|Year : 2011 | Volume
| Issue : 2 | Page : 187-193
A long-term survival pattern for breast cancer treated in a single institution
T Gokce1, I Karadogan2, C Akçay2
1 Izmir Ataturk Egitim Arastirma Hastanesi, Radiation Oncology Clinics and Izmir Oncology Center, Izmir, Turkey
2 Izmir Oncology Center, Izmir, Turkey
|Date of Web Publication||11-Jul-2011|
Izmir Ataturk Egitim Arastirma Hastanesi, Radiation Oncology Clinics and Izmir Oncology Center, Izmir
Source of Support: None, Conflict of Interest: None
Aim: This paper presents a 14-year retrospective study evaluating the survival rates and prognostic factors of breast carcinoma patients treated in private treatment center in the west coast of Turkey. Materials and Methods: The survival rates of breast cancer patients (n = 1746) who have been treated from 1995 until 2008 were analyzed. The clinical data include age, menopausal stage, oestrogen (ER) and progesterone (PR) receptor status, and C-erbB-2 status as well as histopathological evaluation. AJCC (2002) was used for clinical tumor staging. Survival rates were computed using standard Kaplan-Meier methods, and the difference in survival curves was analyzed with the log-rank test. Results: The 14-year overall survival, disease-free survival, local failure-free survival, and distant failure-free survival rates were 77%, 95%, 77%, and 94%, respectively. Early-stage patients had higher overall survival rates compared to advanced-stage patients (stage IIIb and IIIc, AJCC 2002), and early-stage patients had higher survival rates than advanced-stage patients for disease-free survival, local failure-free survival, and distant failure-free survival. The risk for cancer development increases significantly for advanced-stage patients with positive ER and PR receptor as well as C-erbB-2 receptor. Conclusions: The incidence of breast cancer in Turkey is smaller compared to other European countries. Low advanced-stage patient numbers compared to high early-stage patient numbers; and very high median survival times could possibly be the result of the improvement of detection and treatment of breast cancer over the years.
Keywords: Breast carcinoma, chemotherapy, overall survival, radiotherapy
|How to cite this article:|
Gokce T, Karadogan I, Akçay C. A long-term survival pattern for breast cancer treated in a single institution. Indian J Cancer 2011;48:187-93
| » Introduction|| |
Breast cancer is the most common cancer in females in worldwide. The case is similar in Izmir according to the first population-based registry system, Izmir Cancer Registry (ICR), which collects data on new cases of cancer incidence and survival since 1993.  Breast cancer was found to be the most common site of cancer (26.7%) among females living in Izmir. ,
Strongest determinants of breast cancer risk was said to be female gender, age, and country of birth.  Hormones, alcohol intake, obesity, tobacco use, and radiation were also found to be risk factors. Demirkan found that the development of breast tumors with aggressive phenotype increases in Turkish women who were obese and in the postmenopausal stage. 
This high patient number retrospective study aims to evaluate the survival rates and prognostic factors to give the breast cancer facts in Izmir.
| » Materials and Methods|| |
Radiotherapy (RT) treatment was completed in collaboration with university hospitals, state hospitals, municipality hospitals, and private hospitals. The primary evaluation and staging of breast cancer was carried out by a council with participation of the radiation oncology, surgery, pathology, and radiodiagnosis divisions of these referring hospitals. Treatment and post followup of the patients were carried in cooperation with these groups.
A large series of 1746 females who have been diagnosed with breast cancer between 1995 and 2008 included to this study. All of the patient data were obtained by reviewing patient files retrospectively, and interviews of patients and family members. The cases were excluded from the study if they had any missing data of the variables; age, tumor and nodal stage, and menopausal stage.
The clinical diagnosis includes age, menopausal stage, oestrogen (ER) and progesterone (PR) receptor status, and C-erbB-2 status. The histopathological evaluation was performed from biopsies; obtaining histological type, and nuclear grade of the cancer.
The likelihood of developing breast cancer increases dramatically with age. According to American Cancer Institute SEER data, 95% of new cases and 97% of breast cancer deaths occurred in women aged 40 and older. In addition, women between ages 20 and 24 years had the lowest breast cancer incidence rate between the same period, and highest incidence was observed in women aged 75-79 years.  The youngest patient who has been treated was 19 years old, and the oldest patient was 87 years old. Average age at diagnosis of primary breast cancer was 51.26 years with a median of 50 years [Table 1].
The breast cancer risk is known to increase with cumulative number of ovarian cycles. The risk decreases by about 15% for each year of delay in age at menarche and increases by 3% for each year of delay in age at menopause.  The 57.8% of the patients were in their postmenopausal stage when diagnosed.
