循环肿瘤细胞监测在胃肠间质瘤靶向治疗中的意义

Significance of circulating tumor cell monitoring in targeted therapy for gastrointestinal stromal tumors

目的探讨循环肿瘤细胞(CTC)监测在胃肠间质瘤(GIST)靶向治疗效果评估中的意义。方法采用前瞻性研究方法,收集南通大学附属医院2013年8月至2018年12月收治的局部晚期和伴肝转移的GIST患者资料。病例纳入标准:(1)年龄>18周岁;(2)病理组织学诊断为GIST;(3)术前影像学评估发现GIST侵犯周围器官或局部转移,估计难以达到R0切除、或肿瘤最大径>10 cm、或伴有肝转移、或预计手术发生并发症的风险较高而未行手术者;(4)首次接受伊马替尼400 mg/d治疗;(5)美国东部肿瘤协作组(ECOG)评分为0~2分。排除标准:(1)基因检测显示为PDGFRA基因18外显子的D842V突变;(2)丙氨酸氨基转移酶和(或)天冬氨酸氨基转移酶>2.5倍正常值上限;(3)血清总胆红素>1.5倍正常值上限;(4)中性粒细胞计数<1.5×10^(9)/L,或血小板计数<75×10^(9)/L,或血红蛋白<60 g/L;(5)肌酐>1倍正常值上限;(6)入组前12个月患有严重心脑血管疾病;(7)妊娠或哺乳期女性;(8)患有其他严重的急慢性生理或精神问题,经研究者判断,认为不适合参加研究。剔除入组后不能耐受伊马替尼治疗方案、或有严重不良反应以及不按方案服药者。在伊马替尼治疗前、治疗后1个月和2个月时,使用定量聚酶链反应法检测外周血中单核细胞的DOG⁃1表达量,并把DOG⁃1/β⁃肌动蛋白值>3×10^(-5)作为GIST的CTC阳性界值。分析CTC阳性率、伊马替尼治疗效果(包括完全缓解、部分缓解、疾病稳定、疾病进展情况和不良反应发生情况)以及CTC阳性与患者临床病理特征的关系。进一步将治疗后1个月的“DOG⁃1降低量/DOG⁃1基础量”作为评估靶向治疗是否有效的指标,绘制受试者工作曲线(ROC),计算曲线下面积(AUC)。结果共计68例GIST患者入组,39例为局部晚期GIST,29例GIST伴肝转移;男性32例,女性36例;年龄31~74(51.2±11.8)岁。全部患者接受伊马替尼治疗2个月后,有43例评估为部分缓解,11例为疾病稳定,无完全缓解病例,14例评估为疾病进展,伊马替尼有效率为79.4%(54/68)。伊马替尼治疗期间,3级或以上不良反应发生率22.1%(15/68),其中3级粒细胞减少12例,4级药疹3例,均予以保守治疗后症状缓解。68例患者在治疗前、治疗后1个月及2个月的CTC阳性率分别为66.2%(45/68)、41.2%(28/68)和23.5%(16/68)。CTC阳性与肿瘤大小、是否有肝转移、核分裂象及危险程度分级有关(均P<0.05)。将靶向治疗有效组与靶向治疗无效组分别进行分析发现,有效组CTC阳性率呈下降趋势,而无效组CTC阳性率却呈升高趋势。检测治疗后1个月的CTC改变趋势预测GIST靶向治疗效果的AUC=0.823(P<0.001),当治疗后1个月的DOG⁃1含量下降>57.5%时,可作为判断治疗有效的指标,灵敏度为72.2%,特异度为100%。结论检测外周血CTC可以评估GIST患者靶向治疗的效果,可以为进一步的治疗决策提供参考。

