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Prognostic factors for cancer‐specific survival in 220 patients with breast cancer: A single center experience

Prognostic factors for cancer‐specific survival in 220 patients with breast cancer: A single... INTRODUCTIONBreast cancer (BC) is a serious public health issue worldwide. BC affects nearly 1.3 million people worldwide each year, making it the most common type of cancer in women.1 According to World Health Organization (WHO) estimates, cancer accounts for approximately one in every six deaths worldwide, with low‐ and middle‐income countries accounting for approximately 70% of cancer deaths. BC with almost two million new cases in 2018, is the most prevalent cancer in women and the second most common cancer in the world after lung cancer.2,3BC accounts for more than 24% of all cancers in Iran, with a prevalence rate of 24.8–34 per 100 000 women and a death rate of less than 10.2 per 100 000 population in 2018.2 The long‐term prognosis for women with BC has significantly improved over the last 50 years.4 Due to the findings of previous studies,5 BC is often detected in Iranian women in an advanced stage; so treatment is delayed.6 Abedi investigated the survival rate in Iran and discovered that the rates of survival for 1, 3, 5, and 10 years were 95.8%, 82.4%, 69.5%, and 58.1%, respectively.7More express oncogenes Her 2/neu, pre‐menopausal age, undergoing various forms of treatment (surgery, radiotherapy, chemotherapy, and hormone therapy), Socioeconomic status, fertility status, stage of the disease, the number of lymph nodes involved, type of tumor pathology, higher grade or tumor grade, estrogen and progesterone negativity receptors, and high body mass index (BMI) are relevant factors correlated with lower survival rates.5Western Iran has a population of approximately 4 million and there are relatively few studies relating to exploring the relationship in the Iranian population between these prognostic markers and survival. The identification of the factors contributing to higher survival rates for women with BC will help to identify early diagnosis and improve policies for prevention and treatment, both in the nursing system and in other health fields. Therefore, this study was undertaken to assess the survival rate and probability of mortality in BC patients and to assess the predictive factors for survival.MATERIAL AND METHODSStudy population and designThis retrospective analysis was conducted on 578 patients with primary BC who underwent surgery at Imam Reza Hospital in Kermanshah, Iran, between 2004 and 2020. For 234 patients, the survival outcome was not available in the dataset. As a result, they were excluded from the study. In addition, 124 patients were excluded due to exclusion criteria, insufficient medical history, or mortality due to a cause other than BC. In this study, all participants underwent surgery and received radiation, and all except a very limited number received chemotherapy.Ethical considerationAccording to the National Resolution for Human Studies, no informed consent was needed once the present analysis focused on retrospective data collection. Nevertheless, we obtained official permission from the Hospital Majors, labs, municipal, and state Health Secretariats to gain access to databases, laboratory, and medical reports. The research design was approved by the ethical committee and institutional review board of Kermanshah University of Medical Sciences (IR.KUMS.REC.1398.363).Exclusion criteriaPatients with heart failure, cerebrovascular disease, hematologic illness, any inflammatory symptoms or conditions, peripheral arterial disease, coronary artery disease, end‐stage renal disease, peripheral arterial disease, or a lack of pathologic or laboratory data were excluded.Collection dataMedical records for the Hospital Information system (HIS) were reviewed and age, menopause status, lymph node metastasis, diameter and side of the tumor, stage of disease, pathological tumor types, Oral Contraceptive Pill (OCP) consumption, family history, number of babies, breastfeeding status, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor‐2 (HER‐2) levels were collected as dependent variables. BC overall survival (independent variables) was calculated from the date of operation to the date of death for women whose death was specifically due to cancer. Immunohistochemical (IHC) staining in tumor tissue was determined by HER‐2 levels: IHC 3+ and IHC 2+ were classified as HER‐2 positive tumors; IHC 1+ or IHC‐ were classified as HER‐2 negative tumors. Her‐2 status was determined using IHC staining and those with 3+ results assumed positive, 2+ was indeterminate and 1+ assumed negative.Luminal‐A is defined as ER+ and/or PR+ / HER2‐, Luminal‐B is ER+ and/or PR+/HER2+, HER2 overexpressed is ER‐/PR‐/HER2+, and the triple negative is ER‐/PR‐/HER2‐. For BC, the morphological and topographic classifications used were ICD‐O15 and ICD‐1016, respectively.8All patients with a histopathologic diagnosis of cancer during the study period (ICD‐10: C50 and D05.1) corresponding to malignant clinical tumors, primary site (ICD‐O: code 3), and malignant metastatic site (ICD‐O: code 6) were included. All cases were diagnosed pathologically by biopsy or surgical specimens.Distant Metastases have been identified through radiological analysis, such as magnetic resonance imaging, ultrasound, bone scintigraphy, and computed tomography.Following‐up investigationAbout 578 cases of these women underwent follow‐up investigations for 60–192 months following BC surgery.Statistical analysisSPSS version 13.0 software was used for statistical analysis. Survival curves are drawnusing Life‐tables and survival rate comparisons were done by using the Chi‐squared test. Cox regression model analysis and multivariate analysis were performed to determine prognostic factors. A p‐value of less than .05 was considered statistically significant. The study endpoints were 5‐ and 10‐year disease‐free survival.RESULTSOf the 220 studied patients, 81 (36.8) died by the end of the analysis. The age of patients ranged from 20 to 83 years with a mean of 47.48 ± 11.33 and a median of 46 years.The overall survival rates of 1‐, 3‐, 5‐, and 10‐year for the 220 cases were 95%, 80%, 71%, and 62%, respectively, with a median survival period of 96 months (Figure 