Expression of serum keratin fragment 19 in patients with gastric cancer and its predictive power for positive HER-2
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摘要:
背景 HER-2阳性的胃癌患者预后较差,且缺少与胃癌HER-2阳性相关肿瘤标志物的报道。 目的 探讨血清CYFRA21-1表达水平与HER-2阳性胃癌患者的相关性。 方法 收集2019年1月 - 2021年12月在解放军总医院手术治疗的胃癌患者165例,其中男115例,女50例,年龄29 ~ 82岁。分析HER-2基因表达阳性患者的CYFRA21-1水平,并绘制CYFRA21-1在HER-2阳性患者中表达的ROC曲线,分析其预测HER-2阳性胃癌的阈值。 结果 血清CYFRA21-1水平与胃癌的病理组织学分化程度和分型、TNM分期及肿瘤大小有关(P<0.05);HER-2阳性组中CYFRA21-1水平显著高于阴性组(P=0.038);CYFRA21-1阳性表达在HER-2阳性组中的OR值为3.529(95% CI:0.967 ~ 12.878),对HER-2阳性胃癌患者的预测百分比为70.4%,当CYFRA21-1的Cut-off值为3.62 ng/mL时,对胃癌患者HER-2阳性的预测敏感度和特异度达到最高,分别为0.552和0.833。CYFRA21-1<3.62 ng/mL的胃癌患者1年、2年、3年生存率高于CYFRA21-1>3.62 ng/mL者(P=0.002),HER-2阴性胃癌患者1年、2年、3年生存率高于阳性者(P=0.044)。 结论 HER-2基因及血清CYFRA21-1水平在胃癌转移、肿瘤较大、TNM分期较晚的患者中表达升高。CYFRA21-1水平较高、HER-2阳性者生存预后较差。高血清CYFRA21-1水平对胃癌患者HER-2基因阳性表达有一定的预测价值。 -
关键词:
- 人类表皮生长因子受体2 /
- 细胞角质素片段19 /
- 胃癌 /
- TNM分期 /
- 肿瘤标志物
Abstract:Background The prognosis of gastric cancer patients with positive HER-2 is poor, and there is a lack of reports on tumor markers related to positive HER-2 in gastric cancer. Objective To investigate the correlation between serum CYFRA21-1 expression and HER-2 positive gastric cancer patients. Methods From January 2019 to December 2021, 165 gastric cancer patients, including 115 males and 50 females, aged from 29 to 82 years, were enrolled in this study. The CYFRA21-1 level of patients with positive HER-2 gene expression was analyzed. The ROC curve of CYFRA21-1 expression in HER-2 positive patients was drawn to analyze the threshold of predicting HER-2 positive gastric cancer. Results Serum CYFRA21-1 level was correlated with histopathological differentiation and classification of gastric cancer, TNM stage and tumor size (P<0.05). The level of CYFRA21-1 in HER-2 positive group was significantly higher than that in negative group (P=0.038). The OR value of CYFRA21-1 in the positive HER-2 group was 3.529 (0.967-12.878), and the prediction percentage of positive HER-2 gastric cancer patients was 70.4%. When the cutoff value of CYFRA21-1 was 3.60 ng/mL, the sensitivity and specificity of positive HER-2 prediction in gastric cancer patients would reach the highest, which were 0.552 and 0.833, respectively. The 1-year, 2-year and 3-year survival rates of gastric cancer patients with CYFRA21-1<3.62 ng/mL were higher than those with CYFRA21-1>3.62 ng/mL (P=0.0024). The 1-year, 2-year and 3-year survival rates of HER-2 negative