回顾性研究曲妥珠单抗联合化疗治疗HER2阳性晚期胃癌的临床疗效、安全性及治疗前后HER2状态及耐药基因的研究

发布时间：2018-05-06 14:23

本文选题：胃癌 + 人表皮生长因子受体2　；参考：《中国人民解放军医学院》2017年硕士论文

【摘要】：目的回顾性研究曲妥珠单抗联合不同化疗方案治疗HER2阳性晚期胃癌的在一线、二线及跨线治疗中的临床疗效及安全性。探讨HER2阳性晚期胃癌患者应用曲妥珠单抗治疗前后HER2状态及耐药基因的变化。方法1.收集2007年3月至2016年9月我院接受曲妥珠单抗联合化疗治疗的95例HER2阳性晚期胃癌患者的临床病例资料,回顾性分析曲妥珠单抗联合不同治疗方案在一线、二线及跨线治疗中的疗效及安全性;2.收集我院于2009年11月至2016年9月22例HER2阳性晚期胃癌应用曲妥珠单抗治疗前后留取的肿瘤组织,经免疫组化、荧光原位杂交及高通量二代基因检测技术,明确治疗前后HER2的状态及耐药基因的变化。结果1.一线应用曲妥珠单抗联合化疗治疗的患者共74例,其中曲妥珠单抗联合铂类组38例(51.4%),联合紫衫类组36例(48.6%);男性53例(71.6%),女性21例(28.4%)。曲妥珠单抗联合铂类药物治疗组ORR为57.9%, DCR为92.1%;联合紫杉类药物治疗组ORR为55.6%, DCR为94.4%;铂类组及紫杉类组的mPFS分别为7.3个月和7.6个月,mOS分别为26.7个月和19.2个月。两组患者近期疗效及远期生存均相当,差异无统计学意义(P 0.05); 2.曲妥珠单抗联合铂类治疗组及联合紫杉类治疗组均未出现治疗相关性死亡,不良反应患者均可耐受。其中联合铂类治疗组外周神经毒性不良反应较联合紫杉类治疗发生率高,联合紫杉类组脱发的发生率明显高于铂类治疗组;3.二线治疗应用曲妥珠单抗治疗的病例数为48例,其中曲妥珠单抗跨线治疗组27例(56.3%),未跨线治疗组21例(43.7%);全组患者中男性32例(66.7%),女性16例(33.3%);曲妥珠单抗跨线治疗组ORR为7.4%, DCR为66.7%,mPFS为3.4个月,mOS为10.9个月,未跨线治疗组的ORR为33.3%, DCR为71.4%, mPFS为5.5个月,mOS为15.7个月。未跨线组的ORR显著高于跨线组,且差异有统计学意义(P=0.022 ),未跨线治疗组mOS较跨线治疗组延长4.8个月(mOS:15.7个月VS. 10.9个月),差异有统计学意义(P=0.042)。二线治疗中继续应用曲妥珠单抗治疗可改善患者近期疗效及延长远期生存;4. 9例曲妥珠单抗联合化疗治疗未进展组,约55.6% ( 5/9)的病例二次行HER2免疫组化(IHC)检测时出现HER2蛋白表达明显减低,其中2例初始HER2 ( ++ ) /FISH扩增的患者,二线检测HER2免疫组化均为阴性;5. 13例曲妥珠单抗联合化疗治疗进展组,耐药后8例行二次HER2 IHC检测的患者中3例HER2蛋白表达减低,其中1例转为阴性;两例耐药前HER2 IHC3+/基因扩增,耐药后基因未扩增;8例耐药前后均为TP53突变;3例PIK3CA基因耐药前未突变,耐药后为突变型,1例耐药前后KRAS基因均为突变,1例耐药前后ERBB2均为突变,1例耐药前后ERBB3均为突变,1例耐药前后雷帕霉素靶点(mTOR)基因均扩增,1例患者耐药后样本检测到ERBB2与GRB7IKZF3基因间隔区融合。结论曲妥珠单抗联合铂类或紫杉类药物在HER2阳性晚期胃癌一线治疗中近期疗效及远期生存均可获益,两组治疗疗效相当;在HER2阳性晚期胃癌二线治疗中,初始联合曲妥珠单抗治疗组ORR较跨线治疗组的明显提高,mPFS及mOS均有延长的趋势。HER2阳性晚期胃癌患者应用曲妥珠单抗治疗后,无论是否出现曲妥珠单抗耐药均会出现HER2蛋白表达的降低或改变;应用曲妥珠单抗治疗耐药前后伴随HER2、PIK3CA、KRAS、mTOR、ERBB3基因的改变,可能与其的原发或获得性耐药有关。
[Abstract]:Objective to review the clinical efficacy and safety of trastuzumumab combined with different chemotherapy regimens in the treatment of HER2 positive advanced gastric cancer in the first line, second line and cross line therapy. To explore the changes of HER2 status and resistance genes in HER2 positive advanced gastric cancer patients before and after the use of trastuzumab. Method 1. collect the results from March 2007 to September 2016. The clinical data of 95 patients with HER2 positive advanced gastric cancer treated with trastuzumab combined with chemotherapy were reviewed to review the efficacy and safety of trastuzumab combined with different treatments in the first line, second line and cross line treatment. 2. the use of trastuzuma in 22 cases of HER2 positive advanced gastric cancer from November 2009 to September 2016 in our hospital was collected. The tumor tissue retained before and after anti treatment, by immunohistochemistry, fluorescence in situ hybridization and high throughput two generation gene detection techniques, the status of HER2 and the changes of resistance genes before and after treatment were determined. Results the 1. line of 74 cases were treated with trastuzumab combined with chemotherapy, of which 38 cases (51.4%), 38 cases (51.4%) of the combination of trastuzumab combined with platinum group, combined with purple shirts. Group 36 (48.6%), 53 men (71.6%) and 21 women (28.4%). ORR was 57.9% and DCR was 92.1% in the combination of trastuzumab and platinum group. The combined paclitaxel group was 55.6%, DCR was 94.4%, mPFS in group platinum group and Taxus group was 7.3 months and 7.6 months respectively, mOS was 26.7 months and 53 months respectively. And the long-term