Individualized Diagnosis And Treatment Strategy For Metastatic Breast Cancer Based On Circulating Tumor DNA

Objectives:The mechanism of acquired gene mutation plays a major role in resistance to endocrine therapy in hormone receptor(HR)-positive advanced breast cancer.Circulating tumor DNA(ctDNA)has been allowed for the assessment of the genomic profiles of patients with advanced cancer.We performed this study to search for molecular markers of endocrine therapy efficacy and to explore the clinical value of ctDNA to guide precise endocrine therapy for HR-positive/human epidermal growth factor receptor 2(HER2)-negative metastatic breast cancer patients.Methods:We conducted an open-label,single-center,multicohort,prospective study.Patients were assigned to four parallel treatment cohorts and matched according to mutations identified in ctDNA:1)cohort A comprised patients with activation of the PI3K/Akt/mTOR signaling pathway,preferred mTOR inhibitor combined with endocrine therapy;2)cohort B comprised patients with ESR1 mutation,preferred fulvestrant;3)cohort C comprised patients with HER-2 mutations,preferred pyrotinib combined with endocrine therapy;and 4)cohort D comprised patients who have not detected the above mutations,received treatment according to the clinical situation.In cohorts A-D,patients who adhered to the treatment plan were classified into the compliance group,and those who did not adhere to the treatment plan were classified into the violation group.The primary outcome measure was PFS,and the secondary outcome measure was OS.Results:Finally,84 patients were enrolled in the study,median follow-up time is 30.8(95%CI,14.1-47.6)months.In all cohorts,the combined median PFS was 4.9 months,and median PFS for the compliance and violation groups were 6.0 and 3.0 months,respectively[P=0.022,hazard ratio(HR)=0.57].Multivariate Cox regression model showed the risk of disease progression was lower in compliance group than in violation group(P=0.023,HR=0.55).Among the patients with HER-2 mutations,the median PFS was 11.1 months in the compliance group and 2.2 months in the violation group(P=0.011,HR=0.20).There was no significant difference in the median PFS between patients who did and did not comply with the treatment protocol in patients with activation of the PI3K/AKT/mTOR or ESR1 mutation.Conclusions:The results suggest that ctDNA may help to guide the optimal endocrine therapy strategy for metastatic breast cancer patients and to achieve a better PFS.Next-generation sequencing(NGS)detection could aid in distinguishing patients with HER-2 mutation and developing new treatment strategies.Objectives:The assessment of therapeutic response in breast cancer could potentially benefit from the clinical value of circulating tumor DNA(ctDNA).Based on the next-generation sequencing to detect ctDNA in peripheral blood,the tumor clonal evolution rate(TER)algorithm was developed by comparing the somatic mutation of patients with metastatic breast cancer during treatment and explored the clinical value in efficacy and prognosis.Methods:In this study,we collected multiple peripheral blood samples from patients with metastatic breast cancer who had progressed after multi-course therapy and conducted next-generation sequencing.PyClone and Timescape software were used to infer the clonal evolution process of metastatic breast cancer.This study developed algorithms to calculate the TER value for each patient.We used the Kaplan Meier method for survival curve estimation and conducted the log-rank test to compare the progression-free survival(PFS)and overall survival(OS)between the low and high TER groups.Cox regression model was used to compare the relationship between different clinical features,PFS and OS.Results:A total of 139 patients were enrolled and underwent NGS detection of ctDNA more than twice.The frequency of somatic mutation in patients at the second ctDNA test was higher than the baseline level(89.2%vs 84.5%).TP53,PIK3CA,ERBB2,and ESR1 were located in the top four positions of gene mutation spectrum,with an increasing in the frequency of mutations detected during the second detection.The results of clonal analysis showed that most of the breast cancer patients who had undergone multiline treatment after recurrence and metastasis showed branched evolution.The median PFS of patients with branched evolution pattern was extended by 1.8 months compared to patients with linear evolution pattern(HR=1.92;95%CI,1.09-3.38;P=0.0048).In terms of overall survival time,patients with branched evolution pattern showed a better prognostic trend than patients with linear evolution pattern(HR=1.82;95%CI,0.92-3.57;P=0.051).In order to reflect the clonal evolution of breast cancer,considering the distribution between the master clone and subclone,we proposed a new concept of TER by using the somatic mutation frequency detected by ctDNA at different times.Among the 86 patients who were able to obtain the PFS of next treatment regimen after the second ctDNA test,survival analysis results showed that the PFS of the TER-low group was longer than that of the TER-high group,with a median PFS of 4.3 months and 2.8 months,respectively(HR=1.69;95%CI,1.09-2.62;P=0.019).46 patients who had already experienced death events were selected for analysis of OS,and the results showed that the OS in the TER-low group was significantly longer than TER-high group,with a median OS of 21.4 months and 11.5 months,respectively(HR=2.18;95%CI,1.46-5.43;P=0.002).Conclusions:This study described the somatic mutation changes and tumor clonal evolution process of metastatic breast cancer patients after multiline therapy by dynamically monitoring the ctDNA.The results showed that patients with branched evolution pattern had better efficacy and prognosis than those with linear evolution pattern.This study developed TER as a new indicator based on molecular level,which can predict the efficacy of anti-tumor therapy and prognosis.