|Year : 2015 | Volume
| Issue : 1 | Page : 119-125
Clinical outcome of primary non-metastatic breast cancer: A single institution experience
A Jamshed1, MA Shah1, AA Syed2, G Murtaza3, T Mehmood1, SJ Chaudry1, A Loya4, S Hameed1
1 Department of Radiation Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan
2 Department of Surgery, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan
3 The Aga Khan University Hospital, Karachi, Pakistan
4 Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan
|Date of Web Publication||3-Feb-2016|
Department of Radiation Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore
Source of Support: None, Conflict of Interest: None
Background: We report on prognostic factors and long-term survival of non-metastatic breast cancer patients treated at Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH and RC) in Pakistan. Materials And Methods: This retrospective cohort study is based on a review of 2829 pathologically confirmed non-metastatic breast cancer patients managed from January 1995 to May 2009. Median age was 45 years. Stage at presentation: Stage I (9%), stage II (59%), and stage III (32%). Infiltrating ductal carcinoma (92%) constituted the most prevalent histological subtype. Estrogen (ER), progesterone (PR) and Her2-neu were positive in 49%, 50%, and 26%, respectively. A mastectomy was performed in 67% and conservative surgery in 33% of the patients. Post-operative radiotherapy was delivered in 85% of the cases. Ninety percent of the patients received chemotherapy and mainly consisted of anthracycline-based regimens + taxanes. Hormonal manipulation was done in ER/PR positive patients. Results: The 5- and 10-year overall survival (OS) was 70% (95% confidence interval [CI]: 68.2-71.8%) and 54% (95%CI: 51.2-56.8%), while disease free survival (DFS) was 65% (95% CI: 63-67%) and 52% (95% CI: 49.2-54.8%), respectively. Recurrence following primary treatment was seen in 35% of the patients. On multivariate analysis T stage, number of axillary nodal involvement, tumor grade, ER status and family history, were found to be independent predictors for OS and DFS. Conclusions: Over 90% of non-metastatic breast cancer patients present with stagesII and III disease and a significant proportion develop distant metastasis accounting for overall long-term outcome inferior to developed countries. Efforts should be directed to raise the level of health awareness and screening programs to improve early detection in Pakistan.
Keywords: Breast cancer, developing countries, survival
|How to cite this article:|
Jamshed A, Shah M A, Syed A A, Murtaza G, Mehmood T, Chaudry S J, Loya A, Hameed S. Clinical outcome of primary non-metastatic breast cancer: A single institution experience. Indian J Cancer 2015;52:119-25
|How to cite this URL:|
Jamshed A, Shah M A, Syed A A, Murtaza G, Mehmood T, Chaudry S J, Loya A, Hameed S. Clinical outcome of primary non-metastatic breast cancer: A single institution experience. Indian J Cancer [serial online] 2015 [cited 2019 Aug 21];52:119-25. Available from: http://www.indianjcancer.com/text.asp?2015/52/1/119/175599
| » Introduction|| |
Breast cancer is the most frequently diagnosed cancer in women worldwide, accounting for 30% of all female cancers. It remains a primary cause of most of the cancer deaths globally and continues to have a great impact on the health resources and survival in developing countries., The importance of socioeconomic and ethnic differences in relation to breast cancer incidence, diagnosis, and prognosis has been realized in the last decade. The disease is characterized in the developing world by late stage at presentation in a relatively young population associated with biologically aggressive behavior with unfavorable outlook attributed to genetic, economic, cultural differences along with poor access to health-care., The aggressive nature is retained even if these populations migrate to developed countries.,
For nearly two decades, the number of newly diagnosed cases of breast cancer has been increasing at an average of 0.3% a year. At the same time, breast cancer mortality has been declining due to early detection of smaller palpable tumors and the aggressive use of adjuvant therapies. While advanced countries have a high incidence and low mortality the reverse is factual for developing countries. Pakistan has a population approaching 180 million, however, both cancer incidence and survival data are sparse. Karachi Cancer Registry reported that breast cancer was the most common cancer among Pakistani women, accounting for approximately one-third of all reported cancers and the incidence is amongst the highest in Asia.
Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH and RC) serves as a national referral center for the treatment of malignant disorders in Pakistan. Over 40,000 cancer patients are referred to the institute from across the country and approximately 4000 new cases undergo treatment annually. The institute accepts patients for treatment on a policy devised to balance patient load and resources with a preference for curable cases.
In countries without population based cancer registries, hospital based data assumes vital source of information and highlights key issues for local research and corrective strategies in these areas. Few other limited studies have reported on survival in breast cancer from Pakistan., Our initial experience of a small group of breast cancer patients with relatively short follow has been reported. This study describes prognostic factors and long-term survival of a large cohort of non-metastatic breast cancer patients treated in SKMCH and RC
| » Materials and Methods|| |
This study had the approval of SKMCH and RC institutional review board. From January 1995 to May 2009, the hospital tumor registry and information systems identified 3239 patients with newly diagnosed pathologically confirmed breast cancer. Electronic and archived medical records were accessed to obtain data on socio-demographic (age, ethnicity, family history, menopausal status), cancer related (histology, grade, stage, receptor status, treatments), and survival outcome variables. Clinical, radiological, and pathological reports were reviewed to determine the tumor, node and metastasis (TNM) stage of the disease according to American Joint Committee on Cancer (AJCC) criteria (7th edition). Four hundred and ten patients were excluded. Exclusion criteria were as follows: Patients with metastatic disease, incomplete treatment, medically unfit for radical treatment and chemotherapy or radiation elsewhere. The remaining 2829 women with non-metastatic primary breast cancer with a minimum follow-up of 3 years formed the study cohort.
All newly diagnosed breast cancer patients had treatment plans discussed in the weekly breast multi-disciplinary meeting. A mastectomy was performed in 67% and conservative surgery in 33% of the patients. Axillary dissection was routinely done till 2006 and thereafter was reserved for patients with palpable axillary lymph nodes, positive axillary sampling or sentinel lymph node biopsy.
Post-operative radiotherapy was delivered in 85% of the patients. The radiation technique was consistent throughout the study period. All patients were treated with either Co 60 or with 6 MV photons. Chest wall was irradiated with isocentric tangents technique with wedges, while supraclavicular nodes + axilla with non-isocentric single field. Radiation doses to the intact breast consisted of 50 Gy in 25 fractions with an additional boost to the tumor site of 10 Gy in 5 fractions. Patients with node positive disease also received supraclavicular irradiation. Median dose to supraclavicular fossa was 46 Gy in 23 fractions. Post-mastectomy patients received a median dose of 45 Gy in 18 fractions plus scar boost 7.5 Gy in 3 fractions. Median dose to supraclavicular fossa with chest wall irradiation was 40 Gy in 16 fractions. Axillary irradiation when performed was with conventional fractionation to a dose of 46 Gy in 23 fractions with boost 10 Gy in 5 fractions.
Adjuvant or neo-adjuvant chemotherapy was given in 90% of the cases. Indication in general for adjuvant chemotherapy was T stage 2-4, N+ disease or poorly differentiated histology. In patients with large tumor neo-adjuvant chemotherapy was given till maximum response followed by definitive surgery and post-operative radiation treatment or adjuvant chemotherapy [Table 1]. The detailed chemotherapy records for patients treated in the early part of the study period were not available therefore, proportion of patients completing chemotherapy as planned could not be calculated. Hormonal manipulation was given to estrogen/progesterone (ER/PR) receptor positive patients. First line hormone treatment was tamoxifen 20 mg daily for 5 years and in the last 10 years for post-menopausal patients aromatase inhabitors anastrazole 1 mg once daily and letrozole 2.5 mg were used.
After completing treatment, patients were followed every 3-6 months for a physical examination. In most of the patients an annual mammogram was also done. Patients with symptoms were restaged with appropriate investigations.
