JRMS J Res Med Sci Journal of Research in Medical Sciences Journal of Research in Medical Sciences 1735-1995 1735-7136 Medknow Publications Pvt Ltd India JRMS-18-283 24124424 Original Article Detection of prognostic factors in metastatic breast cancer Tazhibi Mehdi Fayaz Mahsa Mokarian Fariborz Department of Biostatistics and Epidemiology, School of Public Health, Isfahan University of Medical Sciences, Isfahan, IranDepartment of Biostatistics and Epidemiology, School of Public Health, Isfahan University of Medical Sciences, Isfahan, IranDepartment of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Address for correspondence:Mahsa Fayaz, No. 38, Salman Avenue, Golzar 3, Golzar Region, Keshavarzi Boulevard, Postal Code: 81786-63831, Isfahan, Iran mahsafayaz@yahoo.com April 2013 18 4 283 290 692012 25122012 Copyright: © Journal of Research in Medical Sciences 2013

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background:

The aim of this study was to detect prognostic factors in recurrent breast cancer metastasis. Materials and Methods:

This retrospective cohort study employed data from 996 breast cancer patients of Isfahan Seyed-o-Shohada research center from 1998 to 2010. Stratified Cox proportional hazards model, marginal approach, was used to evaluate the prognostic value of estrogen receptor, progesterone receptor, tumor protein 53, human epidermal growth factor receptor type 2, diagnosis age, nodal ratio, tumor size, antigen Ki67, and cathepsin D. Survival curves were plotted using Kaplan-Meier method and log-rank test was carried out to compare survival in two categories of nodal ratio (ͳ0.25 vs. >0.25). Results:

In simple Cox regression model, age ( P = 0.037), nodal ratio ( P < 0.0001), and Ki67 ( P = 0.032) were associated with hazard of distant metastasis. Multiple analysis showed that patients with greater nodal ratio had significantly higher adjusted hazard of recurrent metastasis (Hazard ratio: 2.756, 95% Confidence interval: 1.017-7.467; P = 0.046). Tumor size was not an independent prognostic factor for recurrent metastasis. Comparing survival curves, there was significant difference between two categories of nodal ratio in the first ( P < 0.0001), second ( P < 0.0001) and third ( P = 0.024) metastasis; survival was higher in-patients with nodal ratio <0.25. Conclusion:

Our findings indicate that tumor size was insignificant; this raises the question about conventional premise of being a major prognostic factor for distant metastasis. Furthermore, nodal ratio is suggested to clinicians as a prognostic variable in follow-up of breast cancer patients; patients with higher nodal ratio have greater hazard of distant metastasis.

Materials and Methods:

This retrospective cohort study employed data from 996 breast cancer patients of Isfahan Seyed-o-Shohada research center from 1998 to 2010. Stratified Cox proportional hazards model, marginal approach, was used to evaluate the prognostic value of estrogen receptor, progesterone receptor, tumor protein 53, human epidermal growth factor receptor type 2, diagnosis age, nodal ratio, tumor size, antigen Ki67, and cathepsin D. Survival curves were plotted using Kaplan-Meier method and log-rank test was carried out to compare survival in two categories of nodal ratio (ͳ0.25 vs. >0.25). Results:

In simple Cox regression model, age ( P = 0.037), nodal ratio ( P < 0.0001), and Ki67 ( P = 0.032) were associated with hazard of distant metastasis. Multiple analysis showed that patients with greater nodal ratio had significantly higher adjusted hazard of recurrent metastasis (Hazard ratio: 2.756, 95% Confidence interval: 1.017-7.467; P = 0.046). Tumor size was not an independent prognostic factor for recurrent metastasis. Comparing survival curves, there was significant difference between two categories of nodal ratio in the first ( P < 0.0001), second ( P < 0.0001) and third ( P = 0.024) metastasis; survival was higher in-patients with nodal ratio <0.25. Conclusion:

Our findings indicate that tumor size was insignificant; this raises the question about conventional premise of being a major prognostic factor for distant metastasis. Furthermore, nodal ratio is suggested to clinicians as a prognostic variable in follow-up of breast cancer patients; patients with higher nodal ratio have greater hazard of distant metastasis.