Objective To explore the significance of circulating tumor cell(CTC)monitoring in evaluating the efficacy of targeted therapy for gastrointestinal stromal tumor(GIST).Methods A prospective cohort study was performed.The data of patients with locally advanced GIST or liver metastasis who were admitted to The Affiliated Hospital of Nantong University from August 2013 to December 2018 were collected.Inclusion criteria:(1)patients aged older than 18 years;(2)patients who were diagnosed with GIST based on pathology;(3)patients without surgery,whose preoperative imaging evaluation of GIST found the violations of the surrounding organs or partial transfer of an estimated difficulty to achieve R0 resection,or the maximum diameter of the tumor>10 cm,or the liver metastasis,or the expectation of higher risk of surgical complications;(4)patients who were treated with the imatinib 400 mg/d for the first time;(5)Eastern Cooperative Oncology Group(ECOG)score of 0⁃2.Exclusion criteria:(1)genetic testing revealed a D842V mutation in exon 18 of the PDGFRA gene;(2)alanine aminotransferase and/or aspartate aminotransferase>2.5 times the normal upper limit;(3)serum total bilirubin>1.5 times of normal upper limit;(4)neutrophil count<1.5×10^(9)/L,or platelet count<75×10^(9)/L,or hemoglobin<60 g/L;(5)creatinine>normal upper limit;(6)patients had serious cardiovascular and cerebrovascular diseases within 12 months before enrollment;(7)female patients were pregnant or lactating;(8)patients suffered from other serious acute and chronic physical or mental problems,and were not suitable for participating in this study judged by researchers.The patients who could not tolerate treatment regimen,or developed serious adverse reactions and did not follow the medication scheme after enrollment were excluded.Before imatinib treatment and 1⁃month and 2⁃month after treatment,quantitative PCR was used to detect the DOG⁃1 expression of monocytes in peripheral blood,and the ratio of DOG⁃1/β⁃actin>3×10^(-5) was used as the CTC positive threshold of GIST.The positive rate of CTC,the efficacy of imatinib treatment(complete response,partial response,stable disease,progressive disease,and occurrence of adverse reactions),and the relationship between CTC positive rate and clinicopathological characteristics of patients were analyzed.Furthermore,the ratio of DOG⁃1 decrease/baseline DOG⁃1 after 1⁃month of treatment was used as an indicator to evaluate whether targeted therapy was effective.The receiver operating characteristic(ROC)curve was rendered,and the area under the curve(AUC)was calculated.Results A total of 68 GIST patients were enrolled in this study,including 39 cases of locally advanced GIST and 29 cases with liver metastases,32 males and 36 females with the mean age of(51.2±11.8)(range 31 to 74)years.After 2⁃month of imatinib treatment,43 cases were evaluated as partial response,11 cases as stable disease,and 14 cases as progressive disease,with an effective rate of 79.4%(54/68).During the treatment of imatinib,the incidence of grade 3 or higher adverse reactions was 22.1%(15/68),including 12 cases of grade 3 neutropenia and 3 of grade 4 drug eruption,which were all relieved after conservative treatment.The positive rates of CTC in 68 patients before treatment,1⁃month and 2⁃month after treatment were 66.2%(45/68),41.2%(28/68)and 23.5%(16/68),respectively.The positive rate of CTC was associated with tumor size,liver metastasis,mitotic count and risk level(all P<0.05).By analyzing the effective group and the ineffective group of targeted therapy,it was found that the positive rate of CTC in the effective group showed a decreasing trend,while the positive rate of CTC in the ineffective group showed an increasing trend.The AUC of predicting the efficacy of targeted therapy for GIST was 0.823 by detecting the change trend of CTC 1⁃month after treatment(P<0.001).When the DOG⁃1 content decreased by more than 57.5%1⁃month after treatment,it can be used as an indicator to judge the effectiveness of the treatment,whose sensitivity was 72.2%and specificity was 100%.Conclusion The detection of peripheral blood CTC can evaluate the efficacy of targeted therapy in GIST patients and can provide decision⁃making basis for further clinical treatment.