IBM Statistical Package for Social Sciences (SPSS)-17 was used for data analysis. The data were checked for wild codes and internal consistency with frequency tables and cross tabulations. Continuous variables are analyzed as means ± standard deviation for data with a normal distribution and median with inter-quartile ranges for skewed data. Categorical variables are analyzed as proportions and percentages. Overall survival (OS) was calculated for all patients from the date of definitive treatment until death either from BC or from any other cause. Patients with known recurrent disease and subsequently lost to follow-up are considered dead. Disease free survival (DFS) was calculated the date of definitive treatment to relapse or death. Kaplan–Meier estimate was used to plot survival curves and the differences were tested by log rank test at the 5% level of significance. Kaplan Meier survival curves and 5-year survival (OS and DFS) is presented as proportions with 95% confidence interval (CI) for all patients as well as stratified according to clinical TNM stage.
Potential predictors for OS and DFS were analyzed with Cox proportional hazard regression by purposeful selection technique. Multivariable model consisted of statistically significant variables (at the 20% level of significance in univariate analysis) as well as clinically significant (but statistically insignificant) variables. After removing insignificant variables and checking for interaction terms, the final model comprised of significant covariates. The association of covariate with OS and DFS is reported as adjusted hazard ratio with 95% CI.
| » Results|| |
The demographic and tumor-related characteristics for the 2829 are summarized in [Table 2]. The median age of the entire cohort was 45 years and two-thirds of the patients were less than 50 years of age.
TNM stage distribution of the patients is as follows: Stage I in 9%, stage II in 59% and stage IIIA 20%, stage IIIB 6% and stage III C 6% [Table 3].
|Table 3: Cross tabulation clinical American joint committee on cancer AJCC stage|
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Hormone receptor status
ER/PR hormone receptor status was available in 95% (2683/2829) of the patients. We found ER positive in 49%, PR positive in 50% of the cases. Combined receptor profile showed 58% positivity for either ER/PR or both receptors. Her-2 was tested in 70% (2002/2829) of the patients and was positive in 26%, negative in 59% and equivocal in 15%. Fluorescence in situ hybridization (FISH) test was not done in most of the cases with equivocal results. Triple negative cancers were found in 11% of the cases.
The median follow-up duration for the entire cohort was 4.4 years. At the time of last follow-up 1869 (66%) were alive of which 112 were alive with disease and 960 patients were dead. Cause of dead was breast cancer in 922 patients, treatment related toxicity in 8 patients and non-cancer related in 30 patients. Recurrence following primary treatment was seen in 35% of the patients: Local 5%, regional 1%, and distant in 29% of the cases.
The median OS and DFS was 4.45 and 4.04 years, respectively. The 5- and 10-year OS for the whole group was 70% (95% CI: 68.2-71.8%) and 54% (95% CI: 51.2-56.8%), while DFS was 65% (95% CI: 63-67%) and 52% (95% CI: 49.2-54.8%), respectively [Figure 1]. The 5- and 10-year OS by stage was: Stage I 88% and 74%, stage II 76% and 61%, stage III 55% and 35%. The 5- and 10-year DFS by stage was; stage I 86% and 76%, stage II 71% and 59%, stage III 47% and 33% [Figure 2]. The 5- and 10-year survival OS for ER/PR positive patients was 76% and 55% in comparison ER/PR negative patients had a 5-and year OS 65% and 53%. The 5- and 10-year DFS for ER/PR positive patients was 69% and 52% versus ER/PR negative patients had a 5- and 10-year OS 61% and 53% [Figure 3].
|Figure 1: Kaplan–Meier estimates of (a) overall survival and (b) disease-free survival of 2829 patients with non-metastatic breast cancer|
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|Figure 2: Kaplan–Meier estimates of (a) overall survival and (b) disease-free survival of the patients according to stage|
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|Figure 3: Kaplan–Meier estimates of (a) overall survival and (b) disease-free survival of the patients according toestrogen/progesterone receptor status|
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Univariate and multivariate Cox proportional hazards regression for the predictors of OS and DFS are given in [Table 4] and [Table 5].
