靶向治疗药物相关标志物在卵巢透明细胞癌组织中的表达及其临床意义

Clinical significance of targeting drug-based molecular biomarkers expression in ovarian clear cell carcinoma

目的 探讨靶向治疗药物相关标志物在卵巢透明细胞癌（OCCC）组织中的表达及其临床意义.方法 收集2008年1月—2015年12月在复旦大学附属肿瘤医院进行手术治疗的OCCC患者60例,其中40例为初次手术患者,23例为复发后二次手术患者（其中3例患者的初次手术也在本院完成,故重复计数）.采用免疫组化SP法检测OCCC组织中靶向治疗药物相关标志物——表皮生长因子受体（EGFR）、人类表皮生长因子受体2（HER2）、极光激酶A（AURKA）、乳腺癌易感基因（BRCA）1、BRCA2及程序性死亡配体1（PD-L1）的表达,并分析其与患者化疗耐药及预后的相关性.结果（1）免疫组化SP法检测显示,在初次手术患者和复发后二次手术患者的OCCC组织中,EGFR蛋白的阳性表达率分别为20%（8/40）和30%（7/23）,HER2分别为22%（9/40）和35%（8/23）,AURKA分别为38% （15/40）和35%（8/23）,BRCA1分别为42%（17/40）和39%（9/23）,BRCA2分别为20%（8/40）和22%（5/23）,PD-L1分别为25%（10/40）和17%（4/23）,分别比较,差异均无统计学意义（P〉0.05）.（2）仅复发后二次手术患者的OCCC组织中HER2蛋白的表达与其铂类药物耐药明显相关（P=0.039）;而初次手术患者及复发后二次手术患者的其他靶向治疗药物相关标志物的表达与其铂类药物耐药均无明显相关性（P〉0.05）.（3）单因素生存分析显示,40例初次手术的OCCC患者中,HER2、AURKA蛋白阳性表达者的中位无进展生存时间（PFS,分别为4、4个月）均明显短于各自的阴性表达者（分别为10、10个月,P=0.023、P=0.018）;23例复发后二次手术的OCCC患者中,HER2、AURKA蛋白阳性表达者二次手术后的中位总生存时间（OS,分别为10、13个月）也均明显短于各自的阴性表达者（分别为44、43个月,P=0.026、P=0.044）.多因素生存分析显示,6个靶向治疗药物相关标志物均不是影响OCCC患者初次手术后PFS、复发后二次手术后OS的独立危险因素（P〉0.05）.结论 HER2及AURKA表达与OCCC患者初次手术后PFS、复发者二次手术后OS明显相关,可作为判断OCCC患者预后的预测指标.

Objective To assess the expression level of targeting drug-based molecular biomarkers in ovarian clear cell carcinoma（OCCC）tissues and its clinical significance.Methods A total of 63 OCCC patients included 40 primary OCCC and 23 recurrent OCCC for secondary cytoreductive surgery（SCS）,who had received primary surgeries at Fudan University Shanghai Cancer Center between January, 2008 and December, 2015 were enrolled, and immunohistochemistry SP method was used to test human epidermal growth factor receptor （EGFR）, human epidermal growth factor receptor-2 （HER2）, aurora kinase A （AURKA）, breast cancer susceptibility gene 1 （BRCA1）, BRCA2 and programmed death-ligand 1 （PD-L1） protein expression in paraffin-embedded tissues. Results The positive rates of EGFR, HER2, AURKA, BRCA1,BRCA2 and PD-L1 in primary and recurrent tumor tissues were respectively 20%（8/40）vs 30%（7/23）,22%（9/40）vs 35%（8/23）,38%（15/40）vs 35%（8/23）,42%（17/40）vs 39%（9/23）,20%（8/40）vs 22%（5/23）, 25%（10/40）vs 17%（4/23）, and there were no significant differences between primary and recurrent OCCC （all P〉0.05）. χ2-test or Fisher exact analysis revealed that HER2 expression in recurrent tumor tissues had a relationship with chemoresistance （P〈0.05）, while the expression of other biomarkers showed no significant relationship with chemoresistance （all P〉0.05）. Further, Kaplan-Meier survival analysis showed that patients with HER2 and AURKA-positive expression had a significantly shorter progression-free survival time in primary OCCC（4 months vs 10 months,log-rank test,P〈0.05 for HER2;and 4 months vs 10 months,P〈0.05 for AURKA）;and a shorter overall survival time after SCS in recurrent OCCC （10 months vs 44 months, P〈0.05 for HER2;and 13 months vs 43 months, P〈0.05 for AURKA）. However,multivariate Cox proportional hazards regression analysis indicated that none of these 6 biomarkers was independent risk factor of progression-free survival time of primary OCCC or overall survival time after SCS for recurrent OCCC （P〉0.05）. Conclusion HER2 and AURKA could serve as prognostic factors in ovarian clear cell carcinoma.