1).1FIGUREThe plot of overall survival for patients with breast cancerTable 1 provides an analysis of tumor‐related factors and prognosis for 220 women with BC. The highest number of patients was in the age group of 20–50 (predominantly in the age group of 40–50). In addition, 35.9% of patients were in the early stage of diagnosis. The 1‐, 3‐, 5‐, and 10‐year survival was inversely related to the stage at diagnosis (Table 1).1TABLEClinical, pathological, and biological characteristics of patients and univariate analysisVariableN (%)Mean ± SEYearsp‐valueNumber of survivorsMedian OS (month)13510Survival220115.16 ± 3.789621919615970Age (year)20–50138 (63.3%)112.11 ± 4.35a9613812610848.01*50–6048 (22%)113.42 ± 8.96a964841331360–7019 (8.7%)91.5 ± 13.36b84191612670–9513 (6%)76.08 ± 17.07b48131263Marital statusSingle14 (6.5%)100.64 ± 13.9102131397.644Married203 (93.5%)115.70 ± 3.929620318114862MenopausePremenopause145 (66.8%)121.68 ± 4.399614413211250.012*Postmenopause72 (33.2%)102.02 ± 7.068472614520Lump node metastasisYes79 (56.8%)102.36 ± 6.728478694924<.001*No60 (43.2%)145.80 ± 3.4612060605831Lymph node numberLess than 4 or 439 (54.2%)19.07 ± 9.41a10839353016.002*5–922 (30.6%)93.27 ± 11.06a84222012610 or more than 1011 (15.3%)56.09 ± 10.76b4810831MetastasisYes75 (35%)53.18 ± 4.54367453243<.001*No139 (65%)149.60 ± 2.2410813913713265Organ metastasisOCP before menopauseYes150 (70.1%)121.03 ± 4.239614913411648.066No64 (29.9%)105.27 ± 7.218464584120FH family historyYes99 (46.3%)117.47 ± 5.619698897126.642No115 (53.7%)115.27 ± 5.19961151028542Number of childrenLess than 2 or 256 (25.9%)124.33 ± 6.839656524416.134More than 2 and less than 584 (38.9%)116.58 ± 6.0010284756130Or more than 555 (25.5%)109.09 ± 7.858455493916Without children21 (9.7%)101.38 ± 12.04842018137Breast feedingYes185 (86.4%)117.76 ± 4.039618516813858.32No29 (13.6%)104.97 ± 10.918429251810Side of tumor LRL92 (46.2%)114.45 ± 5.879692826733.977R105 (52.8%)114.65 ± 5.5996104937430Size of tumor2 or less than 235 (22%)112.58 ± 8.8810835322713.448More than 2124 (78%)114.27 ± 5.10961231118943Stage0–152 (35.9%)147 ± 3.91a10852525022<.0012a6 (401%)129 ± 2.59a12066642b‐487 (60%)84.16 ± 6.46b6086684318UnknownHistologyDuctal in situ3 (1.4%)120 ± 19.591083331.193Ductal invasive212 (96.8%)115.48 ± 3.869621118915368Others4 (1.8%)66 ± 16.156643269ERPositive136 (61.8%)118.89 ± 4.669613612510148.286Negative84 (38.2%)109.24 ± 6.389683715822PRPositive135 (61.4%)120.82 ± 4.579613412510349.103Negative85 (38.6%)106.23 ± 6.478485715621Her 2Positive116 (53.7%)112.54 ± 5.25961151038137.456Negative100 (46.3%)118.28 ± 5.6096100897431P53Positive52 (36.6%)129.92 ± 6.71108114220.228Negative89 (62.7%)115.38 ± 6.149652496426Ki67Positive86 (92.5%)122.88 ± 5.949686776621.317Negative7 (7.5%)140.57 ± 14.281327764Type of breastLuminar A71 (32.9%)124.41 ± 6.3110871665523.215Luminar B87 (40.3%)104.63 ± 5.439686786029Her2 overexpressed30 (13.9%)109.06 ± 10.71963026207Triple‐negative28 (13%)109.71 ± 11.22902822209Nuclear grading (NG)1/326 (21.7%)123.367 ± 7.1692625239.1452/370 (58.3%)117.56 ± 6.8684706150153/324 (20%)104.29 ± 12.1610223201510Margin grading (MG)1/319 (14.7%)123.36 ± 7.16841917132.4512/388 (68.2%)117.56 ± 6.8696887764293/322 (17.1%)104.29 ± 12.161022221167Vascular invasionPositive95 (75.4%)115.23 ± 5.779694846828.742Negative31 (24.6%)112.13 ± 10.639631272211Skin involvementPositive4 (6.3%)87.00 ± 22.60844422.463Negative69 (93.7%)122.49 ± 6.9810859554529Nipple involvementPositive3 (4.3%)92.00 ± 32.66843221.805Negative66 (95.7%)118.64 ± 6.911466594933Margin involvementPositive8 (14%)94.5 ± 17.42848752.805Negative49 (86%)122.57 ± 7.3910849453920Dissimilar letter indicate a significant difference between groups (*p < 0.05).Univariate analyses of BC patients with tumor‐related factors indicated that factors such as age, menopause status, lymph node metastasis, number of involved lymph nodes, distant metastasis, and stage significantly correlated with disease‐specific survival rates (p < .05) (Table 1).Because of the correlation between the lymph node number and lymph node metastasis, we only included the variables metastasis, lymph node metastasis, age, and menopause in the Cox model. In this model, only the variables of metastasis (HR = 41.77, 95% CI: 15.3–114.15) and metastasis in lymph nodes (HR = 5.26, 95% CI: 1.9–14.6) are significant. According to the Cox model, the risk of death in BC for patients with metastasis is 41.71 times higher than those without metastasis, and the risk of death in people with lymph node metastasis is 5.26 times higher than those without lymph node metastasis (Table 2).2TABLEMultivariate cox regression analysisVariableStandard error (β))WALD)p valueHRa95% CIAge (year)20–50*150–60−1.26 (1.04)1.47.230.28(0.04, 2.18)60–70−0.396 (1.24)0.102.750.67(0.06, 7.6)70–95−0.405 (1.18)0.117.730.67(0.07, 6.8)Premenapose*1Postmenapose0.704 (1.07)0.431.512.02(0.25, 16.54)Lump node metastasisNo*1Yes1.7 (0.52)10.18<.0015.26(1.9, 14.6)MetastasisNo*1Yes3.73 (0.513)52.94<.00141.77(15.3, 114.15)*p < 0.05.There was a significant negative correlation between metastasis and axillary lymph node metastasis and long‐term disease‐free survival rates, as seen in Figure 2. Increased involved lymph node numbers were correlated with higher mortality rates.2FIGUREFactors related to survival rates of breast cancer patients. (A) Relationship between organ metastasis and disease‐specific survival rates. (B) Relationship between lymph‐node metastasis and survival ratesDISCUSSIONCancer is the world's second leading cause of death, accounting for almost 9.6 million deaths in 2018.2 Epidemiological evidence showed that the largest prevalence of BC was among the 50‐ and 60‐year age group, followed by the 40‐ to 49‐year age group. We demonstrated that the largest prevalence of BC was in the age group of 20–50 (predominantly in the age group of 40–50).9,10 This then reinforces the need to do mammography in the age group of 40–50. Various studies conducted in Iran have estimated the mean age at the time of diagnosis to be 45–50 years.11 The mean age of patients at the time of diagnosis in the present study was about 47.71 years, which is consistent with the findings of other studies.12,13 However, these results do not agree with the results of studies in Western Europe and North America.14,15 This could be due to the delay in the diagnosis of cancer in Iran, which