Results:

In simple Cox regression model, age ( P = 0.037), nodal ratio ( P < 0.0001), and Ki67 ( P = 0.032) were associated with hazard of distant metastasis. Multiple analysis showed that patients with greater nodal ratio had significantly higher adjusted hazard of recurrent metastasis (Hazard ratio: 2.756, 95% Confidence interval: 1.017-7.467; P = 0.046). Tumor size was not an independent prognostic factor for recurrent metastasis. Comparing survival curves, there was significant difference between two categories of nodal ratio in the first ( P < 0.0001), second ( P < 0.0001) and third ( P = 0.024) metastasis; survival was higher in-patients with nodal ratio <0.25. Conclusion:

Our findings indicate that tumor size was insignificant; this raises the question about conventional premise of being a major prognostic factor for distant metastasis. Furthermore, nodal ratio is suggested to clinicians as a prognostic variable in follow-up of breast cancer patients; patients with higher nodal ratio have greater hazard of distant metastasis.

Conclusion:

Our findings indicate that tumor size was insignificant; this raises the question about conventional premise of being a major prognostic factor for distant metastasis. Furthermore, nodal ratio is suggested to clinicians as a prognostic variable in follow-up of breast cancer patients; patients with higher nodal ratio have greater hazard of distant metastasis.

Axillary nodal ratio breast cancer distant metastasis marginal approach prognostic factor stratified cox proportional hazards model tumor size
</sec><sec><title>Introduction

The most prevalent cancer among women after non-melanoma skin cancer is breast cancer and its incidence rate is increasing enormously. After lung cancer, the most of mortalities among 40-50-year-old women result from breast cancer and it accounts for 32% of female cancers. 1,2,3,4 Increase of cancer incidence has been reported in the most modern countries of Asia including, Japan, Singapore, Hong Kong and Taiwan. In contrast to reported pattern in West countries, breast cancer in modern Asian countries is appearing in young age. 5 Furthermore, unlike western countries, in which breast cancer incidence has been decreased or stable 6,7,8 it is increasing in majority of Asian countries in the last two decades. 9,10,11,12

In Iran, cancer is the most common cause of death after coronary heart disease and accident. 13 Striking increase of cancer incidence has been reported in Iran. 14 Iranian women develop this disease at least one decade sooner and this makes the subject more important. 15 Incidence and mortality rate of breast cancer among Tehranian women were reported 26.4 and 5.8 in one hundred thousand in 1999, respectively. 16 Isfahan province is among Iranian cities with high-rate of cancer. According to statistics in 2005, 10% of all observed breast cancers in Iran had been seen in Isfahan. 17

Among breast cancer patients, the primary tumor usually does not end in death; in fact distant metastases result in death. 18 Cancerous cells go to other parts of body through blood flow and lymphatic vessels and start to grow and form new tumors. 19 The percentage of breast cancer patients with high-risk of metastasis is about 30-50. 20 In the first 3 years after diagnosis, nearly 10-15% of breast cancer patients develop distant metastasis and it is also likely to happen 10 years after first detection. 21

Speaking of these figures besides low-quality of patients′ lives with metastasis, detection of prognostic factors is crucial. 22 Several studies have found that proportion of involved node (nodal ratio) has been an important prognostic factor. 23,24,25 Large tumor has the high-risk of metastasis in comparison with small ones. 20,26,27,28,29,30,31 Some other risk-factors are age, estrogen receptor (ER), and progesterone receptor (PR), human epidermal growth factor receptor type 2 (HER2), tumor protein 53 (p53), antigen Ki67, and cathepsin D. 32,33,34,35,36,37