gastric cancer patients were higher than those of positive patients (P=0.0442). Conclusion The expression levels of HER-2 gene and sera CYFRA21-1 increase in patients with gastric cancer metastasis, large tumor and late TNM stage. The survival prognosis of patients with high CYFRA21-1 level and positive HER-2 is poor. High sera CYFRA21-1 level has a good warning effect on positive HER-2 gene in gastric cancer patients. -
Key words:
- HER-2 /
- CYFRA21-1 /
- gastric cancer /
- TNM stage /
- tumor marker
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表 1 HER-2阳性和阴性患者的临床基线资料及患者不同状态下HER-2表达(例,%)、CYFRA21-1水平[Md(IQR)]差异比较
Table 1. Baseline data of patients with positive or negative HER-2 and comparison of HER-2 expression (n, %) and CYFRA21-1 level (Md[IQR]) in patients under different conditions
分组 总数/例 HER-2 CYFRA211/(ng·mL-1) 阴性(n=51) 阳性(n=76) χ2值 P值 水平 U/H值 P值 性别 1.928 0.165 -0.738 0.460 男 115 40(38.26) 51(44.35) 2.95(2.35 ~ 5.89) 女 50 11(22.00) 25(50.00) 3.93(2.29 ~ 6.23) 年龄 0.397 0.529 -0.700 0.484 <60岁 69 23(33.33) 30(43.48) 2.76(1.92 ~ 5.82) ≥60岁 96 28(29.17) 46(47.92) 3.00(2.35 ~ 4.44) 分化程度 0.378 0.539 -2.031 0.042 高-中分化腺癌 74 22(29.73) 37(50.00) 2.56(1.98 ~ 4.45) 低分化腺癌-印戒细胞癌 89 29(32.58) 39(43.82) 3.25(2.41 ~ 4.50) Lauren分型 0.232 0.630 -0.627 0.530 肠型 56 23(41.07) 31(55.36) 2.83(2.24 ~ 4.73) 弥散型 + 混合型 90 28(31.11) 45(50.00) 3.14(2.37 ~ 4.48) Borrmann分型 4.651 0.031 -0.117 0.907 早癌 + 结节型 55 12(21.82) 32(58.18) 2.81(2.44 ~ 5.66) 溃疡型 + 弥漫型 110 39(35.45) 44(40.00) 3.21(2.28 ~ 4.45) TNM分期 1.984 0.371 11.291 0.004 Ⅰ 54 17(31.48) 26(48.15) 2.54(2.00 ~ 2.98) Ⅱ+Ⅲ 63 26(41.27) 29(46.03) 3.25(2.38 ~ 5.74) Ⅳ 34 7(20.59) 16(47.06) 4.09(3.22 ~ 6.79) 浸润程度(T) 2.521 0.471 9.077 0.028 黏膜层 50 12(24.00) 26(52.00) 2.56(2.05 ~ 2.87) 固有肌层 15 6(40.00) 6(40.00) 3.21(1.76 ~ 5.66) 浆膜层 44 16(36.36) 19(43.18) 3.00(2.29 ~ 4.50) 胃壁全层 34 15(44.12) 17(50.00) 4.09(3.29 ~ 6.79) 淋巴结转移(N) 5.131 0.274 -3.513 <0.001 无 69 25(36.23) 32(46.38) 2.52(1.92 ~ 3.16) 有 74 24(32.43) 33(44.59) 3.80(2.56 ~ 6.38) 远处转移(M) 1.824 0.177 -3.320 <0.001 无 118 43(36.44) 54(45.76) 2.70(2.23 ~ 4.27) 有 35 7(20.00) 17(48.57) 4.44(3.60 ~ 6.84) 肿瘤个数 1.047 0.306 -1.172 0.241 单个 133 47(35.34) 61(45.86) 3.10(2.36 ~ 4.45) 多个 10 2(20.00) 6(60.00) 2.34(1.66 ~ 7.21) 肿瘤大小 0.076 0.782 -4.111 <0.001 直径<3 cm 86 28(32.56) 40(46.51) 2.56(1.97 ~ 3.14) 直径≥3 cm 56 21(37.50) 27(48.21) 4.38(3.25 ~ 6.78) 表 2 肿瘤标志物水平在HER-2阳性与阴性胃癌患者中的表达差异[Md(IQR)]
Table 2. Differences in the expression of tumor markers levels in patients with HER-2 positive or negative gastric cancer (Md[IQR])