has been mentioned in other studies.11,16 Two other studies also reported that mean age affects the survival of BC.17,18Factors influencing the survival rate of women with BC have become extremely important for patients. Several risk factors related to BC have been reported by Roder et al.,19 including tumor size, higher grade, positive nodal status, ER‐negative status, vascular invasion, and multifocality. Menopausal status, tumor size, axillary lymph node metastasis, and TNM stage were found to be associated with a 5‐year overall survival rate in 246 BC patients.20Findings of this study showed that metastasis and metastasis in lymph nodes were the most important factors that significantly reduced the survival of the subjects, which is consistent with the results of other studies conducted in Iran.12,21In the univariate test, the disease stage, menopausal status, age, and number of lymph nodes involved all showed a significant relationship with decreased survival.In the analysis of the marital status, 93.5% of the patients were married, but no significant relationship was shown between married and single women and survival rate. In another study in Kermanshah, women who had never been married, had a higher chance of developing BC than married, divorced, and widowed women. However, the observed relationship was not statistically significant.22A meta‐analysis review in Iran estimated the 1‐, 2‐, 3‐, 5‐, and 10‐year BC survival rates in Iran to be 95.8%, 82.4%, 69.5%, and 58.1%, respectively, in line with the findings of this study. In general, since this study was not based on data from the national or provincial registration program, it did not make sense to judge whether the observed survival rate increased or decreased. In addition, the generalization of results to BC patients in the country should be done with great caution. The 5‐year overall survival rate in Iran compared to 84% in the United Kingdom,23 89% in the United States,24 71% in Germany,25 65% in Greece,26 64% in Oman27 and 46% in India28 suggesting that Iran's survival is significantly less than that of European countries and the United States, which is in line with the result of Vahdaninia et al. study.21 There are several possible explanations for this. Women's knowledge of BC in Iran is limited—Iranian women know little to nothing about breast self‐examination and its impact on early diagnosis and prognosis.In addition, the difference in the survival rate of BC between countries and regions of the same country, however, persists and is not easy to explain. In one country versus another, the highest survival rate could be due to the availability of better treatment or similar treatment becoming more effective when the diagnosis is made at an earlier stage of the disease.24In BC, the presence of lymph node metastasis is a predictive factor for women's disease survival and recurrence, reducing survival by 40% relative to women with non‐metastatic disease survival.29 This research showed that a greater percentage of positive axillary lymph nodes raised the risk of death associated with BC. This was consistent with another study, which showed that axillary lymph node metastasis was the most significant prognostic factor influencing local regulation, disease‐free survival, and overall survival.30 According to Akbari et al.,31 the most important factor influencing patient survival is axillary lymph node involvement, as patients with involved lymph nodes lived shorter than those without involved lymph node involvement. If the disease is diagnosed at an early stage where the lymph nodes are not involved and the patients are treated correctly, they will survive longer. In this study, lymph node involvement increases the death risk by a factor of 5.26.The number of nodes involved was the most important multi‐factorial research predictor of survival. According to our results, not only did node‐positive patients have a shorter survival rate compared to node‐negative patients, but the risk of mortality also increased as the number of nodes involved increased.32 Compared to non‐metastatic BC, metastatic breast cancer (MBC) is commonly considered to have a low prognosis. Common sites of distant metastasis in BC include bone, liver, lung, and brain.33 Previous studies have shown that in BC patients, the bone is the most common distant metastatic organ.34,35 Similarly, our findings also indicate that the most prevalent subgroup in the study population is bone and liver metastasis, accounting for 21.3% of the total patients.Dabakuyo et al.36 reported that the survival rate was lower in patients above 60 years of age or postmenopausal patients. The cancer mortality rate has also been reported to have risen with age in Northern Vietnam. According to the results of this study, postmenopausal patients were shown to have a significantly lower specific survival rate than premenopausal patients.37 Contrary to the results of this study, D'Eredita et.al38 demonstrated that tumor size was significantly associated with BC survival, as patients with tumor size of 5 cm and more had a higher chance of death than those with tumor sizes of 2 cm and less. This finding was consistent with two other studies.12Similar to other studies, we found that the stage of the disease is one of the most important factors in the survival rate of patients with BC. The late stage of diagnosis was separately related to lower survival rates globally.4,39–41 Of the predictive factors, the absence of metastatic lymph node involvement and the expression of estrogen receptors are the most important for a better prognosis. In the early stages, this enhances the value of detection and care, increasing the chance that the disease has not yet reached the axillary lymph nodes, which improves recovery, cure prospects, and enables less aggressive therapies to be implemented.10,30,42 In contrast to lymph node involvement, we found no significant relationship between estrogen receptor status and survival, which may be due to the small sample size in our study.Since breast‐conserving surgery has become the treatment of choice for early‐stage BC patients, the function of surgical margins is poorly known and is still under discussion.43,44 Fujimoto and colleagues demonstrated that women with positive margins showed poorer 2‐ and 5‐year BC survival compared to women with negative