Hormone Receptors and Other Prognostic Factors in Breast Cancer in Cuba

Transcription

1 Hormoe Receptors ad Other Progostic Factors i Breast Cacer i Cuba Rosa Iree Álvarez Goyaes, Xiomara Escobar Pérez, Rolado Camacho Rodríguez, Maybi Orozco López, Soia Fraco Odio, Leticia LLaes Ferádez, Martha Guerra Yi, Cristia Rodríguez Padilla Traslated from Spaish ad reprited with permissio from Cacerología, Joural of the Istituto Nacioal de Cacerología, Mexico. Cacerología 3(2008): Origial available at: ABSTRACT Cliical maagemet of breast cacer, makig a progosis ad decidig o treatmet, curretly deped o defiig progostic factors, especially hormoe receptors (HR). I additio to cofirmig the heterogeeity of the disease, these biological parameters are idispesable tools for desigig persoalized treatmet. I this study, 1509 tumors from Cuba wome diagosed with breast cacer were examied. Hormoe receptor (HR) expressio was determied ad correlated with a group of progostic factors, such as age, tumor size, histological type, uclear grade, histological grade, umber of metastatic axillary lymph odes, ad cliical stage. Estroge receptor () expressio was associated with low uclear grade ad histological grade, ad with smaller tumor size (p <0.05). Aalysis of age at the time of diagosis showed that expressio was greater i patiets i the group aged >50 years (p <0.05). I geeral, expressio was greater i patiets i earlier cliical stages (p <0.05). With regard to HR expressio, 53% of tumors i this sample were + ad 49% were PR+. I 38% of cases, both receptors were positive ad i 28% both receptors proved egative. The +/PR combiatio was observed i 23% of cases while oly 11% exhibited the /PR+ combiatio. These fidigs idicate that approximately 72% of the tumors studied expressed some level of hormoe depedecy. This is the first report of HR expressio i Cuba usig immuohistochemical techiques ad a represetative sample of breast tumors diagosed i differet provices aroud the coutry. Keywords: Hormoe receptors, breast cacer, progostic factors INTRODUCTION Cacer is the secod cause of death i Cuba ad the first cause of potetial years of life lost, ad therefore the cause most affectig icrease i life expectacy of Cubas at birth. Amog Cuba wome, breast cacer has the highest icidece (excludig ski tumors) ad is the secod leadig cause of cacer mortality. Give that approximately 2500 ew cases are diagosed aually, ad more tha 1000 wome die of breast cacer each year,[1] maligat breast tumors are cosidered a major health problem i the Cuba populatio. With cacer, kowledge of the progosis plays a fudametal role i medical decisio-makig ad disease maagemet.[2] Progostic factors have bee defied as variables that help explai heterogeeity i the course ad developmet of a disease, regardless of the treatmet admiistered, ad that are associated with evet-free ad overall survival. [3] Oce progostic factors are idetified, patiets with similar characteristics ca be classified for the purpose of selectig ad admiisterig therapeutic regimes of greater or lesser itesity. Aalysis of factors predictig respose to treatmet likewise eables admiistratio of specific therapies oly i those patiets expected to respod, thus avoidig harm with o beefit to patiets lackig these factors. Treatmets are becomig icreasigly more persoalized, sigificatly improvig patiets quality of life.[4] This study examied 1509 tumors from patiets at 22 hospitals i 11 of Cuba s 14 provices who were diagosed with breast cacer betwee 2000 ad The expressio frequecy of stadard progostic factors associated with tumors was aalyzed: size, histological type ad grade, uclear grade, umber of metastatic lymph odes, cliical ad post-surgical stage, ad hormoe receptor expressio (HR). Age was the oly patiet-related progostic factor aalyzed. Durig the 1980s, biochemical methods for determiig HR were stadardized at the Natioal Ocology ad Radiobiology Istitute (INOR) of Havaa.