|Table 4: Univariate and multivariate Cox proportional hazards regression for the predictors of overall survival in non-metastatic female breast cancer|
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|Table 5: Univariate and multivariate cox proportional hazards regression for the predictors of disease free survival in non-metastatic female breast cancer|
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| » Discussion|| |
The mean age of 45 years in our study is in concordance with other Asian countries. The low-peak age of incidence in the developing world may be at least partially explained by a lower overall life expectancy observed in developing countries. Pakistan hosts one of the largest proportions of young population in the world. The average life expectancy of Pakistani women is 66 years and only 4.2% of the population is 65 years or older compared to over 80 years in advanced countries.
The two most common histologic types of invasive breast cancer are infiltrating duct carcinoma (IDC) and infiltrating lobular carcinoma (ILC). In a population-based study of over 135,000 patients with invasive breast cancer from the surveillance, epidemiology, and end results database of the National Cancer Institute for the period from 1992 to 2001, 76% were IDC and 8% were ILC. These figures differ from our series where the frequency of IDC is much higher (92%) and that of ILC lower (4%) a finding consistent with other reports from South Asia. The low-frequency of ILC can be due to the reproductive practices and low-frequency of hormone replacement in this region.
In the United Kingdom, the overall frequency of ER and PR positivity is 73% and 58%, respectively. In comparison receptor expression pattern differs in our series with a lower proportion of patients positive for ER/PR receptors. Other authors have reported similar results from South Asia, suggesting that the lower overall fraction of endocrine receptor positivity may be related to the lower average age of our patients. Breast cancer patients with tumors that are ER-positive and/or PR-positive have lower risks of mortality after their diagnosis compared to women with ER-negative and/or PR-negative disease. Studies with longer follow-up suggest that the advantage may not persist in the long-term. In one study, an improved prognosis for ER-positive tumors during the first 3 years of follow-up but not after 3 years. The development of resistance to endocrine therapy acts as a major hurdle to the success of endocrine treatment. Genomic and non-genomic interaction between ER and growth factors is now considered an important factor contributing to hormone resistance, however the exact mechanism remains unclear.
In our study, ER/PR positive patients showed both OS and DFS survival advantage over a longer period of time well beyond 5 years and the benefit was lost beyond 10 years follow-up. Her-2 receptor was tested in 2002 patients and was found to be positive in 26% of the cases. However, the prohibitive cost of transtuzumab allowed only 1% of the patients to receive this treatment.
The proportion of breast cancer patients presenting with aggressive tumors in developing countries is higher than the Western population. Evidence is emerging that a speedy clinical course of the disease in these populations, is associated with the occurrence of a more aggressive breast cancer phenotype. Support for this observation emanates from a higher incidence of the triple negative subtype, compared to developed countries. Le Doussal et al. demonstrated a correlation between histologic grade dismal outcomes for patients with high grade tumors. One-half of all the patients in our series had high-grade tumors and both OS and DFS survival correlated well with the tumor grade. Triple negative tumors were found in 11% of the patients. The lower frequency of triple negative patients may be due to the fact that the Fish test was not done in equivocal cases; the test was unavailable in earlier part of the study and later on for economic reasons.
Prognosis and survival rates for breast cancer differ greatly depending on the histological type, stage, treatment, and geographical location of the patient. Survival rates in the Western world are high and are poor in the developing world reflecting on the inequities in early detection and access to treatment. In the United States, 60% of the patients are diagnosed in the localized stage, 33% with spread to regional nodes and only 5% have distant metastasis at presentation. These figures are in sharp contrast to developing world where disease at presentation is characterized by advanced stage. This prominent difference in the stage distribution of breast cancer patients in the developing and developed countries has been largely attributed to the lack of screening facilities, delays in seeking medical attention, low socioeconomic status, poor health care systems and lack of diagnostic and therapeutic facilities. In our series, less than 10% of the patients had Stage I disease at diagnosis, whereas an overwhelming majority (91%) presented with stage II (59%) and III (32%) disease. Sixty five percent of patients in Pakistan with breast cancer have advanced stage at presentation due to lack of awareness, local customs, poverty, a shortage of medical facilities and reluctance to see a medical doctor., Approximately, 10% of urban and 5% of the rural female population undergo clinical screening for breast cancer. Radiological facilities in this regard are present for less than 3% of urban and 1% of rural females.