margins. In our study, no significant relationship was found between margin involvement and survival rate. Skin and nipple involvement and vascular invasion were not associated with survival, which is consistent with the result of Rezaianzadeh et al.12This research showed no indications of a relationship between BC family history and survival and found that tumor features are identical in patients with a positive and negative family history. This is in line with the findings of several other studies.45–47Contrary to the results of this study, Akbari et al.31 and Fallahzadeh et al.48 found that survival is impacted by the side of the tumor (left or right breast) and that more patients survived with a tumor in their left breast than those with a tumor in their right breast. The study also found no association between histological type and survival in common with other works.49,50Lööf‐Johanson et al.51 reported that there was a higher survival rate for women with primary BC if overall breastfeeding was longer than 6 months and/or if they had at least one pregnancy. The results of our study were in line with other studies that reported different results.52–54 The findings of previous research on OCPs and BC mortality among women were inconsistent; some reported lower mortality among OC Ps users55,56 and some recorded higher mortality57–59 or no effect.60–62The prevalence of TNBC in this research is in line with the literature, as it accounts for 10% to 20% of all BCs.63,64 Patients with TNBC have been found to have a poor prognosis.65 On the other hand, another analysis found that there were no significant differences in 3‐year survival between TNBC cancers and other BCs.66 Further studies have found that the difference between the TNBC and non‐TNBC groups peaked at 3 years, but this difference has declined with time, indicating that long‐term survivors (over 10 years) in the TNBC group may have survival comparable to cases of non‐TNBC.67,68 While there is no difference in OS between patients with TNBC and non‐TNBC in this research, maybe a greater number of cases between the two groups would have yielded different outcomes.There are certain limitations in our analysis. Details on some of the explanatory variables are missing; some patients were not available after 10 years. Information on ER, PR, and HER2, vascular invasion, and nipple and skin involvement was absent in nearly half of the initial sample population.CONCLUSIONIn conclusion, the findings presented in this study indicate a comparatively poor overall survival rate of 5 and 10 years for women diagnosed with BC in Iran. Qualitative information on BC patients and health care providers recognized that a healthier lifestyle and the value of early diagnosis should be obtained to improve their awareness, and also study educational programs should be provided for the target population to prevent deaths related to BC. The findings of the review of 26 explanatory factors presented in this report indicate that the survival of BC in western Iran is impaired by delaying diagnosis and, therefore, by late‐stage disease. We conclude that this is due to a poor level of awareness, cultural differences, and lower access to treatment. Further study is required in Iranian women to test these hypotheses and thus formulate effective approaches to effectively boost survival.AUTHOR CONTRIBUTIONSData curation, M.T.; Investigation, M.T., S.K., E.S.; Methodology, M.T., S.H.M.; Writing – Original Draft, M.T.; Writing – Review and Editing, M.T., S.H.M., E.S.; Formal Analysis, S.K., E.S.; Visualization, S.K.; Conceptualization, S.H.M.; Supervision, S.H.M.ACKNOWLEDGMENTSThe authors would like to thank the Clinical Research Development Center of Imam Reza Hospital for Consulting Services.CONFLICT OF INTERESTThe authors have stated explicitly that there are no conflicts of interest in connection with this article.DATA AVAILABILITY STATEMENTAll data required to assess the research's conclusions are included in the article and/or the supplemental material.REFERENCESBlows FM, Driver KE, Schmidt MK, et al. 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Cancer Epidemiol. 2012;36(6):554‐559.Moraes ABD, Zanini RR, Turchiello MS, Riboldi J, Medeiros LRD. Survival study of breast cancer patients treated at the hospital of the Federal University in Santa Maria, Rio Grande do Sul, Brazil. Cad Saude Publica. 2006;22(10):2219‐2228.Schneider IJC, d'Orsi E. Sobrevida em cinco anos e fatores prognósticos em mulheres com câncer de mama em Santa Catarina. Brasil Cadernos Saúde Pública. 2009;25(6):1285‐1296.Tiezzi DG, Andrade JMD, Reis FJCD, Deriggi DJP, Zola FE, Marana HRC. Impacto prognóstico da recorrência local em pacientes com câncer inicial de mama submetidas a tratamento conservador. Rev Col Bras Cir. 2008;35(5):284‐291.Behm EC, Beckmann KR, Dahlstrom JE, et al. Surgical margins and risk of locoregional recurrence in invasive breast cancer: an analysis of 10‐year data from the breast cancer treatment quality assurance project. The Breast. 2013;22(5):839‐844.Ishida T, Takeda M, Suzuki A, Amari M, Moriya T, Ohuchi N. Significance of irradiation in breast‐conserving treatment: comparison of local recurrence rates in irradiated and nonirradiated groups. Int J Clin Oncol. 2008;13(1):12‐17.Eccles D, Simmonds P, Goddard J, et al. Familial breast cancer: an investigation into the outcome of treatment for early stage disease. Fam Cancer. 2001;1(2):65‐72.Gonzalez‐Angulo AM, Broglio K, Kau SW, et al. Women age ≤35 years with primary breast carcinoma: disease features at presentation. Cancer. 2005;103(12):2466‐2472.Harris EE, Schultz DJ, Peters CA, Solin LJ. Relationship of family history and outcome after breast conservation therapy in women with ductal carcinoma in situ of the breast. Int J Radiat Oncol Biol Phys Ther. 2000;48(4):933‐941.Fallahzadeh H, Momayyezi M, Akhundzardeini R, Zarezardeini S. Five year survival of women with breast cancer in Yazd. Asian Pac J Cancer Prev. 2014;15(16):6597‐6601.Arpino G, Bardou VJ, Clark GM, Elledge RM. Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome. Breast Cancer Res. 2004;6(3):1‐8.Kuru B, Camlibel M, Ali Gulcelik M, Alagol H. Prognostic factors affecting survival and disease‐free survival in lymph node‐negative breast carcinomas. J Surg Oncol. 