[5] Results of work coducted durig those years were, util ow, the oly report of HR expressio i a Cuba populatio sample.[5 10] The objective of this study was to determie the frequecy of HR expressio i breast tumors i wome from differet regios of the coutry usig immuohistochemical (IHC) techiques. Distributio of progostic factors i the sample was also aalyzed ad correlated with estroge receptor () tissue expressio. Patiets ad Methods A total of 1509 breast tumor samples from patiets who uderwet surgery from 2000 through 2006 were received from medical ceters located i differet Cuba provices. Samples were embedded i paraffi blocks cotaiig a tumor fragmet represetative of the pathological-aatomical diagosis, alog with the correspodig glass slide staied with hematoxyli-eosi. The cliical or post-surgical stage of each case icluded i the study accordig to cliical stage (TNM) classificatio valid at the time was also provided with each sample o a data sheet cotaiig iformatio about the patiet (ame, age, medical record umber) ad the tumor (size, histological type, uclear grade, histological grade, umber of axillary lymph odes examied ad umber of metastatic odes).[11] Names of the attedig physicia, hospital ad provice were also recorded. TNM stage was recorded for patiets who received primary or eoadjuvat systemic treatmet, ad post-surgical stage (ptnm) for those who received iitial surgical treatmet. If iformatio was icomplete, the case was icluded i the study ad the data reported as missig. IHC techiques were used to determie HR tissue expressio.[12] Polysie glass slides (Mezel- Glaser, Germay) were used. Atige detectio was carried out 36

2 i a domestic steamer with a ph 6.0 citrate buffer. SP1 ad SP2 moocloal atibody (MAb) cloes were used to detect estroge receptors () ad progesteroe receptors (PR), respectively. These MAbs were obtaied pre-diluted. A ultra-sesitive polyvalet detectio system (MLINK), specific for mice ad rabbit primary atibodies (Ab), was used, cosistig of a secodary Ab marked with bioti ad a ezyme/ ati-ezyme complex with streptavidi ad peroxidase (Px) molecules. Edogeous Px tissue activity was blocked with a diluted 3% H 2 O 2 solutio. Ezymatic activity was revealed usig a cocetrated 3,3 -diamiobezidie tetrahydrochloride (DAB) solutio diluted i buffer substrate, ad 0.6% H 2 O 2. Tissue immue reactio was viewed through a light field microscope (Leica, Germay). The remaiig reagets were obtaied i ready-to-use packets. All reagets were supplied by Aacrom Diagósticos, S.L. Seville, Spai. Tissue samples were staied with Mayer s hematoxyli, ad Eukitt (Kider GmbH & Co, Germay) was used for moutig the slides. Two tissue sectios were used i each experimet for quality ad specificity cotrol. Cofirmed - or PR-positive tissue, alog with a atibody urelated to this atige, or a phosphate-buffered salie (PBS) solutio served as egative cotrols. Positivity criteria was 10% positive tumor cells. StatistICAL ANALysis A descriptive aalysis was made of the variables icluded i the study. Percetages were calculated for qualitative variables ad the mea ad stadard deviatio for quatitative variables. A Chisquare test was used to determie possible associatio betwee ad the rest of the variables aalyzed. A sigificace level of p <0.05 was used i the statistical aalyses. Data was aalyzed with SPSS package (Statistical Program for the Social Scieces, Chicago, IL), versio 11.0 for Widows. Results The study sample is described i Table 1, which shows the