to adjuvant therapies such as hormone therapy [7 9ndash11]The presence or absence of progesterone receptor (PR) canalso be of importance for predicting response to hormonaltreatments Despite previous studies simultaneous ERPRpositivity increases the response to endocrine therapies upto 75 On the other hand one-third of ER-positive and PR-negative cases responded to hormone therapies A hypothesissuggests that the goal of the activity of ER is to facilitatethe development of the tumor so it is an effective aspectof this receptor which is being investigated [11] P53 is atranscription factor which is proposed as a tumor suppressorThe mutation of this gene is associated with increased riskof breast cancer and poorer prognosis [12 13] The activityof P53 in tumor suppression via the stoppage of cell cycleor induction results in apoptosis Many experiments haveindicated that besides their higher prevalence p53mutationsare associated with drug resistance [14ndash17] Currently thestaging evaluation that is used for determining the treatmentprocess of patients is different from previous methods Evengrade I PR-negative and ER-negative patients need moreaggressive adjuvant treatments and vice versa Thereforeconsidering the importance of this matter we decided toinvestigate the prevalence of the above factors in breastcancer patients and measure their relationship with eachother and factors such as age and the type of pathology Withregard to the utmost importance of molecular biology inthe diagnosis treatment and even prevention of cancer thepresent research can be a basis for similar studies
This retrospective cross-sectional study was performed on2000 women whose breast cancer pathology blocks weresent to the Cancer Institute of Imam Khomeini HospitalTehran Iran from 2011 to 2013 All cases whose pathologyresults were one of the types of breast malignancies andalso were investigated for the above factors were selectedfrom about 2750 patients with breast lump whose pathologyblocks were investigated from 2011 to 2013 in this centerThe 2000 present cases in this study were selected from the2750 patients Patients were excluded if they had bilateralbreast cancer untreated brain metastases osteoplastic bonemetastases pleural effusion or ascites as the only evidenceof disease a second type of primary cancer Patients werealso excluded if they were pregnant or had received anytype of therapeutic intervention since their malignancy wasdiagnosed Afterwards the test results of 2000 of them wereextracted from their pathology documents in the archive ofthe Cancer Institute and then recorded All samples wereevaluated by the IHC staining under the direct supervisionof at least two pathology academics HER-2 status was deter-mined by means of IHC using the Dako HercepTest (DakoCopenhagen Denmark) and scored with the Dako scoringsystem [18] Only patients who had weak-to-moderate stain-ing of the entire tumor-cell membrane for Her-2 (referred toas a score of 2+) or more than moderate staining (referred toas a score of 3+) in more than 10 percent of tumor cells onIHC analysis were eligible for the study
ER and PR receptors status was determined with a modi-fied avidin-biotin (ABC) immunoperoxidasemethod accord-ing to standard protocols (Vector Laboratories BurlingameCA)The 331015840-diaminobenzidine was used as the chromogenThe immunostaining results for ER and PR were assessedsemiquantitatively and reported as positive if more than 5of cells immunostained in a tumor P53 overexpression wasdefined as more than 50 of the cells with strong nuclearstaining [19]
Collected data are expressed as mean and standarddeviation values All data were analyzed by using ANOVAtest with SPSS software (Version-13) 119875 value lt 005 wasconsidered significant
The highest rates of breast cancer were observed at the agesof 46ndash55 and lowest rates were observed under the age of25 years and above 66 years The most prevalent malignancywas invasive ductal carcinoma (IDC) at 822 In this group33 and 56 were ERPR-positive and ERPR-negativerespectively Ductal carcinoma in situ (DCIS) and mucinouscarcinoma comprised the highest rates of HER-2-negativeand HER-2-positive cases at 846 and 824 respectivelyInvasive tubular carcinoma (ITC) and medullary carcinomareportedly comprised the highest rates of P53-negative andP53-positive cases at 857 and 90 respectively (Table 1)
The highest rates of PR-negative and PR-positive caseswere observed in medullary and invasive lobular carcinoma(ILC) and ITC at 56 and 857 respectively
The highest rates of positive HER-2 and negative HER-2were observed at the ages of lower than 25 (769) and 26ndash55years (mean age range)The rate of HER-2-positive increasedat the age of over 55 years
The highest and lowest rates of ER-negative and ER-positive were observed at the ages of 56ndash65 and under25 years at 755 and 615 respectively This significantdifference with other studies can be due to sampling bias inthe Cancer Institute The highest rates of PR-negative andPR-positive were observed at the ages of over 66 years andunder 25 years at 611 and 615 respectively There wasno significant relationship between age and P53 (119875 = 0295)(Table 2) It can be noted that 618 of ER-negative cases were
International Journal of Breast Cancer 3
Table 2 Highest and lowest frequency of HER-2 ER and PR statuswithin different age groups