Although, several studies have been undertaken to detect prognostic factors of metastatic breast cancer, most of these studies take in to account conventional risk-factors. In current study, we tried to evaluate not only conventional variables but also some other putative risk-factors like p53, HER2, Ki67, and cathepsin D. On the other hand, most of these researches studied only the first metastasis and used Cox proportional hazard models, 38,39,40,41 though each patient can experience multiple metastases. This is a direct way, which ignores the complexities such as the effect of first event on occurrence of next events. Furthermore, considering only the first event is not satisfying for evaluating the natural history of disease and all information is not considered. 42 There are different regression methods for multiple failures. These methods consider special construct of correlation between events for one subject, which are generalization of survival data analysis. One of non-parametric methods for multivariate failure time data is marginal approach in Cox proportional hazard function. 43 The aim of this study is identification of prognostic factors of metastatic breast cancer as a recurrent event using recurrent survival analysis in order to benefit from all existing information.

Materials and Methods

Participants

This retrospective cohort study employed data from breast cancer patients admitted and treated at Isfahan Seyed-o-Shohada research center from 1998 to 2010 (range of diagnosis date: 5/11/98-21/9/2010). Follow-up cut-off date was May 14, 2011. All registered 1084 breast cancer patients of this center entered to the study. Among these patients, 88 individuals had metastasis at the time of entrance therefore they were withdrawn from the study and size of sample declined to 996.

Variables

Patient information had been extracted from computerized medical records, which included demographic information and tumor characteristics. Demographic background, including age and family history, was collected by interview. Tumor characteristics such as tumor size and status of ER, PR, p53, HER2, cathepsin D, Ki67 and also number of involved and dissected axillary lymph nodes were extracted from pathology report. Other information such as sites of metastasis and survival times was reported by physicians.

Survival time was defined as time between date of diagnosis and consecutive distant metastasis. Follow-up time was calculated starting at date of diagnosis with breast cancer until May 14, 2011 or last contact, whichever came earlier. Nodal ratio was defined as ratio of number of involved nodes to total number of disserted nodes.

Some of patients could not be followed-up and some other did not experience metastasis and the information of these patients was considered in analysis as censored data.

Statistical analysis

The outcome of interest was distant metastasis defined as spread of cancer to distant organs such as lung, bone, liver, and brain. Each patient could experience distant metastasis several times over the follow-up time.

Stratified Cox proportional hazards model, marginal approach, was employed to evaluate the prognostic value of ER, PR, p53, HER2, diagnosis age, nodal ratio, tumor size, Ki67, and cathepsin D using univariate analysis. In marginal stratified Cox model, each subject is considered in risk set for all failures regardless of number of experienced events. Marginal method allows the researcher to consider not only the order of failures, but also different types of failures. 44 The statistical details of this method is described in reference number 61 and briefly given in the appendix [SUPPORTING:1]. Regression parameters were estimated by maximum partial likelihood method. P values were calculated from Wald Z statistics.

Proportional hazards assumption of the model assumes that the hazard proportion of one individual to any other one is independent of time. This assumption was confirmed by graphical methods (comparing-ln-ln survival curves or observed versus predicted curves) and goodness-of-fit test.

We used the cut-off point of 0.25 for nodal ratio, which has been confirmed by previous studies 23,24 and plotted Kaplan-Meier survival curves in first, second and third metastasis over time for two categories of patients (nodal ratio ≤0.25 vs. >0.25). Survival comparison between different categories was made using log-rank test. Tests were two-sided and significant level was established at 0.05. The analyses were performed using SAS 9.2 and SPSS 18.

Results

Over 12 years, 996 breast cancer patients with a median age of 47 years (range: 22-86 years) registered at Isfahan Seyed-o-Shohada research center were studied. A total of 143 patients (14.3%) had metastatic breast cancer; 86 patients (8.6%) experienced metastasis once, 41 ones (4.1%) twice, 15 individuals (1.5%) three times and one of them (0.1%) four times. Diagnosis age for majority of patients was more than 40 years (73.8%). The percentage of patients with more than 2 cm tumor size was 78.7. Axillary Nodal ratio was more than 0.25 among 38.4% of patients Table 1.{Table 1}

The median follow-up time was 6 years (range: 0.6-12.5 years). Among patients with at least 2 years of follow-up (n0 = 848), the percentage of patients with metastasis-free surviving at 2 year was 91.4% and the 5-year metastasis-free survival rate for patients with at least 5 years of follow-up (n = 605) was 81.3%.

