在原发性黑色素瘤中，肿瘤相关巨噬细胞中的YKL-40表达强于黑色素瘤细胞。淋巴结转移灶中巨噬细胞YKL-40高表达与观察组OS缩短相关（HR=2.76；95%CI：1.13-6.76，P=0.02），但在干扰素治疗组中并非如此。YKL-40是IIB-III期黑色素瘤患者OS的独立预后生物标志物。预后较差患者的高血清YKL-40可能源于肿瘤微环境中的巨噬细胞和黑色素瘤细胞。此外我们推测，术后血清YKL-40升高可能预测辅助性IFN治疗的疗效。
