肿瘤时空异质性对进展期胃癌患者HER-2过表达影响的临床研究

发布时间：2018-04-24 02:16

本文选题：进展期胃癌 + 肿瘤时空异质性　；参考：《河北医科大学》2017年硕士论文

【摘要】：目的:通过观察进展期胃癌患者不同个体之间及同一个体的化疗前与化疗后,术前与术后以及原发灶与转移灶,原发灶的不同区域之间HER-2的表达状态,分析肿瘤时空异质性对进展期胃癌患者HER-2过表达的影响,为进一步探讨胃癌的真正个体化精准治疗提供理论依据。方法:选取前瞻性、多中心、开放、随机对照Ⅲ期临床试验(NCT01516944)中胃或胃食管结合部腺癌患者共521例,其中直接手术患者277例和新辅助化疗患者244例,采用免疫组织化学染色(IHC)法,对直接手术的277例进展期胃癌患者术后进行HER-2蛋白表达的检测(其中2+和3+认为是HER-2蛋白过表达),分析肿瘤异质性在进展期胃癌患者不同个体之间HER-2蛋白过表达的影响;观察进展期胃癌患者在术前与术后,化疗前与化疗后HER-2的表达状态,分析肿瘤时间异质性在同一个体中HER-2蛋白的影响;观察进展期胃癌患者原发灶与转移灶(淋巴结转移灶、肝转移灶、腹腔灌洗液脱落细胞(PLC)阳性,原发灶的不同区域HER-2的表达状态,分析肿瘤空间异质性对进展期胃癌患者HER-2过表达的影响。结果:1不同个体之间,277例直接手术患者中,HER-2过表达与患者性别、年龄、肿瘤大小、远处转移、脉管瘤栓、神经受侵无统计学差异(P0.05),而与患者的分化程度、Lauren分型、浸润深度、淋巴结转移、TNM分期具有统计学差异(P0.05);2同一个体,277例直接手术患者中,术前咬检及术后标本经过IHC方法行HER-2蛋白检测,胃镜咬检组织中HER-2过表达率为32.85%,术后标本测得HER-2蛋白过表达率29.60%,两者无统计学差异。虽然在术前标本和术后标本两组中,HER-2评分0/1+和2+/3+两组比例极其相似,但41例(14.8%)配对标本的IHC评分不一致(活检标本评分为0/1+者在手术标本则评分为2+/3+,或活检标本评分为2+/3+者在手术标本则评分为0/1+)。3同一个体,244例接受新辅助化疗患者,经过新辅助化疗后,除去15例患者化疗后胃镜咬检标本病理为炎性组织或异型细胞,在剩下的229例患者中,104例患者为化疗前胃镜咬检的HER-2过表达,HER-2的过表达率为45.41%,86例患者为化疗后胃镜咬检的HER-2过表达,过表达率为37.55%,两者无统计学差异。虽然在化疗前、后胃镜咬检,HER-2评分0/1+和2+/3+两组比例极其相似,但26例(11.35%)配对标本的IHC评分不一致(化疗前标本评分为0/1+者在化疗后标本则评分为2+/3+,或化疗前标本评分为2+/3+者在化疗后标本则评分为0/1+)。4同一个体,244例接受新辅助化疗患者,经过新辅助化疗后,10例患者术后标本组织中未见残余癌(化疗后出现PCR),在剩下的234例患者中,术后标本HER-2蛋白(+)的约86人,过表达率约36.75%。与化疗前胃镜咬检45.41%对比,差异不具有统计学意义(P=0.1660.05)(Table7)。虽然在化疗前胃镜咬检与术后标本,HER-2评分0/1+和2+/3+两组比例极其相似,化疗前胃镜咬检(+)且术后标本HER-2蛋白(+)的共76人,化疗前胃镜咬检(-)且术后标本HER-2蛋白(-)的共118人,一致性为82.90%。但40例(17.47%)配对标本的IHC评分不一致(化疗前咬检评分为0/1+者在化疗后标本则评分为2+/3+,或化疗前咬检评分为2+/3+者在化疗后标本则评分为0/1+)。5 30例左锁骨上淋巴结转移患者中,原发灶与淋巴结HER-2表达一致率为86.67%。不一致率为:13.33%(4/30)。4例蛋白表达不一致病例。其中2例原发灶阴性,而淋巴结转移灶HER-2蛋白过表达(阳性转变),阳性转变率为6.67%;其中2例原发灶阳性,而淋巴结转移灶HER-2阴性表达(阴性转变),阴性转变率为6.67%。12例肝转移穿刺活检阳性的患者的初诊胃镜活检与肝转移标本的HER-2蛋白表达一致性为83.34%,不一致率为:16.67%(2/12)。即2例蛋白表达不一致病例。其中1例原发灶阴性,而肝转移灶HER-2蛋白过表达(阳性转变),阳性转变率为8.34%;其中1例原发灶阳性,而肝转移灶HER-2蛋白阴性表达(阴性转变),阴性转变率为8.34%。5例腹腔灌洗液脱落细胞(PLC)阳性的患者中,初诊胃镜活检与腹腔灌洗液脱落细胞HER-2蛋白表达一致性为40%,不一致率为:60%(3/5)。即3例蛋白表达不一致病例。3例原发灶阳性,而腹腔灌洗液脱落细胞HER-2蛋白阴性表达(阴性转变),没有阳性转变。6 50例直接手术患者中,对同一患者原发灶的不同区域行粗针穿刺取材并进行IHC方法检测,贲门侧、中心、幽门侧三个区域HER-2蛋白表达一致率为:86%(43/50)。其中约14%的的IHC评分不一致。即7例患者中,原发灶中同时存在阴性区域及过表达区域。结论:1不同的个体间,随着胃癌浸润深度、淋巴转移、TNM分期增加,HER-2蛋白过表达率随之增加,并且HER-2蛋白过表达率在中分化胃癌患者中所占比例较大。2同一个体中,HER-2状态存在时间异质性,不同的时间节点,即术前与术后,化疗前与化疗后的HER-2表达状态存在不一致状态,综合术前与术后,化疗前与化疗后的过阳性患者,可提高HER-2阳性检出率。3同一个体中,HER-2表达存在明显的空间异质性,HER-2表达在原发灶和其他转移灶(肝转移灶及淋巴结转移灶和腹腔灌洗液脱落细胞)存在差异性表达,若原发灶HER-2阴性,尤其针对存在转移复发的晚期患者,应进一步检测转移灶。4同一原发灶的不同区域,HER-2表达状态呈差异性表达,说明HER-2阳性率的检测与取材部位及个数有关,由于肿瘤空间异质性的影响,增加肿瘤检测区域,将有助于全面可靠评估HER-2表达。
[Abstract]:Objective: To investigate the effect of HER-2 on the expression of HER-2 in the patients with advanced gastric cancer by observing the expression status of the different regions between pre and post chemotherapy before and after chemotherapy and after chemotherapy, before and after chemotherapy and after chemotherapy, before and after chemotherapy, and after chemotherapy, and after chemotherapy, and after chemotherapy, and after chemotherapy. Methods: 521 patients with gastric or gastroesophageal junction adenocarcinoma were selected in a prospective, multi center, open, randomized controlled clinical trial (NCT01516944), including 277 cases of direct surgery and 244 patients with neoadjuvant chemotherapy, 277 cases of direct operation with immunohistochemical staining (IHC), and 277 cases of direct operation. The expression of HER-2 protein in patients with advanced gastric cancer (of which 2+ and 3+ are considered to be HER-2 protein overexpression), and to analyze the effect of HER-2 protein