2003;83(3):167‐172.Lööf‐Johanson M, Brudin L, Sundquist M, Rudebeck CE. Breastfeeding associated with reduced mortality in women with breast cancer. Breastfeed Med. 2016;11(6):321‐327.Merritt MA, Riboli E, Murphy N, et al. Reproductive factors and risk of mortality in the European prospective investigation into cancer and nutrition; a cohort study. BMC Med. 2015;13(1):252.Song N, Choi J‐Y, Sung H, et al. Tumor subtype‐specific associations of hormone‐related reproductive factors on breast cancer survival. PLoS One. 2015;10(4):e0123994.Trivers KF, Gammon MD, Abrahamson PE, et al. Association between reproductive factors and breast cancer survival in younger women. Breast Cancer Res Treat. 2007;103(1):93‐102.Matthews PN, Millis RR, Hayward JL. Breast cancer in women who have taken contraceptive steroids. Br Med J. 1981;282(6266):774‐776.Schönborn I, Nischan P, Ebeling K. Oral contraceptive use and the prognosis of breast cancer. Breast Cancer Res Treat. 1994;30(3):283‐292.Lees AW, Jenkins HJ, May CL, Cherian G, Lam EW, Hanson J. Risk factors and 10‐year breast cancer survival in northern Alberta. Breast Cancer Res Treat. 1989;13(2):143‐151.Olsson H, Moller T, Ranstam J, Borg Å, Ferno M. Early oral contraceptive use as a prognostic factor in breast cancer. Anticancer Res. 1988;8(1):29‐32.Ranstam J, Olsson H, Garne J, Aspegren K, Janzon L. Survival in breast cancer and age at start of oral contraceptive usage. Anticancer Res. 1991;11(6):2043‐2046.Ewertz M, Gillanders S, Meyer L, Zedeler K. Survival of breast cancer patients in relation to factors which affect the risk of developing breast cancer. Int J Cancer. 1991;49(4):526‐530.Schouten LJ, Hupperets PS, Jager JJ, et al. Prognostic significance of etiological risk factors in early breast cancer. Breast Cancer Res Treat. 1997;43(3):217‐223.Spencer J, Millis RR, Hayward J. Contraceptive steroids and breast cancer. Br Med J. 1978;1(6119):1024‐1026.Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER)‐negative, progesterone receptor (PR)‐negative, and HER2‐negative invasive breast cancer, the so‐called triple‐negative phenotype: a population‐based study from the California cancer registry. Cancer. 2007;109(9):1721‐1728.Esposito A, Criscitiello C, Curigliano G. Highlights from the 14th St Gallen international breast cancer conference in Vienna: dealing with classification, prognostication, and prediction refinement to personalize the treatment of patients with early breast cancer. Ecancermedicalscience. 2015;9:518.Haffty BG, Yang Q, Reiss M, et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early‐stage breast cancer. J Clin Oncol. 2006;24(36):5652‐5657.Abulkhair O, Moghraby JS, Badri M, Alkushi A. Clinicopathologic features and prognosis of triple‐negative breast cancer in patients 40 years of age and younger in Saudi Arabia. Hematol Oncol Stem Cell Ther. 2012;5(2):101‐106.Dent R, Trudeau M, Pritchard KI, et al. Triple‐negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15):4429‐4434.Tischkowitz M, Brunet J‐S, Bégin LR, et al. Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer. 2007;7(1):134. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Reports Wiley

Prognostic factors for cancer‐specific survival in 220 patients with breast cancer: A single center experience

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Abstract

INTRODUCTIONBreast cancer (BC) is a serious public health issue worldwide. BC affects nearly 1.3 million people worldwide each year, making it the most common type of cancer in women.1 According to World Health Organization (WHO) estimates, cancer accounts for approximately one in every six deaths worldwide, with low‐ and middle‐income countries accounting for approximately 70% of cancer deaths. BC with almost two million new cases in 2018, is the most prevalent cancer in women and the second most common cancer in the world after lung cancer.2,3BC accounts for more than 24% of all cancers in Iran, with a prevalence rate of 24.8–34 per 100 000 women and a death rate of less than 10.2 per 100 000 population in 2018.2 The long‐term prognosis for women with BC has significantly improved over the last 50 years.4 Due to the findings of previous studies,5 BC is often detected in Iranian women in an advanced stage; so treatment is delayed.6 Abedi investigated the survival rate in Iran and discovered that the rates of survival for 1, 3, 5, and 10 years were 95.8%, 82.4%, 69.5%, and 58.1%, respectively.7More express oncogenes Her 2/neu, pre‐menopausal age, undergoing various forms of treatment (surgery, radiotherapy, chemotherapy, and hormone therapy), Socioeconomic status, fertility status, stage of the disease, the number of lymph nodes involved, type of tumor pathology, higher grade or tumor grade, estrogen and progesterone negativity receptors, and high body mass index (BMI) are relevant factors correlated with lower survival rates.5Western Iran has a population of approximately 4 million and there are relatively few studies relating to exploring the relationship in the Iranian population between these prognostic markers and survival. The identification of the factors contributing to higher survival rates for women with BC will help to identify early diagnosis and improve policies for prevention and treatment, both in the nursing system and in other health fields. Therefore, this study was undertaken to assess the survival rate and probability of mortality in BC patients and to assess the predictive factors for survival.MATERIAL AND METHODSStudy population and designThis retrospective analysis was conducted on 578 patients with primary BC who underwent surgery at Imam Reza Hospital in Kermanshah, Iran, between 2004 and 2020. For 234 patients, the survival outcome was not available in the dataset. As a result, they were excluded from the study. In addition, 124 patients were excluded due to exclusion criteria, insufficient medical history, or mortality due to a cause other than BC. In this study, all participants underwent surgery and received radiation, and all except a very limited number received chemotherapy.Ethical considerationAccording to the National Resolution for Human Studies, no informed consent was needed once the present analysis focused on retrospective data collection. Nevertheless, we obtained official permission from the Hospital Majors, labs, municipal, and state Health Secretariats to gain access to databases, laboratory, and medical reports. The research