卵巢上皮性癌新辅助化疗后TP53 K351N突变相关的铂类耐药及预后分析

发布时间：2018-04-23 14:24

  本文选题：卵巢上皮性癌 + 新辅助化疗　； 参考：《广西医科大学》2017年硕士论文

【摘要】：背景:卵巢上皮性癌(Epithelial ovarian carcinoma,EOC)的治疗包含基于铂类的新辅助化疗后中间性肿瘤细胞减灭术(Neoadjuvant chemotherapy with interval debulking surgery,NACT-IDS)及初始肿瘤细胞减灭术(Primary debulking surgery,PDS)两种方式。大量研究发现NACT-IDS的无进展生存期(Progression free survival,PFS)比PDS的明显缩短,且NACT-IDS后6个月内复发概率高于PDS。其机制可能与NACT诱导TP53促调亡功能的四聚化结构域(tetramerization domain,TD)突变介导的获得性铂类耐药有关。目的:研究EOC患者中PDS组与NACT组是否存在TP53 TD突变及其与临床预后关系,尤其是在NACT组中。方法:采用组织DNA提取技术、巢式PCR、DNA测序技术检查108例EOC患者(其中NACT组51例,PDS组57例)是否存在TP53 TD突变。并通过查阅病例、电话随访的方式获取临床资料,对患者TP53 TD突变与铂类耐受进行相关性分析。结果:1、在51例新辅助化疗的EOC患者中,检测出4例EOC患者存在TP53 K351N突变(7.8%,4/51),且出现于18例接受4~6周期基于铂类的NACT中,突变率为22.2%(4/18)。2、在PDS组和NACT前标本中未检测出TP53 TD K351N突变。3、NACT组与PDS组患者总生存期(Overall survival,OS)及PFS差别有统计学意义(POS=0.013,PPFS=0.005)。PDS组病人的生存状况明显优于NACT组病人。NACT组中术后6个月内复发的概率为58.2%(30/51),明显高于PDS组6个月内复发的概率(35.1%,20/57);两组6月内复发率差别有统计学意义(P=0.014)。4、在NACT组内,术前化疗3周期的患者的中位PFS较术前化疗≤3周期的患者的中位PFS短,两者差别有统计学意义(P=0.044)。单因素及多因素COX回归分析结果显示,TP53 K351N突变是NACT组中6个月内复发患者较短PFS的独立因素(Hazard ratio,HR=9.309,P=0.043)。结论:1)治疗周期3个周期的,以铂类为基础的NACT可能是导致卵巢癌患者TP53 K351N突变和耐药复发的风险因素之一;2)不超过3个周期的以铂类为基础的NACT可能对降低TP53 K351N突变介导的铂类耐药发生有一定的作用;3)以铂类为基础的NACT-IDS后,检测TP53 K351N突变有利于规避化疗耐药,以及对制定后续化疗方案的选择具有重要的临床意义。
[Abstract]:Background: the treatment of epithelial ovarian carcinoma of ovary (EOC) includes two methods: Neoadjuvant chemotherapy with interval debulking surgeryn NACT-IDSs and primary debulking SurgeryPDSs based on platinum-based neoadjuvant chemotherapy with interval debulking query. A large number of studies showed that the progressive free survival of NACT-IDS was significantly shorter than that of PDS, and the probability of recurrence within 6 months after NACT-IDS was higher than that of PDS. The mechanism may be related to acquired platinum resistance mediated by tetramerization domain tetramerization domain (tetramerization domain) mutation of TP53 induced by NACT. Objective: to study the relationship between TP53 TD mutation and clinical prognosis in PDS and NACT in EOC patients, especially in NACT group. Methods: tissue DNA extraction technique and nested PCR DNA sequencing technique were used to detect the presence of TP53 TD mutation in 108 patients with EOC (including 51 patients with NACT and 57 patients with NACT). The correlation between TP53 TD mutation and platinum tolerance was analyzed. Results in 51 EOC patients with neoadjuvant chemotherapy, 4 patients with EOC had TP53 K351N mutation 7.8 / 51N, and 18 patients with 4G / 6 cycles of platinum-based NACT. The mutation rate was 22. 2 / 18. 2. There was no TP53 TD K351N mutation. 3NACT group and PDS group had significant difference in total survival time and PFS. The survival status of patients in the PDS group was significantly better than that in the NACT group. NACT group was significantly better than the NACT group in the 6 patients after operation. The survival rate of the patients in the PDS group was significantly higher than that in the NACT group. There was no significant difference in the total survival time of the patients in the PDS group and the total survival time of the patients in the PDS group. There was a significant difference in the survival status of the patients in the PDS group and in the PDS group. The probability of recurrence within months was 58.2 / 51%, which was significantly higher than that in PDS group (35.1a / 57) in 6 months. The difference of recurrence rate within six months between the two groups was statistically significant (P 0.014). 4, in NACT group, there was a significant difference between the two groups in the recurrence rate within 6 months. The median PFS of patients with 3 cycles of preoperative chemotherapy was shorter than that of patients with less than 3 cycles of preoperative chemotherapy. The difference between the two groups was statistically significant. Univariate and multivariate COX regression analysis showed that TP53 K351N mutation was an independent factor for short PFS in patients with recurrence within 6 months in NACT group. ConclusionsThe treatment cycle is 3 cycles. Platinum-based NACT may be one of the risk factors for TP53 K351N mutation and drug resistance recurrence in ovarian cancer patients.) Platinum-based NACT with no more than 3 cycles may play a role in reducing platinum resistance mediated by TP53 K351N mutation. After platinum-based NACT-IDS, Detection of TP53 K351N mutation is helpful to avoid chemotherapeutic resistance and has important clinical significance in the selection of subsequent chemotherapy regimen.
【学位授予单位】：广西医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R737.31
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本文编号：1792337