survival was equal, the difference was not statistically significant (P 0.05); 2. the combination of the platinum group and the combined Taxus group had no treatment related death, and the patients with adverse reactions were tolerable. The incidence of group alopecia was significantly higher than that in the platinum group; 48 cases were treated with trastuzumab in 3. second line treatment, including 27 cases (56.3%) of trastuzumab cross line treatment group, 21 cases in the non cross line treatment group (43.7%), 32 in the whole group (66.7%) and 16 in women (33.3%); ORR in the trastuzumab trans line treatment group was 7.4%, DCR was 66.7%, M PFS was 3.4 months and mOS was 10.9 months. The ORR in the non cross line treatment group was 33.3%, DCR was 71.4%, mPFS was 5.5 months and mOS was 15.7 months. The ORR in the non cross line group was significantly higher than the cross line group, and the difference was statistically significant (P=0.022). The mOS in the non cross line treatment group was longer than the cross line treatment group for 4.8 months (mOS:15.7 month VS. 10.9 months), the difference was statistically significant. P=0.042. The continued use of trastuzumab in the second line therapy could improve the short-term efficacy and prolong the long-term survival of the patients; 4.9 cases of trastuzumab combined with chemotherapy in the unprogressed group, about 55.6% (5/9) of the two cases of HER2 immunohistochemical (IHC) detection showed a significant decrease in the expression of HER2 egg white, of which 2 cases of initial HER2 (+ +) /FISH expanded. In addition, the second line detection of HER2 immunohistochemical staining was negative. 5.13 cases of trastuzumab combined with chemotherapy, 3 cases of 8 cases with two HER2 IHC after drug resistance were reduced in the expression of HER2 protein, of which 1 cases were negative, two cases were amplified by HER2 IHC3+/ gene, and the gene was not amplified after drug resistance; 8 cases were all TP53 mutations before and after resistance. 3 cases of PIK3CA gene were not mutated before and after resistance. The KRAS gene was mutated before and after drug resistance in 1 cases, 1 cases were mutated before and after drug resistance, 1 cases were all mutation before and after drug resistance, 1 cases of rapamycin target (mTOR) before and after drug resistance were all amplified, and 1 cases of after drug resistance detected the fusion of ERBB2 and GRB7IKZF3 gene interval. In the treatment of HER2 positive advanced gastric cancer, the combination of trastuzumab combined with platinum or paclitaxel in the treatment of HER2 positive advanced gastric cancer can benefit, and the curative effect is equal. In the second line treatment of HER2 positive advanced gastric cancer, the initial combined trastuzumab treatment group is significantly higher than the cross line treatment group, and the mPFS and mOS have a prolonged trend. After the use of trastuzumab for HER2 positive advanced gastric cancer patients, no matter whether or not the resistance to trastuzumab occurs, the expression of HER2 protein may be reduced or changed. The changes of HER2, PIK3CA, KRAS, mTOR, and ERBB3 genes before and after the use of trastuzumab in the treatment of drug resistance may be related to its primary or acquired resistance.

【学位授予单位】：中国人民解放军医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.2

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