The cancer site and tumor morphology were coded using the International Classification of Diseases: Oncology of the World Health Organization (WHO).  Most of the patients had ductal histology (67.8%).
The presence of hormone receptors for ER and PR is an important biological marker. Hormone therapy can be used to interfere with these receptors, slowing or stopping tumor growth or preventing recurrence. These patients are referred as hormone receptor positive. Women, who had been diagnosed with ER+/PR+ tumours, are more responsive to hormonal treatment and have a better prognosis than those diagnosed with ER-/PR- tumours.  The ER+/PR+ and ER-/PR- diagnosed patient incidence were 31.4% and 21.2%.
Over expression of C-erbB-2 protein is an important factor for the selection of treatment. Different research groups showed that dose-intensive doxorubicin chemotherapy (CT) had significantly longer disease-free survival and overall survival if the tumors exhibited high expression of the C-erbB-2 gene. , Paik et al. also showed that over expression of C-erbB-2 is associated with tumor size, lack of ER receptors, and the number of positive lymph nodes.  The 29.6% of the patients tested C-erbB-2 positive.
An average of 14 lymph nodes (max. n = 62) was extracted during mastectomy and axillary clearance. The lymph nodes removed were tested for the presence of cancer. An average of six lymph nodes was tested to be positive.
Cancer staging was performed according to the American Joint Committee on Cancer staging system  and results are shown in [Table 1].
Surgery is the basic treatment for breast cancer and adjuvant hormonal therapy (with tamoxifen or an aromatase inhibitor) is backed up with CT, and/or RT. A total of 1508 patients (86.4%) operated before receiving any RT and/or CT [Table 2]. In the past, mastectomy was the standard surgical procedure for breast cancer treatment, for that reason half of the patients (52.1%) were operated with radical mastectomy, 7 had mammoplasty, and 20 treated with additional axillary dissection. A total of 788 patients (45.5%) treated with restricted surgery and 600 of them also had additional axillary dissection. Twenty-six patients operated with techniques including graft transposition, reduction mammoplasty, or bilateral mammoplasty. Fifteen patients had only axillary lymph node dissection.
Primary breast carcinomas were treated with conventional RT until 2006. Since then conformal RT was employed. Standard tangential total breast irradiation was given to patients who underwent modified radical mastectomy as 2 Gy fractions to reach a total of 50 Gy. Boost dose was delivered daily 2 Gy fractions (between 10 and 16 Gy) with selected electron energy. Internal mammary lymph node irradiation was administered as 2 Gy fractions to tumors located internal face of the breast, and anterior internal mammary field irradiation was completed with 20 Gy electrons, 30 Gy photons. Peripheral lymphatic irradiation was delivered through anterior field of patients with axillary lymph node involvement. Axillary dosaging was completed from posterior.
The median RT duration was 28 days (10-38 days). A total of 1122 (64.3%) patients treated with both CT and RT postoperatively. More than half of the patients who received CT treated with sitoksan-epirubisin-flourasil (CEF), and number of CT cycles for each specific therapy are shown in [Table 2].
Hormone therapy was used as adjuvant therapy for patients with hormone receptor-positive tumors and half of the patients (49.9%) treated as such. The case was similar for the patients who received CT and RT after surgical operation; only half of them receiving additional hormone therapy. Most of the patients who received adjuvant therapy did not receive any hormone therapy.
The time variable for the analysis was calculated from the date of breast cancer diagnosis until the date of death, end of follow-up, censoring, or until last visit. The Statistical Package for Social Sciences (SPSS), version 15.0, was used for all of the calculations. Overall survival, disease-free survival, local failure-free survival, and distant failure-free survival rates were computed using standard Kaplan-Meier methods, and the difference in survival curves was analyzed by the log-rank test. Independent prognostic factors were analyzed with the Cox proportional hazards regression model. A two-tailed P < 0.05 was considered statistically significant.
| » Results|| |
The 5-year-survival rate for breast cancer calculated was based on averages; nevertheless each patient's individual tumor characteristics, state of health, genetic background, eating habits, environmental factors, etc., will influence her survival. In addition, levels of stress, immune function, will to live, and other nonmeasurable factors also play a significant role in a patient's survival. Average survival of our patient group was 36.98 months with a maximum of 168 months. Median survival time was 10 years (approx. 120 months). Overall survival for the first 5 years was 90%, and 77% after 14 years [Table 3].
|Table 3: Cumulative proportion of survival for 14 years in 5-year intervals (%)|
Click here to view
Of the 1746 patients followed-up, 98% were alive and disease-free for longer than 5 years and 95% were alive and disease-free for 14 years. The median survival time for overall survival, disease-free survival, local failure-free survival, and distant failure-free survival was longer than 150 months, respectively. Distant metastasis was diagnosed in 232 patients (13.3%) during the 168-month follow-up period. The 58% of distant metastases occurred in the first 5 years.