percetage of useful samples of each of the progostic factors aalyzed. The sample size of each of the progostic factors examied varied due to missig data. Useful data raged from 837 (55.5%) to 1509 (100%). As Figure 1 shows, the histological classificatio revealed a predomiace of ivasive duct carciomas (IDC) (73.9%) ad ivasive lobular carciomas (ILC) (10%). Special-type ivasive carciomas (medullary, mucious, tubular ad papillary carciomas) accouted for 5% of the sample, while special cliical varieties, such as iflammatory carcioma ad Paget s disease, represeted less tha 1%. Itermediate ad high uclear ad histological grade tumors predomiated i the sample, with more grade II ad III tumors observed. These morphological fidigs were associated with slower evolutio ad local recurrece. Little variatio was observed i the size of the breast tumors examied. T1 tumors ( 20 mm i diameter) were most frequet (49.2%), followed by T2 (21 50 mm), 45.7% of the sample. Table 1: Characteristics of the Study Sample Total Sample 1509 (100.00) Missig Data Useful Samples (%) Histological Diagosis 1509 (100.00) 0 (0.0) Nuclear Grade 1009 (66.90) 500 (33.1) 66.9 I 200 (19.82) II 518 (51.30) III 291 (28.84) Histological Grade 944 (62.60) 565 (37.4) 62.6 I 130 (13.77) II 518 (54.87) III 291 (30.82) Tumor Size 837 (55.50) 672 (44.5) (49.20) mm 383 (45.75) 50 mm 42 (5.01) Metastatic Lymph Nodes 1018 (67.50) 491 (32.5) (46.80) (25.73) (18.17) (9.23) Cliical Stage** 1006 (66.70) 503 (33.3) 66.7 I 232 (23.06) II 603 (59.94) III 155 (15.40) IV 16 (1.59) Age 1229 (71.50) 280 (18.5) 81.5 < (46.78) (53.21) * Special-type carciomas ** TNM Regardig the presece of metastatic axillary lymph odes, 46.6% of tumors examied were ode-egative (N0); 25.7% exhibited 1 to 3 odes, ad 27.4% exhibited 4 or more odes. Cliical stage aalysis idicated that most patiets i the study were i stages I ad II (83%), while 17% were i advaced stages of the disease. Patiets were divided ito two age groups: aged <50 years (46.8%) ad aged 50 years (53.2%), which idirectly implied their meopausal status. expressio was foud i 53% of the breast tumors examied, while the remaiig 47% did ot exhibit this hormoe receptor (Table 2). Correlatio of this tumor marker with the other progostic factors aalyzed showed that as cliical stage, tumor size, uclear grade ad histological grade icreased, positivity decreased i tumors studied (p <0.05) (Table 3). At the same time, expressio teded to decrease as the umber of metastatic axillary lymph odes Figure 1: Distributio of Sample by Histological Type (%) Duct Lobular Mixed 6.20 Mucious 2.25 Medullary 1.19 Papillary 1.12 Tubular

3 icreased, although this associatio was ot statistically sigificat. With regard to age, expressio was greater i tumors i patiets aged 50 years (p <0.05) (Table 3). Give the curret value of PR as a idepedet predictive factor, determiig expressio of this marker was icluded i the study. Table 4 shows that of the 295 breast tumors aalyzed, 49% were PR+. I patiets studied, 38% exhibited tumors positive for both markers ad 28% egative for both markers, while 23% were +/PR ad oly 33 tumors (11%) were /PR+. Table 2: Distributio of Expressio i Breast Tumor Sample Studied Positive Negative Not useful (53.0) 658 (47.0) 108 (7.15) Table 3: Associatio of Tissue Expressio with Essetial Tumor-Related ad Patiet-Related Progostic Factors Progostic Factor Positive Negative Age (years) 0.040* < (48.3) 284 (51.6) (57.6) 264 (42.3) Tumor Size (mm) * < (65.2) 139 (34.7) (53.6) 182 (46.3) (36.9) 46 (63.0) Metastatic Lymph Nodes (57.2) 196 (42.7) (60.7) 97 (39.3) (52.0) 84 (48.0) (44.8) 48 (55.2) Histological Grade * I 79 (62.2) 48 (37.7) II 288 (56.8) 219 (43.2) III 127 (45.2) 