The Relationship Between ESR1 Gene Mutation And Endocrine Therapy Resistance In Estrogen Receptor-positive Advanced Breast Cancer

Objective:The efficacy and safety of fulvestrant(500 mg)and exemestane(25 mg)for treatment of the postmenopausal,ER-positive,HER2-negative advanced breast cancer patients after treated with adjuvant NSAIs would be compared in this study.The connection between ESR1 gene mutation and acquired drug resistance to AI treatment would also be explored.Methods:This study based on a randomized,open,multicenter clinical trial of fulvestrant(500mg)versus exemestane as the first-line treatment of postmenopausal ER-positive,HER2-negative advanced breast cancer patients after adjuvant NSAIs treatment,proposed by Cancer Hospital,Chinese Academy of Medical Sciences.ESR1 gene mutation in cfDNA was detected by Illumina high-throughput sequencing.Survival analysis was used to compare the PFS of fulvestrant and exemestane group.Mann-Whitney U test was used to analyze other therapeutic indicators,and t test was utilized to calculate the relationships between treatment efficacy and ESR1 gene mutation,gene mutation abundance or metastasis site.Results:(1)Enrollment:From January 1,2016 to March 4,2019,55 patients were enrolled in this study.26 patients were randomized into the exemestane group and other 29 patients in the fulvestrant group.(2)Efficacy evaluation:The efficacy was evaluated in 41 patients.There were 23 patients in the fulvestrant group,including 7 patients as PR,12 patients as SD and 4 patients as PD,and 18 patients in the exemestane group,including 2 patients as PR,8 patients as SD and 8 patients as PD.The median PFS of fulvestrant group(8.4 months)was significantly better than that of the exemestane group(5.6 months)(Log-rank test P=0.006;Hazard ratio=2.81,95%confidence interval(1.19,6.64).The DCR(82.6%),ORR(21.9%),mTTF(5.6 months)and DoR(16.8 months)of the fulvestrant group were also better than those of the exemestane group(55.6%,11.1%,2.8 months and 5.6 months).(3)Safety evaluation:The most serious adverse reactions were increased alkaline phosphatase(grade ?,3.4%)in the fulvestrant group,increased bilirubin(grade?,3.8%)and increased glutamyltransferase(grade ?,3.8%)in the exemestane group.Other adverse reactions included dizziness,nausea,etc.which were all mild.(4)ESR1 gene mutation and efficacy:5 patients with ESR1 gene mutation were detected,including 2 D538G mutations(fulvestrant group,SD,PFS 2.8 months;exemestane group,SD,5.6 months),a L536P mutation(fulvestrant group,PR,14 months),a E380Q mutation(exemestane group,PD,2.8 months),and a D540G mutation(fulvestrant group,PD,2.8 months).PFS of patients with ESR1 mutation in fulvestrant group(6.5 months)was slightly better than that in the exemestane group(4.2 months).(5)Gene mutation abundance and efficacy:There are 10 patients with increased gene mutation abundance,of whom the efficacy evaluations were 5 patients as PD and 5 as SD.4 patients showed decreased gene mutation abundance,including 3 patients as SD and 1 patient as PD.12 paients showed constant mutation abundance,including 4 patients as PR,6 patients as SD and 2 patients as PD.Patients with increased gene mutation abundance showed lower PFS than patients with constant abundance(4.3 months versus 13.8 months,P=0.004)and patients with decreased abundance(11.2 months,P=0.259).Conclusions:(1)The efficacy of fulvestrant(500mg)for posttmenopausal ER-positive,HER2-negative advanced breast cancer patients after NSAIs treatment was significantly better than exemestane,while the safety is similar.(2)Response of patients with ESR1 mutations to exemestane was unsatisfying and fulvestrant was more effective.(3)In this study,patients with increased gene mutation abundance showed worse efficacy.