The 5-year overall survival was found to be highest for Stage I (98%) and Stage IIa (93%) patients. Stage IIIb patients had the lowest overall survival at the end of the first 5 years (76%). The overall survival 14 years after the first diagnosis of the disease was 94% for Stage I, 84% for Stage IIa, 64% for Stage IIb, 74% for Stage IIIa, and 63% for Stage IIIb patients.
When patients were grouped as advanced-stage and early-stage (AJCC 2002) and cancer being operable or not, a total of 1543 patients were early-stage, and 203 patients were advanced-stage. ,, Early-stage patients had higher overall survival rates than advanced-stage patients (P = 0.0001, [Figure 1]). Also, early-stage patients had higher survival rates than advanced-stage patients for disease-free survival (P = 0.022), local failure-free survival (P = 0.0001), and distant failure-free survival (P = 0.015).
|Figure 1: Overall survival for advanced-stage and early-stage patients. Overall log-rank comparisons (P = 0.0001)|
Click here to view
The 14-year overall survival for patients in the premenopausal stage who received both CT and RT after operation was 83%, for patients treated with only RT was 77%, and for patients treated with adjuvant RT and CT was 100%. The 14 year overall survival for patients in the postmenopausalstage who received both CT and RT after operation was 80% and 78% for patients treated with only RT. The overall survival for patients who received additional hormone therapy was significantly different for patients who did not receive any hormone therapy (70% vs. 78%) (P = 0.046) [Table 4].
|Table 4: Relationship between 5-year survival rates and prognostic factors according to AJCC 2002|
Click here to view
The overall survival was significantly lower for advanced-stage patients compared to early-stage patients (P = 0.0001). The highest overall survivor was calculated for ER/PR positive/positive patients (86%), and the lowest overall survival was found for ER/PR positive/negative and ER/PR negative/positive groups (72% and 74%), respectively.
None of the other variables found to have any impact on overall survival according to multivariate comparisons, except advanced-stage patients, who were likely to have a shorter time to death than early-stage patients (P = 0.001; HR = 0.388; 95% CI: 0.225-0.667). Patients with positive C-erbB-2 receptor were at higher risk (P = 0.033; HR = 0.264; 95% CI: 0.078-0.896), and the risk increases with positive C-erbB-2 receptor when patients are in advanced-stage (P = 0.007; HR = 6.374; 95% CI: 1.670-24.320). Interestingly, in multivariate COX analysis it was found that the risk for cancer development increases significantly for advanced-stage patients with positive ER and PR receptor as well as C-erbB-2 receptor (P = 0.006; HR = 2.442; 95% CI: 1.299-4.592). In addition, patients with ER+/PR- were at higher risk regardless of whether hormone therapy received or not (P = 0.004; HR = 2.675; 95% CI: 1.380-5.187).
There was no statistical significance among groups for disease-free survival for most of the prognostic factors. Multivariate analysis showed that the advanced-stage patients were at a higher risk for relapse if they have positive ER and PR receptors (P = 0.022; HR = 2.267; 95% CI: 1.125-4.567).
Even though number of lymph nodes removed did not have any significant difference in local failure-free survival (P = 0.101), the number of lymph nodes tested positive had significant effect on local failure-free survival (P = 0.003). Also, advanced-stage patients with positive lymph nodes more than 10 were at a higher risk for local failure (P = 0.006; HR = 0.481; 95% CI: 0.285-0.810).
Hormone therapy was significantly effective on local failure-free survival compared to the untreated group (P = 0.047). Advanced-stage patients were at a higher risk if they have positive ER receptors (P = 0.004; HR = 2.814; 95% CI: 1.403-5.646) and PR receptors (P = 0.031; HR = 2.190; 95% CI: 1.074-4.467). Also postmenopausal patients were at higher risk for local failure if they had more than 10 positive lymph nodes removed (P = 0.015; HR = 0.439; 95% CI: 0.225-0.854).