154 (54.8) Nuclear Grade * I 125 (65.4) 66 (34.5) II 291 (58.1) 210 (41.9) III 119 (32.6) 166 (45.4) Cliical stage** * I 137 (62.2) 83 (37.3) II 339 (58.1) 245 (41.9) III 58 (34.5) 110 (65.5) IV 5 (31.2) 11 (68.8) *p <0.05 **TNM Table 4: Distributio of PR Expressio i Breast Tumors Studied PR Positive Negative p Not Useful (48.8) 149 (50.5) 2 (0.67) Table 5: Correlatio of HR Expressio PR Positive Negative Total Positive 111 (37.8) 67 (22.8) 178 (60.7) Negative 33 (11.2) 82 (27.9) 115 (39.2) Total 144 (49.1) 149 (50.8) 293 (100.0) Discussio Breast cacer is a heterogeeous disease with a wide rage of cliical maifestatios ad histological types. As a result, a patiet s idividual progosis at time of diagosis requires a detailed examiatio of as may cliical ad pathologicalaatomical parameters as possible. Progostic factors i breast cacer are idicators that reflect the idividual characteristics of the tumor ad the patiet.[13] Aalysis ad evaluatio of these factors play a fudametal role i selectio of the most effective cacer-specific therapy with the least uecessary toxic effects produced by iadequate treatmet regimes. By eablig predictio of the progosis, these factors also cotribute directly to prologig survival of wome diagosed with breast cacer, ad they have a impact, especially i the short term, o breast cacer mortality.[14 16] Progostic factors are used throughout the atural history of breast cacer i chemoprevetio; eoadjuvat, surgical ad adjuvat treatmet; as well as i recurret disease.[3,16,17] The associatio betwee breast cacer ad the edocrie system was first established i 1896.[18] Sice the, umerous scietific studies have demostrated that edocrie therapy is a eligible treatmet for patiets with breast tumors expressig hormoe receptors. Cotiued cliical research has provided evidece of ew therapeutic treatmets with greater beefits for patiets. Hormoe sesitive breast tumors are the target of luteiizig hormoe, progesti, estroge, adroge ad, especially, estroge atagoist aalogues, such as tamoxife, which has bee used for decades ad cotiues to be first-lie treatmet for HR-expressig primary ad metastatic tumors.[19] Fially, aromatase ihibitors (AI) offer ew therapeutic optios, cosidered medically more potet with fewer side effects, leadig to a major chage i treatmet optios for postmeopausal patiets with HR-expressig breast tumors.[20] The cliical role of HR was first studied more tha 30 years ago. Reports of the cliical importace of these molecules first appeared i 1975;[21] two years later, their associatio with the degree of tumor cell differetiatio was cofirmed, ad they were cosidered idepedet progostic factors.[22 25] Tumor size (T), axillary odal metastasis (N) ad distace metastasis (M) are part of the breast cacer stagig system kow as TNM ad are also tumor-associated predictive factors. The presece of metastatic axillary lymph odes is the most relevat progostic factor i primary breast tumors ad is associated with poor progosis: lower evet-free ad overall survival. Approximately 70% of these patiets exhibit recurret tumors after 10 years.[26,27] I the sample studied, 53% of patiets were i this group, i which expressio i breast tissue dimiished as the umber of metastatic lymph odes rose, but the associatio betwee these progostic factors was ot statistically sigificat. Tumor size cotiues to be a importat predictive factor for patiets both with ad without positive axillary odal metastasis. I the latter group, it is the strogest predictive variable for relapse,[28] accoutig for 47% of patiets i this study. I relatio to histological type: medullary, tubular, pure mucious, ad adeoid cystic carciomas are cosidered low-grade tumors, associated with a low frequecy or absece of axillary odal metastasis. Although ifrequecy of these tumors makes quatitative aalysis of their progostic value difficult, they are classified 38

