Analysis On The Biomarkers For Advanced Breast Cancer In The First-line Chemotherapy And Maintenance Chemotherapy

BackgroundEpithelial-mesenchymal transition(EMT)is implicated in the process of metastasis and presents a challenge to epithelial cell adhesion molecule(EpCAM)-based detection of circulating tumor cells(CTCs),which have been demonstrated to be a prognostic indicator in metastatic breast cancer.Although evidence has indicated that heterogeneity of CTCs based on EMT markers is associated with disease progression,no standard recommendations have been established for clinical practice.This study aimed to evaluate the prognostic significance of dynamic CTC detection based on EMT for metastatic breast cancer patients.MethodsWe enrolled 108 female patients from the prospective,multi-institutional study with HER2-negative metastatic breast cancer underwent first-line chemotherapy with docetaxel plus capecitabine and applied the CanPatrol CTCTM enrichment technique to identify CTC phenotypes(including epithelial CTCs,biophenotypic epithelial/mesenchymal CTCs,and mesenchymal CTCs)in peripheral blood samples.Receiver operating characteristic(ROC)curve analyses of total CTC count and the proportion of mesenchymal CTCs for predicting the 1-year progression-free survival(PFS)rate were conducted to determine the optimal cut-off values,and Kaplan-Meier analysis and Cox proportional hazards regression analysis were performed to investigate the prognostic value of the cut-off values of both total CTC count and the proportion of mesenchymal CTCs in combination.ResultsFor predicting the 1-year PFS rate,the optimal cut-off value of total CTC count was 9.5(Area under the curve[AUC]=0.538,95%confidence interval[CI]:0.418-0.657),and that of the proportion of mesenchymal CTCs was 10.7%(AUC=0.581,95%CI:0.463-0.699).We used the two cut-off values in combination to forecast PFS in which the total CTC count was equaled to or exceeded 10/5 mL with the proportion of mesenchymal CTCs surpassed 10.7%.Patients who met the combined criteria had significantly shorter median PFS than those who did not meet the criteria(6.2 vs.9.9 months,P=0.010).A nomogram was constructed based on the criteria and significant clinicopathological characteristics with a C-index of 0.613(P=0.010).ConclusionsThe criteria,which combined the total CTC count and the proportion of mesenchymal CTCs,may be used to monitor therapeutic resistance and predict prognosis in patients with metastatic breast cancer.Background:Although positive Circulating tumor cells(CTCs)status has been validated as a prognostic marker in breast cancer,the interaction between immune cells and CTCs during the progress of Epithelial-mesenchymal transition(EMT),and the clinical implications of CTC-associated white blood cell clusters(CTC-WBC clusters)for metastatic breast cancer are largely uncharacterized.We investigated the predictive value of different phenotypes of CTC-WBC clusters as a prognostic biomarker in a prospective study for metastatic breast cancer.Patients and methods:The prospective,multi-institutional study enrolled 134 patients with HER2-negative metastatic breast cancer underwent first-line chemotherapy with docetaxel plus capecitabine from Nov 2013 to Sep 2017.Serial peripheral blood samples were collected dynamically until disease progression for CTC detection using CanPatrol CTC enrichment technique.Kaplan-Meier analysis was performed to investigate the prognostic value of CTC-WBC clusters.Results:Median age of the 134 female patients was 51.0 years(range,21 to 73 years),and 119(88.8%)of them were estrogen receptor-and/or progesterone receptor-positive.Median progression-free survival(PFS)was 9.9 months(95%CI,8.1 to 11.6 months).116(86.6%)of the 134 patients had detectable CTCs at baseline.Among them,CTC-WBC clusters were detectable in 9 patients,of whom 7 patients had biphenotypic epithelial/mesenchymal CTCs or mesenchymal CTCs contained in the CTC-WBC clusters(EMT-like CTC-WBC clusters).The patients with at least one detectable EMT-like CTC-WBC clusters(including biphenotypic epithelial/mesenchymal CTC-WBC clusters and mesenchymal CTC-WBC clusters)at baseline were characterized by significantly worse PFS,when compared with the patients with no EMT-like CTC-WBC clusters detected(7.2 months vs 10.4 months,P=0.028),as well as the patients with five or more epithelial-based CTCs(including epithelial CTCs and biphenotypic epithelial/mesenchymal CTCs;7.2 months vs 11.4 months,P=0.022).Conclusions:Our data provide evidence that the emergence of CTC-WBC clusters underwent EMT before treatment is associated with significantly poorer PFS in HER2-negative metastatic breast cancer patients underwent first-line chemotherapy,which may be used as a parameter to predict the clinical outcomes for chemotherapy.Purpose:Low-dose metronomic chemotherapy can achieve disease control with reduced toxicity compared to conventional chemotherapy in maximum tolerated dose.Characterizing the gut microbiota of cancer patients under different dosage regimens may describe a new role of gut microbiota associated with drug efficacy.Therefore,we evaluated the composition and function of gut microbiome associated with metronomic capecitabine compared to conventional dosage.Methods:A total of 31 HER2-negative metastatic breast cancer patients who finished the six cycles of chemotherapy with docetaxel plus capecitabine were randomized to receive maintenance chemotherapy with metronomic dose of capecitabine or conventional dose in China National Cancer Center from November 2017 to February 2019.The fecal samples of patients treated with capecitabine as maintenance chemotherapy were collected and analyzed by 16S ribosome RNA gene sequencing.The mice models of breast cancer receiving metronomic and conventional doge of capecitabine were conducted to verify the differences in the distribution of intestinal flora under different dose regimens.Results:15 patients treated with metronomic capecitabine were compared to 16 patients under conventional dose.The differences of a diversity between the two groups were not statistically significant.As for ? diversity,the unweighted-unifrac index of metronomic group were statistically significantly lower than routine group(P=0.025).Besides,Bray-Curtis distance based redundancy analysis(dbRDA)illustrated that the microbial genera between two groups can be separated partly.Meanwhile,similar tendency was observed in the difference of diversity of gut microbiota between the metronomic group and routine group in mice models.Nine Kyoto Encyclopedia of Genes and Genomes(KEGG)modules were enriched in metronomic group,while no KEGG modules was significantly enriched in routine group.Moreover,univariate and multivariate analysis suggested the median progression-free survival(PFS)was significantly shorter in the patients with the gut microbial composition of Slackia(9.2 vs 32.7 months,P=0.004),while the patients with the Blautia obeum had significantly prolonged PFS than those without(32.7 vs 12.9 months,P=0.013).Conclusions:Our proof-of-concept study suggested that gut microbiota of the patients receiving metronomic chemotherapy was different in the diversity,composition and function from those under the conventional chemotherapy,and the presence of specific bacterial species may act as microbial markers associated with drug resistance monitoring and prognostic evaluation.