overexpression between different individuals in advanced gastric cancer patients, and to observe the expression of HER-2 before and after chemotherapy, before and after chemotherapy, and to analyze the tumor in advanced gastric cancer patients. The effect of time heterogeneity on HER-2 protein in the same individual; to observe the primary and metastatic foci (lymph node metastases, liver metastases, PLC) positive and the expression state of HER-2 in different regions of primary gastric cancer, and to analyze the effect of spatial heterogeneity of tumor on the HER-2 overexpression in advanced gastric cancer patients. Fruit: 1 among 277 patients, HER-2 overexpression was significantly different from the patient's sex, age, tumor size, distant metastasis, vascular tumor thrombus, and nerve invasion (P0.05), while the degree of differentiation, Lauren, infiltration, lymph node metastasis, and TNM staging were statistically different from those of the patients (P0.05); 2 of the same individuals and 277 cases were straight. In surgical patients, HER-2 protein was detected by IHC method before and after operation. The rate of HER-2 overexpression in gastroscopy was 32.85%, and the rate of HER-2 protein overexpression was 29.60% after operation. Although there were no statistical differences between the two groups, the HER-2 scores of 0/1+ and 2+/3+ two were very similar in the preoperative and postoperative specimens of two groups. But in 41 cases (14.8%), the IHC score of the paired specimens was inconsistent (the score of the biopsy specimen was 0/1+ in the surgical specimen 2+/3+, or the score of the biopsy specimen was 0/1+).3 in the same individual, and the 244 patients received the neoadjuvant chemotherapy, after the neoadjuvant therapy, the pathology of the gastroscopy specimen after chemotherapy was removed. For the 229 patients with inflammatory tissue or heterotypic cells, in the remaining 229 patients, 104 patients were overexpressed by pre chemotherapy gastroscopy, the overexpression rate of HER-2 was 45.41%, and 86 patients were HER-2 overexpressed by gastroscopy after chemotherapy, and the overexpression rate was 37.55%. There was no statistical difference between the two patients. The HER-2 score was 0/1+ and 2+/ before chemotherapy. The proportion of the 3+ two groups was very similar, but the IHC score of the paired specimens was not consistent in 26 cases (11.35%). The pre chemotherapy specimens were rated as 2+/3+ after chemotherapy, or the pre chemotherapy specimens were 2+/3+ in the specimens after chemotherapy and 0/1+).4 in the same individual, and 244 patients received neoadjuvant chemotherapy, after the neoadjuvant chemotherapy, 10 patients after chemotherapy. There was no residual cancer in the tissue after the operation (PCR after chemotherapy). In the remaining 234 patients, about 86 of the postoperative specimens were HER-2 protein (+), the overexpression rate was about 36.75%. compared with the pre chemotherapy gastroscopy 45.41%, the difference was not statistically significant (P=0.1660.05) (Table7). The HER-2 score was 0/1+ and 2 in the preoperative gastroscopy and postoperative specimens. The proportion of +/3+ two groups was very similar, 76 people with pre chemotherapy gastroscopy (+) and postoperative specimens of HER-2 protein (+), 118 people with HER-2 protein (-) before chemotherapy and after the operation, the consistency was 82.90%., but 40 cases (17.47%) matched the IHC score of the paired specimens (the pre chemotherapy bite score was 0/1+ after chemotherapy, the score was 2+/3+, or Before chemotherapy, the score of 2+/3+ was 0/1+ after chemotherapy. In.5 30 cases of left supraclavicular lymph node metastasis, the consistent rate of HER-2 expression in the primary foci and lymph nodes was 86.67%.: 13.33% (4/30).4 case protein expression inconsistency. 