design was approved by the ethical committee and institutional review board of Kermanshah University of Medical Sciences (IR.KUMS.REC.1398.363).Exclusion criteriaPatients with heart failure, cerebrovascular disease, hematologic illness, any inflammatory symptoms or conditions, peripheral arterial disease, coronary artery disease, end‐stage renal disease, peripheral arterial disease, or a lack of pathologic or laboratory data were excluded.Collection dataMedical records for the Hospital Information system (HIS) were reviewed and age, menopause status, lymph node metastasis, diameter and side of the tumor, stage of disease, pathological tumor types, Oral Contraceptive Pill (OCP) consumption, family history, number of babies, breastfeeding status, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor‐2 (HER‐2) levels were collected as dependent variables. BC overall survival (independent variables) was calculated from the date of operation to the date of death for women whose death was specifically due to cancer. Immunohistochemical (IHC) staining in tumor tissue was determined by HER‐2 levels: IHC 3+ and IHC 2+ were classified as HER‐2 positive tumors; IHC 1+ or IHC‐ were classified as HER‐2 negative tumors. Her‐2 status was determined using IHC staining and those with 3+ results assumed positive, 2+ was indeterminate and 1+ assumed negative.Luminal‐A is defined as ER+ and/or PR+ / HER2‐, Luminal‐B is ER+ and/or PR+/HER2+, HER2 overexpressed is ER‐/PR‐/HER2+, and the triple negative is ER‐/PR‐/HER2‐. For BC, the morphological and topographic classifications used were ICD‐O15 and ICD‐1016, respectively.8All patients with a histopathologic diagnosis of cancer during the study period (ICD‐10: C50 and D05.1) corresponding to malignant clinical tumors, primary site (ICD‐O: code 3), and malignant metastatic site (ICD‐O: code 6) were included. All cases were diagnosed pathologically by biopsy or surgical specimens.Distant Metastases have been identified through radiological analysis, such as magnetic resonance imaging, ultrasound, bone scintigraphy, and computed tomography.Following‐up investigationAbout 578 cases of these women underwent follow‐up investigations for 60–192 months following BC surgery.Statistical analysisSPSS version 13.0 software was used for statistical analysis. Survival curves are drawnusing Life‐tables and survival rate comparisons were done by using the Chi‐squared test. Cox regression model analysis and multivariate analysis were performed to determine prognostic factors. A p‐value of less than .05 was considered statistically significant. The study endpoints were 5‐ and 10‐year disease‐free survival.RESULTSOf the 220 studied patients, 81 (36.8) died by the end of the analysis. The age of patients ranged from 20 to 83 years with a mean of 47.48 ± 11.33 and a median of 46 years.The overall survival rates of 1‐, 3‐, 5‐, and 10‐year for the 220 cases were 95%, 80%, 71%, and 62%, respectively, with a median survival period of 96 months (Figure 1).1FIGUREThe plot of overall survival for patients with breast cancerTable 1 provides an analysis of tumor‐related factors and prognosis for 220 women with BC. The highest number of patients was in the age group of 20–50 (predominantly in the age group of 40–50). In addition, 35.9% of patients were in the early stage of diagnosis. The 1‐, 3‐, 5‐, and 10‐year survival was inversely related to the stage at diagnosis (Table 1).1TABLEClinical, pathological, and biological characteristics of patients and univariate analysisVariableN (%)Mean ± SEYearsp‐valueNumber of survivorsMedian OS (month)13510Survival220115.16 ± 3.789621919615970Age (year)20–50138 (63.3%)112.11 ± 4.35a9613812610848.01*50–6048 (22%)113.42 ± 8.96a964841331360–7019 (8.7%)91.5 ± 13.36b84191612670–9513 (6%)76.08 ± 17.07b48131263Marital statusSingle14 (6.5%)100.64 ± 13.9102131397.644Married203 (93.5%)115.70 ± 3.929620318114862MenopausePremenopause145 (66.8%)121.68 ± 4.399614413211250.012*Postmenopause72 (33.2%)102.02 ± 7.068472614520Lump node metastasisYes79 (56.8%)102.36 ± 6.728478694924<.001*No60 (43.2%)145.80 ± 3.4612060605831Lymph node numberLess than 4 or 439 (54.2%)19.07 ± 9.41a10839353016.002*5–922 (30.6%)93.27 ± 11.06a84222012610 or more than 1011 (15.3%)56.09 ± 10.76b4810831MetastasisYes75 (35%)53.18 ± 4.54367453243<.001*No139 (65%)149.60 ± 2.2410813913713265Organ metastasisOCP before menopauseYes150 (70.1%)121.03 ± 4.239614913411648.066No64 (29.9%)105.27 ± 7.218464584120FH family historyYes99 (46.3%)117.47 ± 5.619698897126.642No115 (53.7%)115.27 ± 5.19961151028542Number of childrenLess than 2 or 256 (25.9%)124.33 ± 6.839656524416.134More than 2 and less than 584 (38.9%)116.58 ± 6.0010284756130Or more than 555 (25.5%)109.09 ± 7.858455493916Without children21 (9.7%)101.38 ± 12.04842018137Breast feedingYes185 (86.4%)117.76 ± 4.039618516813858.32No29 (13.6%)104.97 ± 10.918429251810Side of tumor LRL92 (46.2%)114.45 ± 5.879692826733.977R105 (52.8%)114.65 ± 5.5996104937430Size of tumor2 or less than 235 (22%)112.58 ± 8.8810835322713.448More than 2124 (78%)114.27 ± 5.10961231118943Stage0–152 (35.9%)147 ± 3.91a10852525022<.0012a6 (401%)129 ± 2.59a12066642b‐487 (60%)84.16 ± 6.46b6086684318UnknownHistologyDuctal in situ3 (1.4%)120 ± 19.591083331.193Ductal invasive212 (96.8%)115.48 ± 3.869621118915368Others4 (1.8%)66 ± 16.156643269ERPositive136 (61.8%)118.89 ± 4.669613612510148.286Negative84 (38.2%)109.24 ± 6.389683715822PRPositive135 (61.4%)120.82 ± 4.579613412510349.103Negative85 (38.6%)106.23 ± 6.478485715621Her 2Positive116 (53.7%)112.54 ± 5.25961151038137.456Negative100 (46.3%)118.28 ± 5.6096100897431P53Positive52 (36.6%)129.92 ± 6.71108114220.228Negative89 (62.7%)115.38 ± 6.149652496426Ki67Positive86 (92.5%)122.88 ± 5.949686776621.317Negative7 (7.5%)140.57 ± 14.281327764Type of breastLuminar A71 (32.9%)124.41 ± 6.3110871665523.215Luminar B87 (40.3%)104.63 ± 5.439686786029Her2 overexpressed30 (13.9%)109.06 ± 10.71963026207Triple‐negative28 (13%)109.71 ± 11.22902822209Nuclear grading (NG)1/326 (21.7%)123.367 ± 7.1692625239.1452/370 (58.3%)117.56 ± 6.8684706150153/324 (20%)104.29 ± 12.1610223201510Margin grading (MG)1/319 (14.7%)123.36 ± 7.16841917132.4512/388 (68.2%)117.56 ± 6.8696887764293/322 (17.1%)104.29 ± 12.161022221167Vascular invasionPositive95 (75.4%)115.23 ± 5.779694846828.742Negative31 (24.6%)112.13 ± 10.639631272211Skin involvementPositive4 (6.3%)87.00 ± 22.60844422.463Negative69 (93.7%)122.49 ± 6.9810859554529Nipple involvementPositive3 (4.3%)92.00 ± 32.66843221.805Negative66 (95.7%)118.64 ± 6.911466594933Margin involvementPositive8 (14%)94.5 ± 17.42848752.805Negative49 (86%)122.57 ± 7.3910849453920Dissimilar letter indicate a significant difference between groups (*p < 0.05).Univariate analyses of BC patients with tumor‐related factors indicated that factors such as age, menopause status, lymph node metastasis, number of involved lymph nodes, distant metastasis, and stage significantly correlated with disease‐specific survival rates (p < .05) (Table 1).Because of the correlation between the lymph node number and lymph node metastasis, we only included the variables metastasis, lymph node metastasis, age, and menopause in the Cox model. In this model, only the variables of metastasis (HR = 41.77, 95% CI: 15.3–114.15) and metastasis in lymph nodes (HR = 5.26, 95% CI: 1.9–14.6) are significant. According to the Cox model, the risk of death in BC for patients with metastasis is 41.71 times higher than those without metastasis, and the risk of death in people with lymph node metastasis is 5.26 times higher than those without lymph node metastasis (Table 2).2TABLEMultivariate cox regression analysisVariableStandard error (β))WALD)p valueHRa95% CIAge (year)20–50*150–60−1.26 (1.04)1.47.230.28(0.04, 2.18)60–70−0.396 (1.24)0.102.750.67(0.06, 7.6)70–95−0.405 (1.18)0.117.730.67(0.07, 6.8)Premenapose*1Postmenapose0.704 (1.07)0.431.512.02(0.25, 16.54)Lump node metastasisNo*1Yes1.7 (0.52)10.18<.0015.26(1.9, 14.6)MetastasisNo*1Yes3.73 (0.513)52.94<.00141.77(15.3, 114.15)*p < 0.05.There was a significant negative correlation between metastasis and axillary lymph node metastasis and long‐term disease‐free survival rates, as seen in Figure 2. Increased involved lymph node numbers were correlated with higher mortality rates.2FIGUREFactors related to survival rates of breast cancer patients. (A) Relationship between organ metastasis and disease‐specific survival rates. (B) Relationship between lymph‐node metastasis and survival ratesDISCUSSIONCancer is the world's second leading cause of death, accounting for almost 9.6 million deaths in 2018.2 Epidemiological evidence showed that the largest prevalence of BC was among the 50‐ and 60‐year age group, followed by the 40‐ to 49‐year age group. We demonstrated that the largest prevalence of BC was in the age group of 20–50 (predominantly in the age group of 40–50).9,10 This then reinforces the need to do mammography in the age group of 40–50. Various studies conducted in Iran have estimated the mean age at the time of diagnosis to be 45–50 years.11 The mean age of patients at the time of diagnosis in the present study was about 47.71 years, which is consistent with the findings of other studies.12,13 However, these results do not agree with the results of studies in Western Europe and North America.14,15 This could be due to the delay in the diagnosis of cancer in Iran, which has been mentioned in other studies.11,16 Two other studies also reported that mean age affects the survival of BC.17,18Factors influencing the survival rate of women with BC have become extremely important for patients. Several risk factors related to BC have been reported by Roder et al.,19 including tumor size, higher grade, positive nodal status, ER‐negative status, vascular invasion, and multifocality. Menopausal status, tumor size, axillary lymph node metastasis, and TNM stage were found to be associated with a 5‐year overall survival rate in 246 BC patients.20Findings of this study showed that metastasis and metastasis in lymph nodes were the most important factors that significantly reduced the survival of the subjects, which is consistent with the results of other studies conducted in Iran.12,21In the univariate test, the disease stage, menopausal status, age, and number of lymph nodes involved all showed a significant relationship with decreased survival.In the analysis of the marital status, 93.5% of the patients were married, but no significant relationship was shown between married and single women and survival rate. In another study in Kermanshah, women who had never been married, had a higher chance of developing BC than married, divorced, and widowed women. However, the observed relationship was not statistically significant.22A meta‐analysis review in Iran estimated the 1‐, 2‐, 3‐, 5‐, and 10‐year BC survival rates in Iran to be 95.8%, 82.4%, 69.5%, and 58.1%, respectively, in line with the findings of this study. In general, since this study was not based on data from the national or provincial registration program, it did not make sense to judge whether the observed survival rate increased or decreased. In addition, the generalization of results to BC patients in the country should be done with great caution. The 5‐year overall survival rate in Iran compared to 84% in the United Kingdom,23 89% in the United States,24 71% in Germany,25 65% in Greece,26 64% in Oman27 and 46% in India28 suggesting that Iran's survival is significantly less than that of European countries and the United States, which is in line with the result of Vahdaninia et al. study.21 There are several possible explanations for this. Women's knowledge of BC in Iran is limited—Iranian women know little to nothing about breast self‐examination and its impact on early diagnosis and prognosis.In addition, the difference in the survival rate of BC between countries and regions of the same country, however, persists and is not easy to explain. In one country versus another, the highest survival rate could be due to the availability of better treatment or similar treatment becoming more effective when the diagnosis is made at an earlier stage of the disease.24In BC, the presence of lymph node metastasis is a predictive factor for women's disease survival and recurrence, reducing survival by 40% relative to women with non‐metastatic disease survival.29 This research showed that a greater percentage of positive axillary lymph nodes raised the risk of death associated with BC. This was consistent with another study, which showed that axillary lymph node metastasis was the most significant prognostic factor influencing local regulation, disease‐free survival, and overall survival.30 According to Akbari et al.,31 the most important factor influencing