The Predictive And Prognostic Significance Of The Change Of Biomarkers Expression In The HER2/Neu-positive Breast Cancer Patients Received Neoadjuvant Chemotherapy

Background:HER2/neu-positive breast cancer is a more aggressive phenotype with a poor prognosis.Trastuzumab is one of the most important drugs for HER2/neu-positive breast cancer patients.However,even for these patients,the objective response rates to trastuzumab monotherapy are 12%-34%,and the median duration is about 9 months.Many patients progress within 12 months.Study of the mechanisms of resistance to trastuzumab will help us find some new therapeutic targets and methods to overcome the trastuzumab resistance.Currently,many researchers are focused on the study of the correlation of the change in the biomarkers expression associated with HER/neu pathway to the trastuzumab resistance.But most of them are preclinical research,which are not validated by series of clinical studies.Objective:To evaluate the change in biomarkers expression after neoadjuvant chemotherapy in the treatment of HER2/neu-positive breast cancer,and explore the correlation between the change and prognosis.To identify predictive and prognositic markers that may effectively predict the chemotherapeutic response and the prognosis of HER2/neu-positive breast cancer patients.Patients and Methods:From May 2002 to September 2007,113 HER2/neu-positive breast cancer patients were identified.All these patients were diagnosed by core needle biopsy as invasive ductal breast cancer and treated with anthracyclines-based chemotherapy before operation.Biological markers were evaluated by IHC in the core needle biopsy specimens and postoperative tumor tissue.The relationship between the prognosis and the change in the biomarkers expression were analyzed,Results:Among 113 patients,the ratio of partial remission was 58%,pathological complete remission 12%,stable disease 27%and progression disease 3%.The mean follow up was 35.4 months,60 cases had local recurrence and distant matastasis,32 cases for death.3-year relaps-free survival(RFS) was 51%and overall subvival(OS) was 67%.The positive rates of the biomarkers as TopoIIa,Ki67,MAPK,pMAPK, Akt,pAkt,CyclinDl,P27,PTEN,and IGF-1R are 64.6%,65.5%,81.4%,70%,55.8%,75.2%,52.2%,45.1%,47%,48.7%,respectively.TopoIIa-Ki67 coexpression rates are 46%.The level of Ki67,pMAPK,pAkt expression decreased significantly after chemotherapy,decreased 17.5%,20%,18%,respectively,and TopoIIa-Ki67 coexpression,decrease of pMAPK and pAkt were all the independant predictive factors for anthracyclines-based chemotherapy on Multivariate analysis.On multivariate analysis for RFS,number of positive lyph nodes,TopoIIa-Ki67 coexpression,decrease of pMAPK and pAkt expression were all the independant prognositic factors.On multivariate analysis for OS,only decrease of pMAPK expression and number of positive lyph nodes were the stronger prognostic factors.Conclusions:PI3K/Akt and Ras/MAPK pathway is universaly highly activated in HER2/neu-positive breast cancer patients.TopoIIa-Ki67 coexpression,decrease of pMAPK and pAkt are all independant predictive factors for anthracyclines-based neoadjuvant chemotherapy in HER2/neu-positive breast cancer patients,while,the status of PTEN,P27 and IGF-1R seems to be not correlated to the anthracyclines response.Number of positive lyph nodes and decrease of pMAPK expression are all stronger prognositic factors of outcome for pantients.Therefor,we can hypothesize that PI3K and MEK may be the potential therapeutic targets for HER2/neu-positive breast cancer.