The distant failure-free survival was significantly higher for older patients (P = 0.020), as well as patients in post-menopausal stage (P = 0.026). Advanced-stage patients were found to be at a higher risk if they have positive C-erbB-2 receptor (P = 0.010; HR = 6.413; 95% CI: 1.563-26.315) regardless of ER and PR receptor status.
| » Discussion|| |
This retrospective study evaluates survival rates and prognostic factors of the most common cancer in females in Turkey. The patients who had been treated from 1995 until 2008 were included to the study. The high patient numbers in this study suggests a good representation of breast cancer facts in Izmir.
Female gender, age, and country of birth were identified to be the strongest determinants of breast cancer risk as well as hormones, alcohol intake, obesity, tobacco use, and radiation.  According to American Cancer Society, the survival rates for breast cancer have improved from 75% (1975-1977) to 89% (1996-2004), with early diagnosis and advances in treatment.  A population-based survey by Sirin et al. showed that nearly more than half of the participants in Bornova district in Izmir-Turkey did not smoke and half of them reported alcohol consumption, but also aware that alcohol and tobacco use increase cancer risk.  It was also said that even though there was public awareness, individual cancer prevention and early diagnosis behaviors were insufficient. On the contrary, our results with low advanced-stage patient numbers compared to high early-stage patient numbers, and very high median survival times could possibly be the result of public awareness.
Age found to have no significant impact on overall survival and local failure-free survival, but disease-free survival and distant failure-free survival were higher for older patients when compared to patients younger than 47 years old, supporting the fact that there is an age-related difference in pathophysiology, and tumors being more aggressive and less responsive to treatment in younger women. , Even though stage groups did not have any significant effect on disease-free survival, advanced-stage patients were at higher risk for relapse if they had positive ER and PR receptors.
It is obvious that one specific treatment does not fit every patient; a combination of therapy is required in most cases. The majority of our patients were operated before receiving any further therapy. The patients in the postmenopausal stage who received both CT and RT after operation had higher overall survival than patients treated with only RT. The overall survival for patients who received additional hormone therapy was significantly different for patients who did not receive any hormone therapy.
Our results were similar with the results of Setiawan et al., suggesting patients who had been diagnosed with ER+/PR+ tumors were more responsive to hormonal treatment and have a better prognosis than those diagnosed with ER-/PR- tumors.  There is higher risk for advanced-stage patients with positive ER and PR receptor when they have positive C-erbB-2 receptor.
Studies also conducted for the protective effects against various cancers. According to Zhang et al.'s study, greater intake of vegetables and fruits is associated with a decreased risk of breast cancer among Chinese women.  Different dietary influences have been proposed and examined since 1980s, and recent research suggests that low-fat diets may significantly decrease the risk of breast cancer as well as the recurrence of breast cancer.  The incidence of breast cancer is lesser in Mediterranean populations than in northern Europeans, which is related to traditional Mediterranean diet, commonly characterized by high consumption of foods of plant origin, relatively low consumption of red meat, and high consumption of olive oil. 
The incidence of breast cancer in Turkey is smaller compared to other European countries. Diet and hormonal status are important factors as well as age. Still, each patient's individual tumor characteristics, state of health, genetic background, eating habits, levels of stress, immune function, will to live, and other factors play a significant role, and influence her survival. Early detection and protection are the most important components of cancer management. Even though Turkey is a country with low income, primary healthcare for adequate treatment is provided by Ministry of Health. The population-based registry system is the first step for an extended project and will make a grand progress for cancer research. According to these survival results, the detection and treatment of breast cancer have achieved extensively over the years. Public awareness can be improved with the guidance of national cancer screening program.