Median (range) interval between detection of breast cancer and first metastasis was 23.23 (0.43-103) months; It was 5.9 (0.03-95.87) months between the 1 st and 2 nd metastasis and 6.15 (0.1-40.9) months between 2 nd and 3 rd metastasis.

Lung, bone, liver, and brain metastasis were determined as major sites of metastasis and their frequencies were shown in Table 2. Considering some of patients experienced several metastases at each event, the most prevalent site of metastasis was bone in the first event (47.5%).{Table 2}

In univariate analysis, simple Cox regression model, age, and tumor size were entered into model as categorical variables. Results showed that age (P0 = 0.037), nodal ratio (P < 0.0001) and Ki67 (P = 0.032) were statistically significant. Patients who are less than 40 years old, have 33.5% higher Hazard of recurrent metastasis in comparison with more than 40-year-old patients. On the other hand, the risk of recurrent metastasis increased as the value of nodal ratio and Ki67 increased Table 3.{Table 3}

Table 3 also shows the results of multiple survival analysis. ER, PR, p53, HER2, diagnosis age, nodal ratio, tumor size, Ki67, and cathepsin D were putative prognostic variables. First order interaction effect as the product of binary age and binary PR and also between binary age and Ki67 were considered in the model. Among all possible prognostic factors, nodal ratio was the only significant variable; patients with greater nodal ratio had a significantly higher adjusted hazard of recurrent metastasis (Hazard ratio = 2.756; 95% Confidence interval [CI]: 1.017-7.467). Tumor size was not an independent prognostic factor for recurrent metastasis.

Comparing survival into two categories of nodal ratio (≤0.25 vs. >0.25) without adjustment for covariates, there was a significant difference between these two categories in the first (P < 0.0001), second (P < 0.0001), and third metastasis (P = 0.024); higher survival was seen in patients with nodal ratio <0.25.

Survival curves are shown in the Figure 1,Figure 2 and Figure 3. The risk of first metastasis increased numerically faster in patients with nodal ratio >0.25 in comparison with nodal ratio <0.25. However, this difference decreased gradually in the next metastases.

Survival curve in the first metastasis

Figure 1

Survival curve in the second metastasis

Figure 2

Survival curve in the third metastasis

Figure 3

Discussion

In this study, high-nodal ratio was associated with a shorter survival from recurrent metastasis. According to the survival curve in the first metastasis, risk of metastasis in patients with nodal ratio >0.25 is significantly higher than nodal ratio <0.25. The risk decreased through next metastases (because of some patient′s deaths) however, the difference remained significant. So this factor can be used to categorize patients into two different groups; a high-risk group with nodal ratio >0.25 and low-risk group with nodal ratio <0.25. Findings indicate that tumor size did not influence the hazard of distant metastasis. A possible explanation might be some breast cancer tumors behave aggressively despite being small. 45

Our findings are in agreement with other studies in which only first metastasis was considered. 38,39,40,41,46,47,48,49,50,51,52 To the best of our knowledge, there are rare reports, which studied prognostic factors of metastatic breast cancer using recurrent survival analysis. However, there are several studies evaluated this issue by multivariate survival analysis. Although the significant factors and studied samples were different in these studies , they consistently comprised of axillary nodal ratio. Truong et al. 24 performed multivariate analysis on distant recurrence of 542 women who had pathologic T1-T2 breast cancer and one to three positive lymph nodes. It was indicated that patients with >25% positive lymph nodes, age ≥45 years, T2 classification of tumor, grade 3 and lymphovascular invasion had higher-risk of distant recurrence. In retrospective study, by Tausch et al. 53 lymph node ratio, age, PR, grade, and tumor stage were detected as prognostic factors of recurrent breast cancer among 7052 patients. Van der Wal et al. 25 examined 453 stage I or II breast cancer patients and found out lymph node ratio ≥0.2, ≥14 lymph nodes removed and vascular invasion increased risk of distant metastases in node positive patients. In multivariate Cox proportional hazard regression analysis of 205 breast cancer patients with stage II or III who treated with neoadjuvant chemotherapy, Keam et al. 23 reported that nodal ratio was prognostic factor for relapse free survival (RFS) besides initial clinical stage and ER. In univariate analysis, nodal ratio >0.25 was associated with shorter RFS.

