基于脑脊液和血液样本的乳腺癌脑转移相关耐药基因突变的鉴定及功能分析

Identification and Functional Verification of Drug-Resistant Gene Mutations Associated with Breast Cancer Brain Metastasis Based on Cerebrospinal Fluid and Blood Samples

【目的】探讨乳腺癌脑转移患者脑脊液和血液来源的基因突变情况,筛查耐药基因及分析耐药机制。【方法】本院收治的70例乳腺癌脑转移患者为研究对象,采用二代基因测序技术检测患者脑脊液和血液样本中的循环肿瘤DNA(ctDNA)了解基因突变情况,并进行耐药性筛查及分析其与突变基因的关联性。【结果】70例患者中主要检测出TP53、HER2、PIK3CA、BRCA1和BRCA2五个主要突变基因,脑脊液来源的样品中基因突变的检出率为100%(70/70),高于血液来源样品的65.71%(46/70)(P<0.05)。以不带有HER2和PIK3CA突变的21例样品为对照组,HER2突变的患者对曲妥珠单抗的耐药性比例高于对照组(P<0.05);PIK3CA突变的患者对曲妥珠单抗、阿替利珠单抗、紫杉醇和阿霉素4种药的耐药性比例与对照组比较,差异均无统计学意义(P>0.05)。同时,HER2突变患者对阿替利珠单抗、紫杉醇和阿霉素的耐药性比例与对照组比较,差异均无统计学意义(P>0.05)。【结论】乳腺癌脑转移患者的脑脊液比血液更能准确反映脑转移情况,若检出HER2突变,则提示可能有对应的耐药基因存在,这对用药指导、耐药监测等意义重大。

【Objective】This study aims to investigate the gene mutation profile in cerebrospinal fluid(CSF)/blood-derived samples from patients with brain metastases of breast cancer for screening drug-resistant genes to verify their resistance mechanisms.【Methods】A total of 70 patients with brain metastases from breast cancer treated in our hospital were selected for the study.Second-generation sequencing technology was used to detect circulating tumor DNA(ctDNA)in CSF and blood samples to understand the gene mutation status,and to screen drug resistance and analyze the association with mutant genes.【Results】The main gene mutations detected in the 70 patients included TP53,HER2,PIK3CA,BRCA1,and BRCA2.The mutation detection rate in CSF-derived samples was 100%(70/70),which was higher than 65.71%(46/70)in blood-derived samples(P<0.05).Compared to 21 samples without HER2 and PIK3CA mutations(considering as the control group),patients with HER2 mutations showed higher resistance to trastuzumab(P<0.05).Patients with PIK3CA mutations did not show statistically significant differences in resistance to trastuzumab,atezolizumab,paclitaxel,and doxorubicin,if compared to the control group(P<0.05).Similarly,the resistance of HER2 mutation patients to atezolizumab,paclitaxel,and doxorubicin was not significantly different from that of the control group(P<0.05).【Conclusion】CSF in patients with breast cancer brain metastases can more accurately reflect possible brain metastasis status in comparison to the blood.The detection of HER2 mutations suggests the presence of corresponding drug resistance,which is of significant importance for medication guidance and monitoring of drug resistance.