| Purpose: Breast cancer is one of the most common malignant tumorsoccurring in women. With the development of medical science andtechnology, the therapeutic approaches for breast cancer have beendeveloped rapidly. Since surgical therapy, chemotherapy andradiotherapy are too conventional to enhance their potential efficacies,more and more oncologists have paid attention to the endocrine therapy.Thus, endocrine therapy is now becoming the most importanttherapeutics for breast cancer and leading to an increased survival rateand a lowed relapse rate among the women whose estrogen receptor(ER) and/or progesterone receptor (PR) are positive. It is fairly wellaccepted that the presence of ER identified those breast cancerpatients with a lower risk of relapse and a better overall survival and thereceptors also provide a guideline for those tumors who may beresponsive to endocrine therapy. In breast cancer patients, about twothird of the tumors are estrogen receptor positive and one third areestrogen receptor negative. Nearly 90% ER-negative and about 50% ofthe ER-positive cancers are resistant to endocrine therapy. Although thepresence of ER is critical in the clinical response to endocrine therapyand several genetic polymorphisms in ESR1 have been related tobreast cancer, the molecular mechanisms leading to the changes ofestrogen receptor phenotype and the mechanisms of effects of geneticpolymorphisms on the resistance to tamoxifen(TAM) are poorlyunderstood. To detect the distribution of inherited variations, that is, thesingle nucleotide polymorphisms (SNP) in the estrogen receptorα(ESR1) gene in Chinese patients with breast cancer and to evaluate therelationship between the SNP genotypes, allele frequencies and theresponse to endocrine therapy, we conducted a population-based studyamong Chinese women with breast cancer as follows.We also try toexplore the pathological, clinical features and survival status of Chinesebreast cancer patients, and to elucidate the difference of constituentratio and clinical parameter of breast cancer between Changchun andShanghai. A multifactorial analysis was made to investigate theprognostic factors of breast cancer.Methods: We reviewed the data of all 1000 cases from China-JapanUnion hospital of Jilin University and 1009 cases from Renji hospital ofMedical College of Shanghai Jiaotong University with primary breastcarcinoma who were inpatient during 1995 to 2005 by looking up thecase report, telephone to the patients and asking them in out-patientclinic or visiting them at home.The variables entered into the analysisincluded age at presentation, age of menarche and menopausal status,tumor size, tumor grade, presence of lymphatic invasion, expression ofestrogen receptor(ER),progesterone receptor(PR),Her-2/neu in tumortissure, and relapse rate,disease-free survival rate,overall survival rateof 1 year,3 years and 5 years. All data were analyzed by SPSS11.0software, including χ2 test,t test,Kaplan-meier analysis and Cox'sproportional hazards regression model analysis. Based on theidentification of the whole DNA sequence of ESR1 and the singlenucleotide polymorphisms database (dbSNP), this pharmacogenomicalstudy was undertaken on breast cancer patients with endocrine therapyand the efficacy is definite. A total of 240 Chinese breast cancer patientswith TAM or the third generation AI administration and without bloodrelationship were randomly involved. We selected 15 SNPs loci ofESR1 gene as genetic markers, rs872921, rs2077647, rs3904766,rs2234693, rs11155816, rs827419, rs2347867, rs3798759, rs 1801132,rs985191, rs9340931, rs9397463, rs722209, rs3778099 and rs3798577.All SNPs except for rs1801132 were examined by polymerase chainreaction (PCR) and restriction fragment length polymorphisms(RFLP);The genotype of 40 samples of rs2347867 was detected by PCR-DNAsequencing.The genotype of rs1801132 was determined by real timebase pair specific PCR. We examined the relationship betweenallele/genotype frequencies of the SNP Loci and the clinical endocrineresponse to assess the function of the SNPs. Then linkagedisequilibrium analysis is performed to see the association between thegene polymorphisms and efficacies of endocrine therapy. The sensitivegenotypes for the therapy will be identified further with long time clinicalpractice follow-up. The SPSS11.0 software were applied as the mainstatistical approaches to compare the relationship between genotypeand endocrine efficacy. Hardy-weinberg genetic equilibrium test wasperformed by POPGENE software, and linkage disequilibrium (LD)analysis and haplotype analysis was performed by SHEsis software.Results: The peak age of breast cancer patients at presentation was46～50 years;The incidence costitutent ratio of Shanghai increasedagain after 60 years old, and formed another age peak at about 70years old. ⑵ There was great difference between Changchun andShanghai in history of breast related disease, history of their familydisease, age at presentation, age of menarche and menopausal status,menstruation status, histopathology, lymphnode metastasis andfaraway metastasis,clinical stage and expression of estrogene receptorand progestogen receptor;The relapsed rates of 1 year,3 years and 5years were significantly higher in Changchun than in Shanghai;Thesurvival rate of 3 years and 5 years were positively lower in Changchunthan in Shanghai. The expression of HER-2 and 1 year survival rate hadno difference in the two area。All patients received sequently systemicadjuvant theatment after surgery, but in the choose of which therapy asthe first line treatment, there was difference between the two areas fordifferent stage and performance status. ⑶ As the monofactorialanalysis showed that the most important prognosis factors inChangchun are tumor size, method of surgery, histopathology,lymphnode status, the number of LN metastasis, faraway metastasis,stage and expression of PR,whereas the most important prognosisfactors in Shanghai were menstruation status, lymphnode status, thenumber of LN metastasis, stage, expression of ER,PR and ER/PR,adjuvant chemotherapy with marcellomycin or paclitaxel and adjuvantendocrine therapy. The factors affecting the recrudent and prognosticsignificance were tumor size, lymphatic invasion number and stage inChangchun and the state of ER in Shanghai by Cox multifatorialanalysis. Although all the fifteen SNPs had been reported in normalpopulations by NCBI-db SNP database, we found only thirteenpolymorphisms in Chinese breast cancer patients with the exception ofrs872921 and rs 3904766, which is given up for too poorpolymorphisms. In the test of chi-square, the frequencies of the twoalleles and the genotypes of all the other SNPs except rs2077647 andrs3798759 had no significant difference between the patients whopositively responsed to TAM or not. We also assessed the potential roleof the hapotype between the two SNPs in ESR1 with endocrine therapyefficacy. There was four linkage disequilibrium blocks in ESR1 gene.They were rs2077647~rs2234693(LD1), rs2234693~rs111 55816 (LD2),rs9397463~ rs722209(LD3) and rs3778099~rs3798577(LD4). Therewas a significant association between the hapotype ofrs2234693~rs11155816, s11155816~rs827419 and rs2347867~ rs1801-132 with endocrine therapy.Conclusion: The results of our study are compatible with thehypothesis that there is difference in history, clinical pathologicalfeatures and prognosis factor feature in breast cancer patients inChangchun and Shanghai. The polymorphisms of ESR1 gene mayaffect the expression and function of the receptors. Though most ofthese SNPs may not be associated with the efficacy of endocrinetherapy of breast cancer in Chinese population, but some of the SNPsand the haplotypes we have studied are positively associated withendocrine response, we therefore concluded that the inherited geneticvariation maybe account for the endocrine response breast cancer,Based on the principle of linkage disequilibrium, we also conclude thatthere may be positive region of sensitive genes near the geneticmarkers, and a study with more samples and more genetic markersshould be conducted further.
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