Furthermore, several studies evaluated the prognostic value of number of involved nodes; 38,39,40,41 Voogd et al. 38 studied risk-factors for local and distant recurrence after breast-conserving therapy or mastectomy. Among 1,772 patients of two randomized clinical trial for stage I and II, the result of multivariate Cox proportional hazards survival analysis showed that large tumor size , positive nodal status, high-histological grade, and vascular invasion were highly associated with increased hazard of distant metastasis. In a study by Touboul et al., 39 risk-factors for local recurrences and distant metastases after breast-conserving surgery and radiation therapy in 528 patients with stage I or II breast cancer were studied using multivariate generalization of the proportional hazards model. It was found that the hazard of distant metastasis increased by the number of involved axillary nodes, high-histological grade, and isolated local recurrence.

Tumor size has been an important prognostic factor of distant metastasis in several studies 24,38,40,41,51,54,55 however, this is not a fixed pattern. Other studies indicated that tumor size was not a significant factor in some subtypes of breast cancer. 39,56,57,58,59,60

The present longitudinal study expanded the findings of previous studies by considering metastasis as a recurrent event and using relevant statistical models. Furthermore, the other strong point is studying the effect of some recent prognostic factors such as p53, HER2, Ki67, and cathepsin D besides conventional prognostic factors.

However, this study had some limitations. First of all, it feels a need for more information about tumor characteristic including, tumor grade. Information about tumor grade was available for few numbers of patients and it was not possible to consider in the model. Pathologic results including tumor grade imposed more cost on patient however, it has an important role in decisions made by physicians and eventually on the survival of patients. Second in spite of adjustment for large spectrum of possible risk-factors, there is always the possibility of ignoring some influential factors; So using frailty models seems logical in order to account for variability due to unobserved factors. However, the multifarious nature of breast cancer metastasis makes detection of all risk-factors difficult.

In conclusion, insignificant tumor size in this study and some other studies raised the question about conventional premise of being a major prognostic factor for distant metastasis. High-nodal ratio was associated with an increased risk of recurrent metastasis in breast cancer patients. So it is suggested for clinical management and to clinicians as a prognostic factor in follow-up of breast cancer patients; patients with higher-nodal ratio have greater hazard of distant metastasis.

The authors are grateful to the members of "Isfahan Seyed-o-Shohada Research Center" for their collaboration in this study. Furthermore, we would like to thank Mr. Yaser Tazhibi for editing this paper.[61]

