The Status Of CEP17 In The Prediction Of Breast Cancer's Responsiveness To Anthracycline-containing Chemotherapy In The Neoadjuvant Setting-a Preliminary Clinical Study

Background and purpose:Chromosome 17 has the second highest density of genes in the human genome,containing several key genes that take part in breast tumorigenesis(HER2,TOPO ?A,BRCA1 and Tau)and DNArepair(P53,RAD51CandRAD52B).Chromosome17centromere(CEP17)is highly proximal to the locus of HER2/TOPO2A amplicon.Duplication of CEP17 can lead to copy number aberrations of key genes centered around it,such as HER2 amplification,TOPO ?A amplification/deletion,P53 deletion and BRCA1 deletion/mutation.Clinical studies have demonstrated that CEP17 duplicated patients receiving anthracycline-containing chemotherapy had better RFS and overall OS in the adjuvant setting.Currently,there lack studies regarding the predicative value of CEP17 status in the prediction of breast cancer's responsiveness to anthracycline-containing chemotherapy in the neoadjuvant setting.Our study aims to explore the impact of CEP17 duplication on breast cancer's responsiveness to neoadjuvant chemotherapy containing anthracycline.Method:Patient's medical records from June,2012 to February,2018in Department of Endocrine&Breast Surgery,The First Affiliated Hospital of Chongqing Medical University(Chongqing Breast Cancer Center)were retrospectively reviewed.101 Patients were included in our study,meeting the following criteria:1.Core needle biopsied tissue from breast masses were of carcinoma;2.Breast cancer associated IHC and HER2 FISH were performed on those biopsied tissues;3.All those included patients had undergone anthracycline-based chemotherapy in the neoadjuvant setting.Tumors'long diameters measured by imaging methods(ultrasound,mammography and CT)were collected before and after neoadjuvant chemotherapy(4~8 cycles).According to the RECIST(The Response Evaluation Criteria in Solid Tumors)version 1.1,breast cancer's responsiveness to neoadjuvant chemotherapy is divided into PD,SD,PR and CR,with a definition of OR that is composed of PR and CR.Data of CEP17 copy numbers(CEP?2.25 was defined as CEP17 duplication)were collected from the existing laboratory testing reports of HER2/CEP17dual-color FISH performed on the core needle biopsied tissues.We divided the status of CEP17 into two groups(duplication vs.non-duplication).In univariate analysis,we compared the difference in the OR rates between the two groups.After adjustment for age,clinical staging(stage ?,? and ?),HR status(<1%,1%~10%,10%),HER2 status and ki67 scores(<15%,15%~35,>35%),we further analyzed whether the status of CEP17 has an impact on breast cancer's responsiveness to neoadjuvant chemotherapy.Results:1.Up to 101 patients meeting the criteria of our study were included.Patients with CEP17 duplication accounted for 51.4%(n=52)and among them,the proportions of patients of stage ?,? and ? were 1.9%(n=1),48.1%(n=25)and 50.0%(n=26),respectively;patients with CEP17duplication accounted for 48.6%(n=49)and among them,the proportions of patients of stage ?,? and ? were 6.1%(n=3),59.2%(n=29)and34.7%(n=17),without statistical significance(p=0.236).HER2 gene is prone to be amplified(59.6%,n=31)in CEP17 duplicated tumors than in tumors without CEP17 duplication(18.4%,n=9,p=0.000).2.After neoadjuvant chemotherapy,there is no statistical difference in the alteration of tumor's long diameter between CEP17 duplication group(10±16mm)and non-duplication group CEP17(14±13mm,U=1065.0,Z=-1.412,p=0.155).In HER2 negative patients(n=61),there also exits no statistical difference in the alteration of tumor's long diameter between the two groups(10±10mm vs.12±16mm,U=331.5,Z=-1.345,p=0.179)and neither did the HER2 positive patients(n=40)(10±18mm vs.17±11mm,U=118.5,Z=-0.618,p=0.503).3.The proportions of PD,SD,PR and CR is 3.9%(n=4),41.6%(n=42),49.6%(n=50)and 4.9%(n=5),respectively.The incidence of OR is54.5%(n=55),while tumors not reaching OR accounts for 45.5%(n=46).The OR rate is 42.3%in the group of CEP17 duplication,while that increases to 67.3%in the group of CEP17 non-duplication,which is statistical significant by chi-square test(?~2=6.377,p=0.012).Univariate analysis also reveals that there is no statistical difference in the incidence of ORamongvariousERstatus(<1%,1%~10%,10%),HER2status(amplification and non-amplification),ki67 scores(<15%,15%~35,>35%).After adjustment for various clinicopathological parameters including age and clinical staging,the incidence of OR in patients without CEP17 duplication is much higher than that in patients with CEP17duplication(OR=3.300,95%CI:1.210~8.999,P=0.020).Still,clinical staging,HR status,HER2 status and ki67 scores are irrelevant to breast cancer'sresponsivenesstoneoadjuvantchemotherapycontaining anthracycline.Conclusions:1.After adjustment for age,clinical staging(stage ?,? and ?),ER status(<1%,1%~10%,>10%),HER2status(amplificationand non-amplification)and ki67 scores(<15%,15%~35%,>35%),based on RECIST version 1.1,the incidence of OR in patients decreases in patients with CEP17 duplication,revealing the potential predictive value of CEP17status as a biomarker.But the result still needs to be confirmed in retrospective studies of large size and prospective randomized clinical trials.2.There is no statistical significance in the incidence of different clinical staging,ER status and ki67 scores between groups of OR and non-OR,indicating that CEP17 duplication has no impact on the clinicopathological features of breast cancer.3.The incidence of HER2 gene amplification is higher in the group of CEP17 duplication,suggesting the tendency of co-amplification of HER2gene and CEP17.