| » References|| |
|1.||Eser S, Zorlu F, Divtik RT, Cal C, Ozkan M, Kirkali Z. Incidence and epidemiological features of cancers of the genitourinary tract in Izmir between 1993-2002. Asian Pac J Cancer Prev 2009;10:491-6. |
|2.||Gulhan I, Eser S, Yakut C, Bige O, Ilhan E, Yildirim Y, et al. Second primary gynecologic cancers after breast cancer in Turkish women. Int J Gynecol Cancer 2009;19:648-50. |
|3.||Fidaner C, Eser SY, Parkin DM. Incidence in Izmir in 1993 and 1994: First results from Izmir Cancer Registry. Eur J Cancer 2001;37:83-92. |
|4.||Hulka BS, Moorman PG. Breast cancer: Hormones and other risk factors. Maturitas 2008;61:203-13. |
|5.||Demirkan B, Alacacioglu A, Yilmaz U. Relation of body mass index (BMI) to disease free (DFS) and distant disease free survivals (DDFS) among Turkish women with operable breast carcinoma. Jpn J Clin Oncol 2007;37:256-65 |
|6.||American Cancer Society, Breast Cancer Facts and Figures 2007-2008. Available from: http://www.cancer.org/downloads/STT/BCFF-Final.pdf. [cited in 2008]. |
|7.||World Cancer Report 2008, International Agency for Research on Cancer, Lyon, 2008. Available from: http://www.iarc.fr/en/publications/pdfs-online/wcr/2008/index.php. [cited in 2008]. |
|8.||Devilee P, Tavassoli FA, editors. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Breast and Female Genital Organs. Lyon: IARC Press; 2003. |
|9.||Setiawan VW, Monroe KR, Wilkens LR, Kolonel LN, Pike MC, Henderson BE. Breast cancer risk factors defined by estrogen and progesterone receptor status: The multiethnic cohort study. Am J Epidemiol 2009;169:1251-9. |
|10.||Wood WC, Budman DR, Korzun AH, Cooper MR, Younger J, Hart RD, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 1994;330:1253-9. |
|11.||Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, et al. erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. N Engl J Med 1994;330:1260-6. |
|12.||Paik S, Bryant J, Park C, Fisher B, Tan-Chiu E, Hyams D, et al. erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 1998;90:1361-70. |
|13.||Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG, et al. AJCC Cancer Staging Manual, 6th ed. New York: Springer; 2002. |
|14.||De Mascarel I, MacGrogan G, Debled M, Brouste V, Mauriac L. Distinction between isolated tumour cells and micrometastases in breast cancer: Is it reliable and useful? Cancer 2008;112:1672-8. |
|15.||Franceschini G, Terribile D, Fabbri C, Magno S, D′Alba P, Chiesa F, et al. Management of locally advanced breast cancer. Minerva Chir 2007;62:249-55. |
|16.||Vlastos G, Mirza NQ, Lenert JT, Hunt KK, Ames FC, Feig BW, et al. The feasibility of minimally invasive surgery for stage IIA, IIB, and IIIA breast carcinoma patients after tumour downstaging with induction chemotherapy. Cancer 2000;88:1417-24. |
|17.||Ries LA, Melbert D, Krapcho M, Stinchcomb DG, Howlader N, Horner MJ, et al, editors. SEER Cancer Statistics Review, 1975-2005, National Cancer Institute. Bethesda, MD. Available from: http://seer.cancer.gov/csr/1975_2005/. [submitted on 2007 Nov 2007] [cited in 2008]. |
|18.||Sirin A, Atan SU, Tasci E. Protection from cancer and early diagnosis applications in Izmir, Turkey: A pilot study. Cancer Nurs 2006;29:207-13. |
|19.||Kroman N, Jensen MB, Wohlfahrt J, Mouridsen HT, Andersen PK, Melbye M. Factors influencing the effect of age on prognosis in breast cancer: Population based study. BMJ 2000;320:474-8. |
|20.||Benz CC. Impact of aging on the biology of breast cancer. Crit Rev Oncol Hematol 2008;66:65-74. |
|21.||Zhang CX, Ho SC, Chen YM, Fu JH, Cheng SZ, Lin FY. Greater vegetable and fruit intake is associated with a lower risk of breast cancer among Chinese women. Int J Cancer 2009;125:181-8. |
|22.||Chlebowski RT, Blackburn GL, Thomson CA, Nixon DW, Shapiro A, Hoy MK, et al. Dietary fat reduction and breast cancer outcome: Interim efficacy results from the Women′s Intervention Nutrition Study. J Natl Cancer Inst 2006;98:1767-76. |
|23.||Trichopoulou A, Lagiou P, Kuper H, Trichopoulos D. Cancer and Mediterranean dietary traditions. Cancer Epidemiol Biomarkers Prev 2000;9:869-73. |
[Table 1], [Table 2], [Table 3], [Table 4]
|This article has been cited by|
||The Global and Regional Survival Rate of Women With Breast Cancer: A Systematic Review and Meta-analysis
| ||Khadije Maajani,Arash Jalali,Sadaf Alipour,Mahmoud Khodadost,Hamid Reza Tohidinik,Kamran Yazdani |
| ||Clinical Breast Cancer. 2019; 19(3): 165 |
|[Pubmed] | [DOI]|
||Relations of disease-free survival and overall survival with age and primary metastases in patients with breast cancer
| ||Mokarian, F. and Mokarian, S. and Ramezani, A. |
| ||Journal of Isfahan Medical School. 2013; 31(225) |
|| result 1 Document Magnitude of breast diseases in OJHA histopathology department
| || Vakil, M., Mustanser, T., Shaikh, N.A., (...), Mirza, T., Ali, A. |
| ||Medical Forum Monthly. 2013; |