变量 HER-2阴性
(n=51)HER-2阳性
(n=76)U值 P值 CEA/(μg·L-1) 2.39(1.60 ~ 3.37) 2.80(1.36 ~ 5.73) -1.810 0.070 AFP/(μg·L-1) 2.97(1.93 ~ 3.78) 2.67(2.37 ~ 3.03) -0.234 0.815 CA19-9/(U·mL-1) 8.87(6.38 ~ 11.11) 10.25(6.30 ~ 25.34) -1.195 0.232 CA15-3/(U·mL-1) 7.65(6.37 ~ 10.94) 9.34(6.81 ~ 12.45) -1.820 0.069 CA724/(U·mL-1) 2.35(1.20 ~ 3.99) 3.19(1.41 ~ 9.96) -1.006 0.314 CYFRA21-1/(ng·mL-1) 2.38(2.20 ~ 3.38) 3.91(2.57 ~ 6.60) -2.073 0.038 NSE/(ng·mL-1) 11.66(9.84 ~ 16.53) 12.50(9.48 ~ 15.24) -0.909 0.364 SCC/(ng·mL-1) 0.90(0.70 ~ 1.30) 0.85(0.70 ~ 1.03) -0.156 0.876 PGⅠ/(ng·mL-1) 47.10(29.00 ~ 73.80) 53.80(33.80 ~ 111.88) -1.009 0.313 PGⅡ/(ng·mL-1) 10.40(7.00 ~ 15.90) 15.55(8.50 ~ 23.73) -1.446 0.148 PGⅠ/Ⅱ 5.79(2.64 ~ 7.67) 4.03(2.39 ~ 6.34) -0.895 0.371 表 3 HER-2表达与CYFRA21-1水平相关性分析
Table 3. Correlation analysis of HER-2 expression and CYFRA21-1 level
变量 CYFRA21-1 r值 P值 HER-2 0.251 0.037 表 4 基于CYFRA211、CEA、CA153建立的二元logistic回归模型
Table 4. Binary logistic regression model based on CYFRA211
变量 B $S \bar x $ Wald Sig OR OR 95% CI CYFRA211 1.261 0.661 3.644 0.056 3.529 0.967 ~ 12.878 CEA 0.859 0.945 0.825 0.364 2.360 0.370 ~ 15.049 CA153 0.998 1.240 0.648 0.421 2.713 0.239 ~ 30.828 常数 -0.023 0.322 0.005 0.944 0.978 - 表 5 血清肿瘤标志物预测HER-2阳性胃癌患者的效能
Table 5. Efficacy of serum tumor markers in predicting HER-2 positive gastric cancer patients
变量 敏感
度特异
度约登
指数截断
值P值 AUC 95% CI CEA 0.310 0.944 0.255 4.25 0.470 0.563 0.399 ~ 0.727 AFP 0.897 0.333 0.230 2.03 0.584 0.452 0.264 ~ 0.640 CA19-9 0.310 0.944 0.255 20.95 0.294 0.592 0.431 ~ 0.753 CA15-3 0.690 0.556 0.245 7.72 0.406 0.573 0.406 ~ 0.740 CA724 0.414 0.889 0.303 5.57 0.165 0.622 0.459 ~ 0.784 NSE 0.586 0.611 0.197 12.17 0.965 0.496 0.317 ~ 0.675 SCC 0.690 0.389 0.079 0.80 0.470 0.437 0.264 ~ 0.609 PGⅠ 0.345 0.889 0.234 88.70 0.375 0.578 0.407 ~ 0.748 PGⅡ 0.586 0.722 0.308 14.00 0.189 0.615 0.445 ~ 0.785 PGⅠ/Ⅱ 0.793 0.278 0.071 2.72 0.336 0.416 0.243 ~ 0.588 CYFRA21-1 0.552 0.833 0.385 3.62 0.020 0.704 0.548 ~ 0.860 -
[1] Feng RM,Zong YN,Cao SM,et al. Current cancer situation in China:good or bad news from the 2018 Global Cancer Statistics?[J]. Cancer Commun (Lond),2019,39(1): 22. doi: 10.1186/s40880-019-0368-6 [2] Sitarz R,Skierucha M,Mielko J,et al. Gastric cancer:epidemiology,prevention,classification,and treatment[J]. Cancer Manag Res,2018,10: 239-248. doi: 10.2147/CMAR.S149619 [3] 左婷婷,郑荣寿,曾红梅,等. 中国胃癌流行病学现状[J]. 