Receptors status Highest age range () Lowest age range ()HER-2+minus lt25 yo (769) 26ndash55 yoER+minus 56ndash65 yo (755) lt25 yo (615)PR+minus gt66 yo (611) lt25 yo (615)
positive regarding HER-2 (poor prognosis) and 481 of ER-positive cases were reported negative regarding HER-2 (goodprognosis)
Additionally 642 of PR-negative cases were positiveregarding HER-2 (poor prognosis) and 49 of PR-positivecases were negative regarding HER-2 (good prognosis)Furthermore 468 of P53-negative cases were negativeregarding HER-2 (good prognosis) and 613 were positiveregarding both factors (poor prognosis)Moreover 844 thecases were negative regarding both factors and 987 of ER-positive cases were PR-positive
In addition 731 of ER-negative cases were P53-positive501 of ER-positive cases were P53-negative 723 of ER-negative cases were P53-positive and 438 of ER-positivecases were P53-negative Interestingly the result obtainedregarding the relationship between HER-2 and the type ofmalignancy and ER and PR had a relationship with thesimilarity of ER and PR receptors in a way that therewas a significant relationship between the above 3 factorsonly if both ER and PR receptors were reported to bepositive or negative Regarding the relationship between ageand the HER-2 receptor poorer prognosis was associatedwith younger ages as expected (with more positive HER-2)However in the others hormone receptor-positive (ER andPR) patients have a higher age range and a good prognosisThis point indicates the need for further research with regardto the lower prevalence of ER and PR in our study
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] R J Pietras J Arboleda D M Reese et al ldquoHER-2 tyro-sine kinase pathway targets estrogen receptor and promoteshormone-independent growth in human breast cancer cellsrdquoOncogene vol 10 no 12 pp 2435ndash2446 1995
[2] K B Horwitz and W L McGuire ldquoSpecific progesteronereceptors in human breast cancerrdquo Steroids vol 25 no 4 pp497ndash505 1975
[3] W L McGuire M De La Garza and G C Chamness ldquoEvalua-tion of estrogen receptor assays in human breast cancer tissuerdquoCancer Research vol 37 no 3 pp 637ndash639 1977
[4] R Hahnel T Woodings and A B Vivian ldquoPrognostic value ofestrogen receptors in primary breast cancerrdquoCancer vol 44 no2 pp 671ndash675 1979
[5] U Bohn J Aguiar C Bilbao et al ldquoPrognostic value of thequantitative measurement of the oncoprotein P185 Her-2neu
in a group of patients with breast cancer and positive nodeinvolvementrdquo International Journal of Cancer vol 101 no 6 pp539ndash544 2002
[6] C DimasM Frangos-Plemenos E Kouskouni and A Kondis-Pafitis ldquoImmunohistochemical study of p185 HER2 and DF
3
in primary breast cancer and correlation with CA-15-3 serumtumor markerrdquo International Journal of Gynecological Cancervol 12 no 1 pp 74ndash79 2002
[7] H K W Koeppen B D Wright A D Burt et al ldquoOverexpres-sion of HER2neu in solid tumours an immunohistochemicalsurveyrdquo Histopathology vol 38 no 2 pp 96ndash104 2001
[8] M Tanner D Gancberg B A D Leo et al ldquoChromogenicin situ hybridization a practical alternative for fluorescence insitu hybridization to detect HER-2neu oncogene amplificationin archival breast cancer samplesrdquo The American Journal ofPathology vol 157 no 5 pp 1467ndash1472 2000
[9] BM Ryan G E Konecny S Kahlert et al ldquoSurvivin expressionin breast cancer predicts clinical outcome and is associatedwithHER2 VEGF urokinase plasminogen activator and PAI-1rdquoAnnals of Oncology vol 17 no 4 pp 597ndash604 2006
[10] M C Ronckers C A Erdmann and C E Land ldquoRadiationand breast cancer a review of current evidencerdquo Breast CancerResearch vol 7 no 1 pp 21ndash32 2005
[11] S Kaptain L K Tan and B Chen ldquoHer-2neu and breastcancerrdquo Diagnostic Molecular Pathology vol 10 no 3 pp 139ndash152 2001
[12] Y Hatanaka K Hashizume Y Kamihara et al ldquoQuantita-tive immunohistochemical evaluation of HER2neu expressionwith HercepTestŮ in breast carcinoma by image analysisrdquoPathology International vol 51 no 1 pp 33ndash36 2001
[13] M A Olayioye ldquoUpdate on HER-2 as a target for cancertherapy intracellular signaling pathways of ErbB2HER-2 andfamily membersrdquo Breast Cancer Research vol 3 no 6 pp 385ndash389 2001
[14] A-M Martin and B L Weber ldquoGenetic and hormonal riskfactors in breast cancerrdquo Journal of the National Cancer Institutevol 92 no 14 pp 1126ndash1135 2000
[15] RM Elledge andD C Allred ldquoThe p53 tumor suppressor genein breast cancerrdquo Breast Cancer Research and Treatment vol 32no 1 pp 39ndash47 1994
[16] D J Slamon W Godolphin L A Jones et al ldquoStudies ofthe HER-2neu proto-oncogene in human breast and ovariancancerrdquo Science vol 244 no 4905 pp 707ndash712 1989
[17] C W Elston and I O Ellis ldquoPathological prognostic factorsin breast cancer I The value of histological grade in breastcancer experience from a large study with long-term follow-uprdquo Histopathology vol 19 no 5 pp 403ndash410 1991
[18] T W Jacobs A M Gown H Yaziji M J Barnes and S JSchnitt ldquoSpecificity of HercepTest in determining HER-2neustatus of breast cancers using the United States Food and DrugAdministration-approved scoring systemrdquo Journal of ClinicalOncology vol 17 no 7 pp 1983ndash1987 1999
[19] D M Barnes E A Dublin C J Fisher D A Levison and RR Millis ldquoImmunohistochemical detection of p53 protein inmammary carcinoma an important new independent indicatorof prognosisrdquo Human Pathology vol 24 no 5 pp 469ndash4761993
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