Analysis Of HER2Heterogeneity And Signal Transduction Mechanism Of Breast Cancer

BackgroundBreast cancer is a kind of carcinoma origining from glandular epithelium of breast, thebreast cancer morbidity increased globally in last decades. Althought with theimprovement of prevention, screening and early treatment, the motality of breast cancerhas been reduced, it still a main cause of death in patients with tumor. The treatments ofbreast cancer includ surgery, chemotherapy, radiotherapy, endocrine therapy and targettherapy, and the target therapy has becomed an important part of the first-line treatmentof breast cancer. With the increasing of application of target treatment, the clinicalproblems of resistence and low respons have been a challenge in breast cancer therapy.The genetic hetrogeneity of HER2gene, which is the target of the therapy, has beenthought the important reason which caused the failure of target therapy. But theprevalence, mechanism and clinical effect of genetic heterogeneity still not clear.HER2genetic heterogeneity includes intratumoral heterogeneity and intertumoralheterogeneity. Intratumoral heterogeneity means the HER2gene status is discordancebetween cells in the same or different regions of a single tumor. Intertumoralheterogeneity defined as HER2gene different between primary tumor and its metastases.There are some studies that confirmed genetic heterogeneity in breast cancer, whichinfluenced the judgement of HER2status, and then influenced the decision of HER2target therapy.With the advance in research on genetic heterogeneity, the standard definition andalgorithm of HER2genetic heterogeneity has been published. Althought the succedentstudies used the same definition, the results of prevalence and clinical significance areinconsistent.ObjectiveThis study aimed to explicit the overall and actural prevalence of HER2geneticheterogeneity, and examine the association between genetic heterogeneity andclinicopathologic parameter, and the influence of downstream signal pathway of HER2gene. MeasurementsWe use Meta analysis to evaluate the HER2genetic heterogeneity. We use theelectronic and other supplementary search in the foreign and chinese databases withcomputer. Two investigators screening the realated references and extrat data. We use theReview Manage5.1software perform the Meta-analysis.Results1.A total of7english lieteratures were included and total of11448patients wereincluded in the Meta-analysis. In the total included patients,3192patients were foundHER2genetic heterogeneity, account of27.88%of total patients.2.Meta-analysis confirmed that HER2genetic heterogeneity may cause the equivocalresult of IHC of FISH assays. Moreover, HER2genetic heterogeneity influence the FISHassays in more extent of equivocal results. We also found that HER2geneticheterogeneity may not affect the positve result of FISH assays.3.We found HER2genetic heterogeneity prevalence in FISH equivocal results is53.3%. We also found that in FISH equivocal results with HER2genetic heterogeneity,the estrogen receptor postive rate is lower than patients without HER2geneticheterogeneity, and the association has statistical significance. But the age,histopathological type, tumor size, tumor gade, lymph node metastasis, progesteronereceptor status and Ki-67status do not have statistical significance.ConclusionHER2genetic heterogeneity does exist in breast cancer, but since the update of HER2test guideline and the polysomy of chromosome17, the definition and the standardalgorithm of HER2genetic heterogeneity assay still not uniform. HER2geneticheterogeneity may not be an independent prognostic factor. Firstly, We recommend thatthe studies about HER2genetic heterogeneity should obey an uniform standard. Secondly,the more accuate technique should be used in complicated cases. Thirdly, the studiesabout HER2genetic should combine clinical data, especially combine the trastuzumabtherapy, in order to confirm the treatment response, resistance and clinical effects. Finally,studies combined the HER2genetic heterogeneity with signal pathways, circulating tumor cells, circulating tumoar cell DNA and Tumor infiltrating lymphocytes mayhelpful to improve the HER2target therapy.