中国肿瘤临床,2017,44(1): 52-58. [4] Kaito A,Kuwata T,Tokunaga M,et al. HER2 heterogeneity is a poor prognosticator for HER2-positive gastric cancer[J]. World J Clin Cases,2019,7(15): 1964-1977. doi: 10.12998/wjcc.v7.i15.1964 [5] Caviglia GP,Ciruolo M,Olivero A,et al. Prognostic role of serum cytokeratin-19 fragment (CYFRA 21-1) in patients with hepatocellular carcinoma[J]. Cancers (Basel),2020,12(10): E2776. doi: 10.3390/cancers12102776 [6] 中华医学会肿瘤学分会,无,徐惠绵. 中华医学会胃癌临床诊疗指南(2021版)[J]. 中华医学杂志,2022,102(16): 1169-1189. [7] Erratum: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2020, 70(4): 313. [8] Ma Z,Wu XX,Xu B,et al. Development of a novel biomarker model for predicting preoperative lymph node metastatic extent in esophageal squamous cell carcinoma1[J]. Oncotarget,2017,8(62): 105790-105799. doi: 10.18632/oncotarget.22399 [9] Uğraş N,Yerci Ö,Özgün G,et al. Immunohistochemical expression of CDX2,CK7,HER2 and HER4 in periampullary adenocarcinoma:implications for clinicopathology and patient outcomes[J]. Acta Gastroenterol Belg,2017,80(1): 31-37. [10] Li ZT,Chen SY,Feng WJ,et al. A pan-cancer analysis of HER2 index revealed transcriptional pattern for precise selection of HER2-targeted therapy[J]. EBioMedicine,2020,62: 103074. doi: 10.1016/j.ebiom.2020.103074 [11] Faruki H,Mayhew GM,Serody JS,et al. Lung adenocarcinoma and squamous cell carcinoma gene expression subtypes demonstrate significant differences in tumor immune landscape[J]. J Thorac Oncol,2017,12(6): 943-953. doi: 10.1016/j.jtho.2017.03.010 [12] 杨翠红. 胃癌中HER-2与Lauren分型的临床病理关系[D]. 哈尔滨: 哈尔滨医科大学, 2020. [13] 魏振. 胃癌Borrmann/Lauren/WHO各分型的临床病理特征和联系[D]. 天津: 天津医科大学, 2014. [14] Lei YY,Huang JY,Zhao QR,et al. The clinicopathological parameters and prognostic significance of HER2 expression in gastric cancer patients:a meta-analysis of literature[J]. World J Surg Oncol,2017,15(1): 68. doi: 10.1186/s12957-017-1132-5 [15] Zhou WW,Yang YH,Wang ZZ,et al. Impact of HSP90α,CEA,NSE,SCC,and CYFRA21-1 on lung cancer patients[J]. J Healthc Eng,2021,2021: 6929971. [16] Xu BH,Huang CY,Yang XZ,et al. Significance and prognostic role of human epidermal growth factor receptor 2 and RAB1A expression in gastric cancer[J]. Oncol Lett,2018,15(4): 5185-5192. [17] 刘晨旭,秦艳茹,常志伟. 胃癌患者HER2表达状态的影响因素分析[J]. 河南医学研究,2021,30(32): 5982-5986. [18] Wang Y,He L,Cheng Y. An independent survival prognostic role for human epidermal growth factor receptor 2 in gastric cancer:evidence from a meta-analysis[J]. Clin Transl Oncol,2018,20(2): 212-220. doi: 10.1007/s12094-017-1711-5 -