Clinical And Basic Studies On The Effect Of Chemotherapy In Early And Advanced Triple Negative Breast Cancer

Background and objective:Triple negative breast cancer(TNBC)constitutes 10%to 20%of all breast cancers.Because of lack of available targeted or biological agents,chemotherapy is the mainstay treatment for TNBC.A high proportion of TNBC patients eventually develop resistance to chemotherapy,thus leading to treatment failure and recurrence.Therefore,it is extremely valuable to explore novel molecular markers which can predict resistance to chemotherapeutic agents and metastatic risk in TNBC patients.Mutation or abnormal expression of the ATM gene and autophagy-related genes are associated with the development,chemoresistance and prognosis of breast cancer.Our study was aimed to explore the relationship between the single nucleotide polymorphisms(SNPs)in the ATM and autophagy-related genes and the effect of chemotherapy in early stage TNBC.Methods:A total of 331 early TNBC patients with blood samples were included in this study.All the patients were treated with the anthracyclines-and/or taxanes-based chemotherapy in Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College from December 1999 to July 2015.We genotyped 24 SNPs in the ATM gene and autophagy-related genes(ATG5,ATG7,ATG12,ATG13,MAP1LC3A and MAP1LC3B)using the sequenom's MassARRAY system.Chi-squared test,Kaplan-Meier survival analysis and Cox proportional hazard regression were utilized to analyze the association between the SNPs and disease free survival(DFS)of TNBC patients.In addition,patients were stratified according to different clinicopathological characteristics and Kaplan-Meier survival analysis was used to study the association between different genotypes of SNPs and the prognosis of patients in different subgroups.Results:Three genotypes including AA,GA and GG were detected in the rs473543 of ATM gene.The distribution of rs473543 genotypes was statitistically different between the recurrent group and disease free group(P = 0.024).Kaplan-Meier survival analysis suggested that the carriers of the A-allele of rs473543 were significantly associated with increased risk of recurrence and shortened disease-free survival(DFS),compared with those carrying the variant genotype of GG in rs473543(P = 0.034).In addition,after adjusting for the clinical factors,multivariate Cox regression analyses revealed that the GA/AA genotype of rs473543 was an independent risk factor for the DFS in the present cohort(HR,1.73;95%CI,1.04-2.87;P= 0.034).Subgroup analyses showed that:1.In patients less than or equal to 40 years of age,the CC genotype of ATG13 rs 13448 was significantly associated with prolonged DFS(P?0.004),while the AA genotype of MAP1LC3A rs4911429 was significantly associated with shortened DFS(P = 0.001);in patients older than 40 years,the CC genotype of ATG13 rs10838611 was related to better prognosis(P = 0.028).2.In lymph node negative subgroup,the AA genotype of rs4911429(P = 0.036)and the TT genotype of rs228589(P = 0.028)were associated with decreased DFS of TNBC patients,while the GG genotype of ATG5 rs473543 was significantly related to extended DFS(P = 0.027);in the lymph node positive subgroup,patients with the GG genotype of ATG7 rs4684789 had better prognosis(P = 0.042)3.In patients without vascular invasion,the AA genotype of rs4911429 was associated with shorter DFS(P = 0.003);in patients with vascular invasion,the CC genotype of MAP1LC3A rs6088521 was significantly related to decreased DFS(P = 0.000)4.In the TNM ?/? stage patients,the AA genotype of rs4911429 was related to worse prognosis(P = 0.042).5.In patients without family history of breast cancer,the AA genotype of rs4911429 was related to worse prognosis(P=0.026).Conclusion:ATG5 rs473543 genotypes may serve as a potential marker for predicting chemoresistance and recurrence of early stage TNBC patients who received anthracyclines-and/or taxanes-containing regimens as adjuvant chemotherapy.Besides,multiple SNPs of ATM and autophagy-related genes showed potential prognostic values in specific clinicopathological subgroups of early stage TNBC patients.Background and objective:Currently,there is no preferred standard chemotherapy regimen available for patients with metastatic triple negative breast cancer(mTNBC)and no cohort studies on the efficacy of vinorelbine plus platinum(NP)regimen in patients with mTNBC who failed to anthracyclines and/or taxanes have been reported.We present the single-center,retrospective experience of NP regimen in a total of 41 patients with mTNBC.Methods:All patients were treated with NP regimen from 2001 to 2014,main combination used was vinorelbine-cisplatin in 34 patients(82.9%).Results:The median follow-up was 36.8 months.Objective response rate was 34.1%(n=14)in the whole study group.Three patients experienced complete response(7.3%),11 patients acquired partial response(26.8%),stable disease was observed in 14 patients(34.1%),and 10 patients(24.4%)had progressive disease.Response evaluation was not applicable in 3 patients who received the treatment of NP regimen after surgical removal of the metastatic lesions.The median overall survival and progression-free survival were 18.9 months(95%confidence interval,15.6-22.1 months)and 6.7 months(95%confidence interval,2.9-10.5 months),respectively.The main adverse events were grade 3/4 neutropenia(n=20,48.8%)and grade 1/2 gastrointestinal toxicity(n=20,48.8%).Conclusion:NP regimen is active and tolerable in patients with mTNBC pretreated with anthracyclines and/or taxanes.Therefore,among other chemotherapy regimens,NP combination may provide a rational treatment option for this patient subset.