目的

探讨多基因联合检测预测激素受体阳性晚期乳腺癌患者内分泌治疗耐药的临床应用价值。

方法

采用回顾性病例分析方法,收集2015 年1 月至2016 年8 月中国医学科学院北京协和医学院肿瘤医院收治的30 例激素受体阳性晚期乳腺癌患者的临床资料。 于患者治疗前采集其外周血10 ml,利用目标区域捕获测序技术检测循环肿瘤DNA(ctDNA)突变情况。 根据患者是否存在耐药相关基因(TP53、PIK3CA、mTOR、ERBB2、ESR1、FGFR1)突变,将其分为基因突变组和非基因突变组。 分析内分泌治疗耐药与基因突变的关系。 采用Kaplan-Meier 法绘制2 组患者的无进展生存(PFS)曲线,用Log-rank 检验比较两者之间的差异。 并用χ² 检验比较基因突变组与非基因突变组患者发生原发耐药的差异。

结果

在30 例患者中,基因突变组与非基因突变组患者分别有20 例和10 例。 随访1 ～19 个月,中位随访时间为3 个月,2 组患者中位PFS 分别为3 个月和5 个月,并且,基因突变组患者6 个月PFS 率明显低于非基因突变组(10%比50%,χ²=8.328,P=0.004)。 20 例基因突变组患者中,原发耐药者18 例,继发耐药者2 例,而10 例非基因突变组患者中原发耐药者5 例,继发耐药者5 例;基因突变组原发耐药者比非基因突变组多(χ²=5.963,P=0.026)。

结论

联合检测多个耐药相关基因的ctDNA,能够预测晚期乳腺癌患者内分泌治疗耐药。

Objective

To evaluate the feasibility of serial gene-panel circulating tumor DNA(ctDNA) sequencing in predicting resistance to endocrine therapy of hormone receptor (HR) positive advanced breast cancer.

Methods

We retrospectively analyzed the clinical data of 30 patients with HR positive advanced breast cancer in the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from January 2015 to August 2016. Blood sample of 10 ml was collected from these patients before endocrine therapy. ctDNA mutation was assayed by gene-panel target-capture next-generation sequencing. Based on the existence of drug resistance-related gene mutation (TP53, PIK3CA, mTOR,ERBB2, ESR1 and FGFR1), all samples were further subdivided into two groups: mutant group and nonmutant group. The relationship between resistance to endocrine therapy and gene mutation was analyzed.Survival curves of progression-free survival (PFS) were estimated using the Kaplan-Meier method and comparison of these estimates was performed using log-rank test. χ² test was used to compare the primary drug resistance rates between mutant group and non-mutant group.

Results

In all 30 patients, there were 20 patients in mutant group and 10 patients in non-mutant group respectively. The median follow-up was 3 months (range 1-19 months). The median PFS was 3.0 months in the mutant group and 5.0 months in nonmutant group respectively. The 6-month PFS in mutant group was significantly lower than that in non-mutant group (10% vs 50%, χ² =8.328, P=0.004). In mutant group (20 patients), 18 patients had primary resistance to endocrine therapy and 2 patients had secondary resistance. In non-mutant group (10 patients),5 patients had primary resistance to endocrine therapy and 5 patients had secondary resistance. The primary resistance rate in mutant group was significantly higher than that in non-mutant group (χ² = 5.963, P =0.026).

Conclusion

The combined detection of ctDNA in multiple drug resistance-related genes can predict the resistance to endocrine therapy in HR positive advanced breast cancer patients.