Kumar V Robbins S Cotran RS Robbins pathologic basis of disease, 6 th ed SaundersPhiladelphia 1999 1093 120 Jalali-Nadoushan MR Davati A Tavakoli A Expression of Bcl-2 gene in primary breast cancer and its correlation with some prognostic factors.J Mazandaran Univ of Med Sci 2007;17:30-6Persian Expression of Bcl-2 gene in primary breast cancer and its correlation with some prognostic factors J Mazandaran Univ of Med Sci 2007;17:30-6 Persian Ferlay J Bray F Pisani P Parkin DM GLOBCAN 2002: Cancer incidence, mortality and prevalence Worldwide IARC cancerbase No.5, Version 2 0 GLOBCAN 2002: Cancer incidence, mortality and prevalence Worldwide IARC cancerbase No 5, Version 20 Lyon: IARCPress; 2004 Brunicardi FC Schwartz SI The breast.Schwartz′s principles of surgeryth ed 8 th The breast Schwartz's principles of surgery 8 th ed New York: McGraw-Hill, Health Pub Division; 2005 p 453 Kuo WH Yen AM Lee PH Chen KM Wang J Chang KJ Cumulative survival in early-onset unilateral and bilateral breast cancer: An analysis of 1907 Taiwanese womenBr J Cancer 2009 100 563 70 Ravdin PM Cronin KA Howlader N Berg CD Chlebowski RT Feuer EJ The decrease in breast-cancer incidence in 2003 in the United StatesN Engl J Med 2007 356 1670 4 Fontenoy AM Leux C Delacour-Billon S Allioux C Frenel JS Campone M Recent trends in breast cancer incidence rates in the Loire-Atlantique, France: A decline since 2003Cancer Epidemiol 2010 34 238 43 Wang PP Cao Y Incidence trends of female breast cancer in Saskatchewan, 1932-1990Breast Cancer Res Treat 1996 37 197 207 Sim X Ali RA Wedren S Goh DL Tan CS Reilly M Ethnic differences in the time trend of female breast cancer incidence: Singapore, 1968-2002BMC Cancer 2006 6 261 Medina VM Laudico A Mirasol-Lumague MR Brenner H Redaniel MT Cumulative incidence trends of selected cancer sites in a Philippine population from 1983 to 2002: A joinpoint analysisBr J Cancer 2010 102 1411 4 Takiar R Srivastav A Time trend in breast and cervix cancer of women in India - (1990-2003)Asian Pac J Cancer Prev 2008 9 777 80 Hirabayashi Y Zhang M Comparison of time trends in breast cancer incidence (1973-2002) in Asia, from cancer incidence in five continents, Vols IV-IXJpn J Clin Oncol 2009 39 411 2 Kolahdoozan S Sadjadi A Radmehr AR Khademi H Five Common Cancers in IranArch Iran Med 2010 13 143 6 Yavari P Abadi A Mehrabi Yad Elah Mortality and changing epidemiological trends in Iran during 1979-2001Hakim Res J 2003 6 7 14 Persian Harirchi I Karbakhsh M Kashefi A Momtahen AJ Breast cancer in Iran: Results of a multi-center studyAsian Pac J Cancer Prev 2004 5 24 7 Mousavi SM Montazeri A Mohagheghi MA Jarrahi AM Harirchi I Najafi M Breast cancer in Iran: An epidemiological reviewBreast J 2007 13 383 91 Asadpour A Isfahan: First degree of cancer in Iran.Jame Jam J 2007:15-16Persian Isfahan: First degree of cancer in Iran Jame Jam J 2007:15-16 Persian Weigelt B Peterse JL van′t Veer LJ Breast cancer metastasis: Markers and modelsNat Rev Cancer 2005 5 591 602 Thomas ES Gomez HL Li RK Chung HC Fein LE Chan VF Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatmentJ Clin Oncol 2007 25 5210 7 Gonçalves A Esterni B Bertucci F Sauvan R Chabannon C Cubizolles M Postoperative serum proteomic profiles may predict metastatic relapse in high-risk primary breast cancer patients receiving adjuvant chemotherapyOncogene 2006 25 981 9 Brunner WN Stephens RW Dano K Diseases of the Breast, 4th ed Lippincott Williams and WilkinsPhiladelphia 2009 367 76 Welch DR Harms JF Mastro AM Gay CV Donahue HJ Breast cancer metastasis to bone: Evolving models and research challengesJ Musculoskelet Neuronal Interact 2003 3 30 8 Keam B Im SA Kim HJ Oh