4 amog the tumors with better progosis. The fidigs of this study coicide with those described by other authors regardig expressio of these histological subtypes.[29] Histological grade ad uclear grade are fudametal progostic factors that over time have bee show to play a importat role. High-grade tumors are geerally associated with worse progosis ad a lower overall survival rate. It has bee observed that 10% of patiets with low-grade tumors relapse after five years, compared to 30% of patiets with high-grade tumors.[30] expressio is higher i tumors i older patiets.[31,32] Results of this study also showed higher expressio i the group of patiets aged 50 years. expressio i the breast cacer sample aalyzed was associated with good progostic factors, such as low histological ad uclear grade, smaller tumor size ad fewer metastatic axillary lymph odes. I geeral, expressio was higher i patiets i earlier cliical stages of the disease. Some biological ad socioecoomic factors, such as lifestyle, utritioal status ad evirometal exposure may ifluece expressio i breast tumors. Positive expressio differs amog certai populatio groups. This factor was reported i 80.6% of Austria wome,[33] ad i the Uited States, i 63.9% of white o-hispaic wome ad 48.3% of black wome.[34] At the same time, 53.4% of Thai wome exhibit + tumors, [35] ad expressio rages betwee 53% ad 61.6% i Chiese wome, depedig o their pre- ad post-meopausal status.[36] I some coutries, icludig Lebao (43%),[37] Iraq (34.2%),[38] ad Saudi Arabia (33.3%)[39] i the Middle East, ad Nigeria (24%) i Africa,[40] HR expressio is <50%. I this study, expressio i Cuba wome was 53%, very similar to that reported for Thai ad Chiese wome. Approximately 60% of wome with + tumors respod to hormoe therapy.[41] Determiatio of the presece of this receptor is fudametal, ot oly for its progostic value but also for its uquestioable predictive value of respose over time to sustaied cacer-specific therapy. The same has ot occurred with PR, which lost its idepedet predictive value durig the 1990s. [42,43] Studies coducted by Baum et al, Bardou et al, ad Cui et al i 2002, 2003 ad 2005, associated the loss of PR expressio with a icrease i growth factor sigals ad aggressiveess of the tumor.[44 48] The existece of a umber of patiets who respod to hormoe therapy (approximately 8%),[41] has reewed iterest i studyig the respose rage to this type of therapy. PR has ow regaied importace ad bee redefied as a predictive marker of activity, of growth factors, ad also as a fudametal marker for idicatig hormoe therapy i breast cacer patiets.[49,50] PR tissue expressio has bee reported i 13.9% to 61.3% of primary ad metastatic breast tumors.[35,36,40,51] I this study we observed 49% PR expressio, very close to the upper limit of its expressio rage. It has bee well established that the presece of both HR i the same tumor icreases the possibility of respose to hormoe treatmet up to 80%.[52] HR expressio i breast tumor tissue i white wome i the Uited States has bee extesively studied; 63.9% of tumors are +/PR+ ad 16.4% express at least oe of these receptors, which predicts respose to hormoe treatmet i 80.3% of patiets. This study showed co-expressio of both HR i 38% of breast tumors i Cuba wome, while 34% express at least oe receptor, idicatig that 72% of our patiets could beefit from hormoe therapy. I Cuba i 1982, Pascual et al produced the first report o HR expressio i breast tumors usig biochemical methods, showig 56% ad 43% PR expressio i a sample of patiets at the Natioal