patient survival is axillary lymph node involvement, as patients with involved lymph nodes lived shorter than those without involved lymph node involvement. If the disease is diagnosed at an early stage where the lymph nodes are not involved and the patients are treated correctly, they will survive longer. In this study, lymph node involvement increases the death risk by a factor of 5.26.The number of nodes involved was the most important multi‐factorial research predictor of survival. According to our results, not only did node‐positive patients have a shorter survival rate compared to node‐negative patients, but the risk of mortality also increased as the number of nodes involved increased.32 Compared to non‐metastatic BC, metastatic breast cancer (MBC) is commonly considered to have a low prognosis. Common sites of distant metastasis in BC include bone, liver, lung, and brain.33 Previous studies have shown that in BC patients, the bone is the most common distant metastatic organ.34,35 Similarly, our findings also indicate that the most prevalent subgroup in the study population is bone and liver metastasis, accounting for 21.3% of the total patients.Dabakuyo et al.36 reported that the survival rate was lower in patients above 60 years of age or postmenopausal patients. The cancer mortality rate has also been reported to have risen with age in Northern Vietnam. According to the results of this study, postmenopausal patients were shown to have a significantly lower specific survival rate than premenopausal patients.37 Contrary to the results of this study, D'Eredita et.al38 demonstrated that tumor size was significantly associated with BC survival, as patients with tumor size of 5 cm and more had a higher chance of death than those with tumor sizes of 2 cm and less. This finding was consistent with two other studies.12Similar to other studies, we found that the stage of the disease is one of the most important factors in the survival rate of patients with BC. The late stage of diagnosis was separately related to lower survival rates globally.4,39–41 Of the predictive factors, the absence of metastatic lymph node involvement and the expression of estrogen receptors are the most important for a better prognosis. In the early stages, this enhances the value of detection and care, increasing the chance that the disease has not yet reached the axillary lymph nodes, which improves recovery, cure prospects, and enables less aggressive therapies to be implemented.10,30,42 In contrast to lymph node involvement, we found no significant relationship between estrogen receptor status and survival, which may be due to the small sample size in our study.Since breast‐conserving surgery has become the treatment of choice for early‐stage BC patients, the function of surgical margins is poorly known and is still under discussion.43,44 Fujimoto and colleagues demonstrated that women with positive margins showed poorer 2‐ and 5‐year BC survival compared to women with negative margins. In our study, no significant relationship was found between margin involvement and survival rate. Skin and nipple involvement and vascular invasion were not associated with survival, which is consistent with the result of Rezaianzadeh et al.12This research showed no indications of a relationship between BC family history and survival and found that tumor features are identical in patients with a positive and negative family history. This is in line with the findings of several other studies.45–47Contrary to the results of this study, Akbari et al.31 and Fallahzadeh et al.48 found that survival is impacted by the side of the tumor (left or right breast) and that more patients survived with a tumor in their left breast than those with a tumor in their right breast. The study also found no association between histological type and survival in common with other works.49,50Lööf‐Johanson et al.51 reported that there was a higher survival rate for women with primary BC if overall breastfeeding was longer than 6 months and/or if they had at least one pregnancy. The results of our study were in line with other studies that reported different results.52–54 The findings of previous research on OCPs and BC mortality among women were inconsistent; some reported lower mortality among OC Ps users55,56 and some recorded higher mortality57–59 or no effect.60–62The prevalence of TNBC in this research is in line with the literature, as it accounts for 10% to 20% of all BCs.63,64 Patients with TNBC have been found to have a poor prognosis.65 On the other hand, another analysis found that there were no significant differences in 3‐year survival between TNBC cancers and other BCs.66 Further studies have found that the difference between the TNBC and non‐TNBC groups peaked at 3 years, but this difference has declined with time, indicating that long‐term survivors (over 10 years) in the TNBC group may have survival comparable to cases of non‐TNBC.67,68 While there is no difference in OS between patients with TNBC and non‐TNBC in this research, maybe a greater number of cases between the two groups would have yielded different outcomes.There are certain limitations in our analysis. Details on some of the explanatory variables are missing; some patients were not available after 10 years. Information on ER, PR, and HER2, vascular invasion, and nipple and skin involvement was absent in nearly half of the initial sample population.CONCLUSIONIn conclusion, the findings presented in this study indicate a comparatively poor overall survival rate of 5 and 10 years for women diagnosed with BC in Iran. Qualitative information on BC patients and health care providers recognized that a healthier lifestyle and the value of early diagnosis should be obtained to improve their awareness, and also study educational programs should be provided for the target population to prevent deaths related to BC. The findings of the review of 26 explanatory factors presented in this report indicate that the survival of BC in western Iran is impaired by delaying diagnosis and, therefore, by late‐stage disease. 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Journal

Cancer ReportsWiley

Published: Aug 5, 2022

Keywords: breast cancer; breast cancer prognosis factors; clinical parameters; retrospective analysis

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