DY Kim JH Lee SH Clinical significance of axillary nodal ratio in stage II/III breast cancer treated with neoadjuvant chemotherapyBreast Cancer Res Treat 2009 116 153 60 Truong PT Berthelet E Lee J Kader HA Olivotto IA The prognostic significance of the percentage of positive/dissected axillary lymph nodes in breast cancer recurrence and survival in patients with one to three positive axillary lymph nodesCancer 2005 103 2006 14 van der Wal BC Butzelaar RM van der Meij S Boermeester MA Axillary lymph node ratio and total number of removed lymph nodes: Predictors of survival in stage I and II breast cancerEur J Surg Oncol 2002 28 481 9 Nguyen PL Taghian AG Katz MS Niemierko A Abi Raad RF Boon WL Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapyJ Clin Oncol 2008 26 2373 8 Haffty BG Yang Q Reiss M Kearney T Higgins SA Weidhaas J Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancerJ Clin Oncol 2006 24 5652 7 González LO Pidal I Junquera S Corte MD Vázquez J Rodríguez JC Overexpression of matrix metalloproteinases and their inhibitors in mononuclear inflammatory cells in breast cancer correlates with metastasis-relapseBr J Cancer 2007 97 957 63 Colleoni M Rotmensz N Peruzzotti G Maisonneuve P Mazzarol G Pruneri G Size of breast cancer metastases in axillary lymph nodes: Clinical relevance of minimal lymph node involvementJ Clin Oncol 2005 23 1379 89 Mauriac L Keshaviah A Debled M Mouridsen H Forbes JF Thürlimann B Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trialAnn Oncol 2007 18 859 67 Koizumi M Yoshimoto M Kasumi F Iwase T An open cohort study of bone metastasis incidence following surgery in breast cancer patientsBMC Cancer 2010 10 381 Hashemi E Montazeri A Akbari M Najafi M Haghighat S Kaviani A Role of tumor markers in breast cancer recurrence.J Guilan Univ Med Sci 2006;15:28-32Persian Role of tumor markers in breast cancer recurrence J Guilan Univ Med Sci 2006;15:28-32 Persian Mylonas I Makovitzky J Jeschke U Briese V Friese K Gerber B Expression of Her2/neu, steroid receptors (ER and PR), Ki67 and p53 in invasive mammary ductal carcinoma associated with ductal carcinoma In Situ (DCIS) Versus invasive breast cancer aloneAnticancer Res 2005 25 1719 23 Gao D Du J Cong L Liu Q Risk factors for initial lung metastasis from breast invasive ductal carcinoma in stages I-III of operable patientsJpn J Clin Oncol 2009 39 97 104 Spyratos F Hacene K Rouëssé J Brunet M Andrieu C Desplaces A Cathepsin D: An independent prognostic factor for metastasis of breast cancerLancet 1989 334 1115 8 Shoker BS Jarvis C Clarke RB Anderson E Hewlett J Davies MP Estrogen receptor-positive proliferating cells in the normal and precancerous breastAm J Pathol 1999 155 1811 5 Evans AJ James JJ Cornford EJ Chan SY Burrell HC Pinder SE Brain metastases from breast cancer: Identification of a high-risk groupClin Oncol (R Coll Radiol) 2004 16 345 9 Voogd AC Nielsen M Peterse JL Blichert-Toft M Bartelink H Overgaard M Differences in risk factors for local and distant recurrence after breast-conserving therapy or mastectomy for stage I and II breast cancer: Pooled results of two large European randomized trialsJ Clin Oncol 2001 19 1688 97 Touboul E Buffat L Belkacémi Y Lefranc JP Uzan S Lhuillier P Local recurrences and distant metastases after breast-conserving surgery and radiation therapy for early breast cancerInt J Radiat Oncol Biol Phys 1999 43 25 38 Veronesi U Galimberti V Zurrida S Merson M Greco M Luini A Prognostic significance of number and level of axillary node metastases in breast cancerBreast 1993 2 224 8 Spyratos F Hacene K Tubiana-Hulin M Pallud C Brunet M Prognostic value of estrogen and progesterone