Iqbal et al. reported on 200 patients with stage III breast cancer. Sixty four percent of the patients had T3/T4 tumors and 40% had extensive nodal involvement. At 5 and 10 years, event free survival was 25% and 7%, and OS was 52% and 31%, respectively. Loco-regional disease was the most common site of relapse (28.5%). In another study of 525 patients: Stage I 6%, stage II 48%, and stage III 46%, Aziz et al. reported 5- and 10-years event free survival and OS for all patients were 57% and 37%, and 72% and 61%, respectively. The significant difference in event free survival and OS in these studies suggests a high recurrence rate in comparison to our results and this could be related to a larger number of patients with more advanced loco-regional disease in these studies as in our study group only 12% of the patients had stages IIIB or IIIC. The relatively small number of patients with very advanced loco-regional disease reflects on our hospital acceptance criteria for treatment in the institution.
Analysis based on population based registries of Asian, African, and South American countries shows 5-year survival for Asian countries ranged from 47% to 82%. On further stratifying according to socio-economic status and stage of disease, average 5-year survival for localized and locally advanced breast cancer reported from advanced countries was 89% and 75%, respectively, whereas from developing countries it was 76% and 47%, respectively. While our 5- and 10-year OS of 70% and 54 and DFS was 65% and 52% is similar to the developing world, survival by stages I, II and III was 86%, 73% and 55%; figures that are comparable with advanced countries.
On multivariate analysis a decreasing trend of OS and DFS was observed for higher T stage, increasing number of lymph nodes involved, high tumor grade, negative ER/PR receptor status. These factors are well recognized prognostic factors in breast cancer. The impact of treatments and patient related co-morbidities that influence survival were not explored in this study.
The proportion of patients with T stage 4 (7%) in our series is less than expected. Our hospital in the initial years accepted patients with very advanced primary breast tumors, with time the hospital policy was revised and the number of patients with very advanced local disease was curtailed.
The influence of number of involved axillary nodes and survival is well established. Survival for patients with 0, 1-3, 4-12, and >12 positive nodes was 83%, 73%, 46%, and 28%. Our results are consistent with published literature and in this study, the 5-year survival of patients with 0, 1-3, 4-9, and >9 pathologically involved nodes was 80%, 70%, 60%, and 50%, respectively. Family history of breast cancer has been investigated previously; few studies have reported better survival in patients with a family history of breast cancer attributed to either early health seeking behavior or unknown genotypic variation., Others did not find any significant difference in phenotype, health seeking behavior or prognosis., In this report, the information on family history of breast cancer was available in 69% of the patients and those with a family history of breast cancer had better survival.
Our study is one of the largest series on clinical outcome in breast cancer from developing countries. The low local-regional failure rate and comparable stage for stage survival rates with developed countries underscores multi-disciplinary care, practice of evidence based medicine and availability of quality surgery, radiotherapy and chemotherapeutic drugs in this institution. However, only a small fraction of breast cancer patients in Pakistan are treated in this hospital. Efforts are needed to improve public and professional awareness, health-services infrastructure, human-resources development and referral pathways to focus on balanced investments in prevention and early detection. There is an urgent need to adopt corrective strategies best suited to the local culture if survival rates are to improve. In conclusion, studies on clinical outcome of breast cancer in developing countries might offer a better understanding for a more effective approach of the problem both in developing as well as developed countries.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]