Ocology ad Radiobiology Istitute i Havaa. I the preset study, usig IHC techiques ad a sample of almost four times as may breast tumors obtaied from the pricipal sites of cacer icidece i the coutry, expressio was 53% ad PR 49%, very similar to the values previously reported for both HR. This study is the secod report o hormoe receptor expressio i breast tumors coducted i Cuba, ad the first report of HR expressio i breast tumors usig IHC techiques i a represetative sample of wome throughout the coutry. Refereces 1. Reporte del Registro Nacioal de Cácer y del Auario Estadístico. Cuba Rizzi D.A.. Medical progosis- some fudametals. Theor Med 1993; 14: Stockler M., Boyd N., Taock I. 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Progostic Factors i Cacer, 2d ed, Gospodarowicz M.K., Heso D.E., Hutter R.V. P., O Sulliva B., Sobi L.H., Wittekid Ch Beatso, G.W. O the treatmet of ioperable cases of carcioma of the mamma: Suggestios for a ew method of treatmet with illustrative cases. Lacet 1896; 2: Budzar, A., Valero V., Theriault R.L., et al. Pathological complete respose to chemotherapy i related with hormoal receptor status. Breast Cacer Res Treat 2003; 82: abstract;

5 20. Mouridse H., Gershaovich M., Su Y., et al. Superior efficacy of Letrozole (Femara) versus Tamoxife as first-lie therapy for postmeopausal wome with advaced breast cacer: Results of Phase III Study of the Iteratioal Letrozole Breast Cacer Group. J Cli Ocol 2001; 19: Mass H., Egle B., Trams G. Steriod hormoe receptors i huma breast cacer ad the cliical sigificace. J Steriod Biochem 1995; 6: Kight W.A., Livigsto R.B., Gregoty B.H., et al. Estroge receptor as a idepedet progostic factor for early recurrece i breast cacer. Cacer Res 1977; 37: McCarty, K.S. Jr ad McCarty, K.S. Sr. Steroid hormoe receptors i the regulatio of differetiatio. Am J Pathol 1978; 86: Cotesso G., Delarue J.C., Mouriesse H., et al. Aatomopathologie du cacer du sei et recepteurs hormaux. Pathol Biol 1983; 31: Elsto C.W., Blamey R.W., Johso J., et al. The relatioship of oestradiol receptors (RE) ad histological tumours differetiatio with progosis i huma primary breast carcioma i Moridse, Palshof, (eds): Breast Cacer: Experimetal ad cliical aspects. Oxford, Pergamo 1980; Veroesi U., Galimberti V., Zurrida S., et al. Progostic sigificace of umber ad level of axillary odal metástasis i Breast cácer. Breast 1993; 2: Jatoi I.,Hilsebeck S.G., Clark G.M., et al. Sigificace of axillary lymph ode metastasis i primary breast cacer. J Cli Ocol 1999; 17: Wilkiso N.W., Shahryariejad, A., Wisto, J.S., et al (2003) Cocordace with breast cacer pathology reportig practice guidelies. J. Am. Coll. Surg 2003; 193: Rose P.P. Rose s Breast Pathology. Philadelphia: Lippicott-Rave White J., Morrow, M., Mougha, J., et al. Compliace with breast coservatio stadards for patiets with early stage breast carcioma. Cacer 2003; 97: Thorpe S. Estroge ad progesteroe receptor determiatios i breast cacer. Techology, biology ad cliical sigificace. Acta Ocol 1998; 27: Cheug K., Howell A., Robertso J. Preoperative edocrie therapy for breast cacer. Edocr- Relate Cacer 2000; 7: Josly S.A. Hormoe receptors i breast cacer: racial differeces i distributio ad survival. Breast Cacer Res Treat 2002; 73: Chu K.C., Aderso W.F., Fritz a., et al. Frequecy distributios of breast cacer characteristics classified by estroge receptors ad progesteroe receptor status for eight racial/ethic groups. Cacer 2001; 92: Lertsaguasichai P., Chottetaaprasith T., Chatamra K., et al: Estroge ad progesteroe receptors status i Thai female breast cacer patiets: a aalysis of 399 cases at Kig Chulalogkor Memorial Hospital. J med Assoc Thai 2002; 85, Suppl 1: s Chow L.W., Ho P. Hormoal