2 cases were negative, while HER-2 protein overexpression in lymph node metastasis (positive) was positive. The positive conversion rate was 6.67%, of which 2 cases were positive, and the lymph node metastases HER-2 negative expression (negative transformation). The negative transformation rate was 83.34% for the HER-2 protein expression of the first diagnosed gastroscopy and liver metastasis of 6.67%.12 cases with positive liver metastases, and the inconsistency rate was 16.67% (2/12). That is, 2 cases of protein table. Of these cases, 1 cases were negative, and the liver metastases HER-2 protein overexpression (positive transformation) and positive conversion rate were 8.34%, of which 1 cases were positive, and the negative transformation of HER-2 protein in liver metastases (negative transformation), negative transformation rate was in 8.34%.5 cases of PLC positive of peritoneal lavage fluid (PLC). The concordance of HER-2 protein expression in the exfoliative cells of the peritoneal lavage fluid was 40%, the inconsistency rate was 60% (3/5), that is, 3 cases of protein expression inconsistency in.3 cases were positive, and the negative expression of HER-2 protein (negative transformation) in the exfoliated cells of the peritoneal lavage fluid (negative transformation), and no positive transformation of.6 in 50 cases of direct surgery, the different areas of the same patient's primary focus were performed. HER-2 protein expression in three regions of the cardia side, center and pylorus was 86% (43/50). Among them, about 14% of the IHC scores were inconsistent. That is, there were negative regions and overexpressed regions in the primary foci. Conclusion: 1 different individuals, with the depth of infiltration of gastric cancer, lymphatic metastasis, TNM The over expression rate of HER-2 protein increases with the increase of stages, and the rate of overexpression of HER-2 protein in patients with differentiated gastric cancer is larger in.2, HER-2 state has time heterogeneity. Different time nodes, that is, preoperative and postoperative, the state of HER-2 expression before and after chemotherapy, comprehensive before and after the operation. The positive rate of HER-2 positive in the same individual before and after chemotherapy can improve the positive rate of.3 in the same individual, and the expression of HER-2 has obvious spatial heterogeneity. The expression of HER-2 in the primary and other metastatic foci (liver metastasis and lymph node metastasis and peritoneal lavage exfoliative cells) is differential expression, if the primary focal HER-2 is negative, especially for the survival of the metastasis. In the advanced patients with metastatic recurrence, the different regions of the same primary focus of.4 should be further detected. The expression of HER-2 expression is differential expression, indicating that the detection of HER-2 positive rate is related to the location and number of the material. The increase of the tumor detection area due to the effect of tumor spatial heterogeneity will help to comprehensively and reliably evaluate the expression of HER-2.

【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.2

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