Clinical And Translational Study Of Fulvestrant In The Treatment Of Advanced Breast Cancer

Background and purpose Fulvestrant is one of endocrine regimen belonging to selective estrogen receptor down-regulators,which can more completely block the transduction of ER and downstream signaling pathways.Fulvestrant 500mg has shown its good efficacy and tolerance in randomized controlled trials of hormone receptor(HR)positive and human epidermal growth factor receptor 2(HER2)negative breast cancer.However,the real-world evidence in complex clinical situations is still insufficient.At present,the dominant group that can benefit more from fulvestrant have not been clearly described,especially the question of whether fulvestrant can do better than traditional endocrine therapy in patients with visceral metastasis has not yet been answered.Mutations in the ESR1 gene encoding the estrogen receptor(ER)a can lead to ligand-independent activation of the ER,thereby promoting the non-hormone-induced growth of tumor cells.The conformational change of ER caused by ESR1 mutation also reduces the affinity of fulvestrant to ER.Therefore,tumor cells with ESR1 mutation gain their resistance to fulvestrant to a certain extent,but the impact of different ESR1 mutations on the efficacy of fulvestrant may be inconsistent.This study aims to collect and analyze the real-world data of fulvestrant in HR-positive and HER2-negative advanced breast cancer patients in China,and explore the efficacy and safety of fulvestrant in real patient groups,especially the actual effect in patients with visceral metastasis.In addition,this study explored the characteristics of HR-positive and HER2-negative advanced breast cancer gene profiles,with the focus on ESR1 mutation,and then analyzed and discussed the relationship between the ESRI mutation or other related genes and efficacy of fulvestrant.Methods The data of patients who were treated with fulvestrant 500 mg monotherapy in the Department of Breast Medicine,Peking University Cancer Hospital from January 2015 to December 2018 were collected.Then we statistically analyzed the efficacy of fulvestrant and its relationship with various clinicopathological characteristics.The data of patients who were treated with fulvestrant 500 mg monotherapy in the Department of Breast Medicine,Peking University Cancer Hospital from December 2018 to June 2020 were collected for independent external verification.We collected blood samples of patients before starting fulvestrant treatment.Illumina sequencing technology is used to detect genes in circulating tumor DNA(ctDNA)that are closely related to the incidence and treatment of breast cancer.This study focused on analyzing the incidence and mutation types of ESR1 gene,comparing the clinical characteristics between the mutant group and the wild group,and the effect of ESR1 and other related genes on the efficacy of fulvestrant.Results 1.Basic characteristics:A total of 303 patients were included.Among them,87.13%were patients with recurrence breast cancer,and 12.87%were primary stage ? breast cancer patients.When receiving fulvestrant treatment,68.32%of patients had visceral metastases.Bone is the most common site of metastasis.The number of patients receiving fulvestrant as first-line,second-line and?third-line treatment was 53(17.49%),73(24.09%)and 177(58.42%),respectively.2.Efficacy:The objective response rate and clinical benefit rate of fulvestrant in first-line,second-line and ?ird-line treatment were 3.77%and 86.79%,5.48%and 75.34%,1.13%and 66.10%,respectively(p=0.014).The median progression free survival(PFS)of fulvestrant in the overall population is 8.5 months(95%CI:7.0-10.0 months),and the values in first-line,second-line,and?third-line treatments were 14.1 months,11.2 months and 6.7 months,respectively(p=0.002).3.Predictors of efficacy:short disease-free survival(p=0.027),more metastatic sites(p<0.001)and previous palliative chemotherapy(p=0.003)are risk factors that affects the efficacy of fulvestrant,but stratified by age,menstrual status,expression level of hormone receptor and Ki67 index,no significant difference was obtained.4.First-line population:Compared with primary and secondary endocrine therapy resistance,sensitivity to endocrine therapy is a positive predictor of PFS for first-line fulvestrant therapy(p<0.001,median PFS:not reached vs 3.7 vs 15.9 months).5.Maintenance treatment:the median PFS of patients receiving fulvestrant as maintenance therapy after palliative chemotherapy was numerically greater than those who progressed after first-line chemotherapy(10.6 vs 4.9 months,p=0.356).6.Patients with visceral metastases:Short disease-free survival(p=0.005),more metastases(p=0.004)and liver metastases(p=0.001)are independent risk factors related to the efficacy of fulvestrant for patients with visceral metastases.And the presence of lung metastasis and other site of the metastasis did not significantly affect the PFS of fulvestrant.7.Adverse effect:A total of 15 cases/times of adverse events occurred,with an incidence rate of 4.95%.The most common adverse reactions are headache and palpitations.8.Validation results:There is no statistical difference between the objective response rate and clinical benefit rate of the validation group and the study group,but the median PFS of the validation group is worse than that of the study group,which may be due to the relatively short disease-free survival of the validation group.In the analysis of predictive factors in the validation group,menstrual status and the number of metastases showed the same predictive value as the study group,and other related factors were consistent with the overall trend of the subgroup data in the study group.9,ESR1 mutations:A total of 6 patients with ESR1 mutations were detected in 19 patient specimens.,with mutation rate of 31.6%.A total of 11 mutations were detected,and the most common mutation type was p.Asp538Gly(D538G).10.ESR1 mutation with efficacy of fulvestrant:PFS of wild group and mutation group were 5.8 months(95%Cl:4.5-7.1 months)and 4.9 months(95%CI:0.98.9 months),respectively(p=0.811).11.Other genes:The most frequently combined gene mutations in the mutant group and the wild group were TP53 and PIK3CA,respectively.Stratified by the PIK3CA mutation,there was no significant difference in the efficacy of fulvestrant treatment,but the PFS of fulvestrant in the subgroup with high frequency of PIK3CA mutation tended to shorten.Conclusion This study found that the timing to start fulvestrant treatment is an important factor affecting treatment response.Palliative chemotherapy before fulvestrant may adversely affect the efficacy of fulvestrant.For patients who initially require chemotherapy,maintenance therapy with fulvestrant after relief or stability of disease is also a very promising treatment strategy.Fulvestrant is still an optional and effective regimen after failure of traditional endocrine therapy as SERMs and/or AIs.In the analysis of factors related to the efficacy of fulvestrant,it was found that short disease-free survival,more metastatic sites and previous palliative chemotherapy were risk factors for the efficacy of fulvestrant.Age,menstrual status,expression level of HR and Ki67 index did not significantly affect the efficacy of fulvestrant.The treatment of fulvestrant combined with GnRH-a in premenopausal patients can achieve the same therapeutic benefit as postmenopausal patients.The efficacy of fulvestrant inpatients with visceral metastasis is inferior to that of patients without visceral metastasis,and the most important metastatic site that affects the efficacy of fulvestrant is liver metastasis.In addition to liver metastasis,short disease-free survival and more metastatic sites are also independent risk factors for PFS of fulvestrant in patients with visceral metastasis.This study observed that fulvestrant 500 mg monotherapy is well tolerated,and the most common adverse effects are headache and palpitations.In addition,patients with ESRI mutations can still benefit from fulvestrant,so fulvestrant is one of the alternative strategies after resistance to AIs.