receptor determiatio of 1052 Chiese breast cacers. J Surg Ocol 2000; 75: Abadjia G., Atou R. Breast carcioma a evaluatio of hormoe receptors ad ps2,erb- B2, P-glycoprotei ad Ki-67 markers. J Med Liba 1996; 44: al-alwa N.A., al-kubaisy W., al-rawaq K. Assessmet of respose to tamoxife amog Iraqi patiets with advaced breast cacers. East Mediterr Health J 2000; 6: Samir S. Amr, Abdul Rahma M. Sa`di., Fazal Ilahi., et al. Spectrum of breast diseases i Saudi Arab females: A 26 year pathological survey at Dhaara Health Ceter. A Med Saudi 1995; 15: Ikpatt O.F., Ndoma-Egba R.: oestroge ad progesteroe receptors i Nigeria breast cacer: relatioship to tumor histopathology ad survival of patiets. Cet Afr J Med 2003; 49: Mayard P.V., Davis C.J., Blamey R.W., et al. Relatioship betwee estroge receptor cotet ad histological grade i huma primary breast tumors. Br J Cacer 1978; 38: Bezwoda W.R., Esser J.D., Dasey R., et al. The value of estroge ad progesteroe receptor determiatios i advaced breast cacer. Estroge receptor level but ot progesteroe receptor level correlates with respose to tamoxife. Cacer 1991; 68: Early Breast Cacer Trialists Collaborative Group. Systemic treatmet of early breast cacer by hormoal, cytotoxic, or immue therapy: 133 radomised trials ivolvig 31 recurreces ad deaths amog wome. Lacet 1992; 339: Baum M., Buzdar A.U., Cuzicck J., et al. Aastrozole aloe or i combiatio with tamoxife versus tamoxifee aloe for adjuvat treatmet of postmeopausal wome with early breast cacer: First results of the ATAC radomizaed trial. Lacet 2002; 359: Baum M., Buzdar A. The curret status of aromatase ihibitors i the maagemet of Breast cacer. Sur Cli North Am 2003; 83: Bardou J.V., Arpio G., Elledge R.M, et al. Progesteroe receptor status sigificatly improves outcome predictio over estroge receptor status aloe for adjuvat edocrie therapy i two large breast cacer databases. J. Cli Ocol 2003; 21: Cui X., Zhag P., Deg W., et al. Isulie like growth factor-1 ihibits progesteroe receptor expressio i breast cacer cells via the phosphatidyliositol 3 kiase/akt/mammalia target of rapemyci pathway: Progesteroe receptor as a potecial idicator of growth factor activity i breast cacer. Mol. Edocriol 2003; 17: Cui X., Schiff R., Arpio G., Osbore C.K., Lee A. V. Biology of progesteroe receptor loss i Breast Cacer sd its implicatios for edocrie therapy. J. Cli Ocol 2005; 23: Koecy G., Pauletty G.,Pegram M., et al. Quatitative associatio betwee H2/eu ad steroid hormoe receptors i hormoe receptor positive primary breast cacer. J atl Cacer. Ist 2003; 95: Pozoe F., Motemurro F., Maggiorotto C., et al. Cliical outcome of adjuvat edocrie treatmet accordig to RP ad H2 status i early breast cacer. A Ocol 2006; 17: Stierer M., Rose H., Weber R., et al. Imuohistochemical ad biochemical measuremet of estroge ad progesteroe receptors i primary breast cacer. Correlatio of histopathology ad progostic factors. A Surg 1993; 218: Early Breast Cácer Trialist Collaborative Group (EBCTCG), Effects of chemotherapy ad hormoal therapy for early breast cacer o recurrece ad 15 year survival: a overview of the radomised trials. Lacet 2005; 365: THE AUTHORS Rosa Iree Álvarez Goyaes (Correspodig Author: ialvarez@ifomed.sld.cu), Xiomara Escobar Pérez, Maybi Orozco López, Leticia LLaes Ferádez, Martha Guerra Yi, Experimetal Research, Natioal Ocology ad Radiobiology Istitute, Havaa, Cuba. Rolado Camacho Rodríguez, Breast Cacer Service, Natioal Ocology ad Radiobiology Istitute, Havaa, Cuba. Soia Fraco Odio, Pathological Aatomy Departmet, Natioal Ocology ad Radiobiology Istitute, Havaa, Cuba. Cristia Rodríguez Padilla, Immuology Departmet, Faculty of Biology, Autoomous Uiversity of Nuevo Leo, Mexico. 40