receptors in primary infiltrating ductal breast cancer.A sequential multivariate analysis of 1262 patientsEur J Cancer Clin Oncol 1989 25 1233 40 Rondeau V Mathoulin-Pélissier S Tanneau L Sasco AJ Macgrogan G Debled M Separate and combined analysis of successive dependent outcomes after breast-conservation surgery: Recurrence, metastases, second cancer and deathBMC Cancer 2010 10 697 Wei LJ Lin DY Weissfeld L Regression analysis of multivariate incomplete failure time data by modeling marginal distributionsJ Am Stat Assoc 1989 84 1065 73 Kleinbaum DG Klein M Survival analysis: A Self-Learning Text, 2 nd ed Springer VerlagNew York 2005 347 53 Foulkes WD Reis-Filho JS Narod SA Tumor size and survival in breast cancer: A reappraisalNat Rev Clin Oncol 2010 7 348 53 Cascinelli N Greco M Bufalino R Clemente C Galluzzo D Delle Donne V Prognosis of breast cancer with axillary node metastases after surgical treatment onlyEur J Cancer Clin Oncol 1987 23 795 9 Veronesi U Marubini E Del Vecchio M Manzari A Andreola S Greco M Local recurrences and distant metastases after conservative breast cancer treatments: Partly independent eventsJ Natl Cancer Inst 1995 87 19 27 Page DL Prognosis and breast cancer: Recognition of lethal and favorable prognostic typesAm J Surg Pathol 1991 15 334 49 Merkel DE Osborne CK Prognostic factors in breast cancerHematol Oncol Clin North Am 1989 3 641 52 Rosen PP Groshen S Saigo PE Kinne DW Hellman S Pathological prognostic factors in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma: A study of 644 patients with median follow-up of 18 yearsJ Clin Oncol 1989 7 1239 51 Arriagada R Rutqvist LE Johansson H Kramar A Rotstein S Predicting distant dissemination in patients with early breast cancerActa Oncol 2008 47 1113 21 Carter CL Allen C Henson DE Relation of tumor size, lymph node status, and survival in 24,740 breast cancer casesCancer 1989 63 181 7 Tausch C Taucher S Dubsky P Seifert M Reitsamer R Kwasny W Prognostic value of number of removed lymph nodes, number of involved lymph nodes, and lymph node ratio in 7502 breast cancer patients enrolled onto trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG)Ann Surg Oncol 2012 19 1808 17 Silvestrini R Daidone MG Di Fronzo G Morabito A Valagussa P Bonadonna G Prognostic implication of labeling index versus estrogen receptors and tumor size in node-negative breast cancerBreast Cancer Res Treat 1986 7 161 9 O′Reilly SM Camplejohn RS Barnes DM Millis RR Rubens RD Richards MA Node-negative breast cancer: Prognostic subgroups defined by tumor size and flow cytometryJ Clin Oncol 1990 8 2040 6 Foulkes WD Grainge MJ Rakha EA Green AR Ellis IO Tumor size is an unreliable predictor of prognosis in basal-like breast cancers and does not correlate closely with lymph node statusBreast Cancer Res Treat 2009 117 199 204 Mokarian F Abdeyazdan N Motamedi N Tabesh P Mokarian S Hashemi F Risk factors of metastasis in women with breast cancer.J Isfahan Med Sch 2012;29:2785-96Persian Risk factors of metastasis in women with breast cancer J Isfahan Med Sch 2012;29:2785-96 Persian Foulkes WD Metcalfe K Hanna W Lynch HT Ghadirian P Tung N Disruption of the expected positive correlation between breast tumor size and lymph node status in BRCA1-related breast carcinomaCancer 2003 98 1569 77 Fisher B Slack NH Bross ID Cancer of the breast: Size of neoplasm and prognosisCancer 1969 24 1071 80 Dent R Hanna WM Trudeau M Rawlinson E Sun P Narod SA Time to disease recurrence in basal-type breast cancers: Effects of tumor size and lymph node statusCancer 2009 115 4917 23 Wei L Johnson WE Combining dependent tests with incomplete repeated measurementsBiometrika 1985 72 359