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The Breast 20 (2011) S75eS80

Contents lists available at ScienceDirect

The Breast

journal homepage: www . elsevier . com/brst

Breast cancer in a multi-ethnic Asian setting: Results from the SingaporeeMalaysia hospital-based breast cancer registry

Nirmala Bhoo Pathy a, b, c, d, *, Cheng Har Yip d, e, Nur Aishah Taib d, e, Mikael Hartman f, g, h, Nakul Saxena f, Philip Iau g, Awang M. Bulgiba a, Soo Chin Lee i, Siew Eng Lim i,
John E.L. Wong j, Helena M. Verkooijen f, k for SingaporeeMalaysia Breast Cancer Working Group

a Julius Centre University of Malaya, Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia

b Julius Center for Health Sciences and Primary Care, University Medical Center, PO Box 85500, 3508 GA Utrecht, The Netherlands

c Ministry of Health, Malaysia

d University Malaya Cancer Research Institute (UMCRI), University Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia

e Department of Surgery, Faculty of Medicine, University of Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia

f Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, MD3, 16 Medical Drive, Singapore 117597, Singapore

g Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, MD3, 16 Medical Drive, Singapore 117597, Singapore

h Department of Medical Epidemiology and Biostatistics Karolinska Institutet, Stockholm, Sweden

i Department of Hematology Oncology, National University Cancer Institute, National University Health System, Singapore 119228, Singapore

j Department of Medicine, National University Hospital, 5 Lower Kent Ridge Rd., Singapore 119074, Singapore

k Department of Radiology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands

Keywords:

Breast cancer Asian

Asia

Cancer registry

a b s t r a c t

Two hospital-based breast cancer databases (University Malaya Medical Center, Malaysia [n ¼ 1513] and National University Hospital, Singapore [n ¼ 2545]) were merged into a regional registry of breast cancer patients diagnosed between 1990 and 2007. A review of the data found 51% of patients diagnosed before the age of 50 years. and 72% percent of the women were Chinese followed by Malays (16%), Indians (8%), and other races (4%). Median tumor size at presentation was 26 mm and about 25% of patients presented with TNM stage III or IV disease. Most tumors were of ductal histology (87%). Fifty-seven percent of tumors were estrogen receptor positive and 40% were poorly differentiated. Of those patients who had surgery, 70% had mastectomy while 30% had breast conserving surgery. Overall, chemotherapy was administered to 56% of patients and hormonal treatment to 60%. Five-year overall survival was 82.5% in patients with TNM stage 0 to stage II cancer, and 30.2% in those with later stages.

2011 Elsevier Ltd. All rights reserved.

Introduction

In contrast to the West, where breast cancer incidence rates have stabilized or even decreased,1e3 the incidence of breast cancer has escalated in most Asian countries over the past two decades.4e7 Changes in reproductive factors, environmental exposures, and lifestyle such as dietary intake and physical activity have all been proposed to explain this trend. With the westernization of Asian countries, one can expect this trend to continue and it is not unthinkable that in the relatively near future, the majority of breast cancer patients will be of Asian ethnicity. Therefore, it is crucial that

* Corresponding author. Julius Centre University of Malaya, Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia. Tel.: þ60 03 79673797.
E-mail address: [e-mail] (N. Bhoo Pathy).

0960-9776/$ e see front matter 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2011.01.015

we improve our understanding of breast cancer among Asian women.

An important step in the above process warrants monitoring of the nature of disease presentation, tumor characteristics, management, and survival of Asian women with breast cancer. Since longitudinal studies of breast cancer are scarce in this part of the world, we have set up the SingaporeeMalaysia Breast Cancer Working Group (SMBCWG), which is an international, multidisci-plinary collaboration between epidemiologists, breast surgeons and oncologists of the National University Hospital, Singapore (NUH), National University of Singapore (NUS), collectively known as National University Health Systems or NUHS, University Malaya Medical Center (UMMC) and University of Malaya (UM), Kuala Lumpur, Malaysia. Under this initiative, the breast cancer registries of two academic hospitals (NUHS, UMMC) were merged, to allow a multitude of clinical studies on breast cancer and facilitate implementation of research projects, including clinical trials and

S76 N. Bhoo Pathy et al. / The Breast 20 (2011) S75eS80

detailed molecular studies. The mission of the SMBCWG is to optimize the management, survival, functional status, and long-term quality of life of Asian breast cancer patients.

In the current study, we describe the setting-up of the Singa-poreeMalaysia Breast Cancer Registry (SMBCR) as well as the clinical and pathological tumor characteristics, treatment patterns, and outcomes of breast cancer among our cohort of Southeast Asian women.

Methods

Data for this study were retrieved from the hospital-based breast cancer registries of two teaching hospitals in Singapore and Malaysia: the NUHS Breast Cancer Registry and the UMMC Breast Cancer Registry.

The NUHS Breast Cancer Registry currently consists of 2545 consecutive patients who were newly diagnosed with breast cancer between 1990 and 2007. Details of this registry have been described elsewhere.8 Data were collected retrospectively for patients diagnosed between 1990 and 1995 and prospectively for patients diagnosed after 1995. The database includes data on patient’s basic demography, tumor characteristics and treatment profile, follow-up and vital status. This registry has been approved by the Institutional Ethics Review Board.

The breast cancer registry in UMMC was started in 1993 and currently encompasses 1513 patients, newly diagnosed with breast cancer between 1993 and 2002. Data on basic demography, clinical and pathological tumor profile, as well as treatment details was collected prospectively for each patient, using a written form (proforma) based on the input from patient interviews and medical records, as well as radiology and pathology reports. The details from the proforma were gradually transferred into an electronic database. Ten percent of patients from the database were randomly selected and had their data verified with their proforma for quality audit purposes. Errors were found in 8% of the sub-sample of 148 patients. This registry has received approval from the Ethical Review Committee of UMMC.

In both centers, patients were monitored through follow-up in the specialist outpatient clinics. Data on mortality were obtained from the hospitals’ medical records, as well as active follow-up through the patients’ next-of-kin. In addition, we regularly updated vital status through direct linkage with the respective National Registration Department in both countries. Follow-up time was calculated for all patients, starting at date of diagnosis with breast cancer until death (all causes) or date of last contact, whichever came earlier.

Variables

In both registries, we had data on basic demography of patients such as age at diagnosis, ethnicity and nationality. Other variables such as occupation, age at menarche, age at first delivery, parity, breastfeeding, use of oral contraceptive, menopausal status, use of hormone replacement therapy (HRT), and family history of breast cancer were largely unavailable. Information on patients’ comor-bidities was available from the Malaysian registry but not from the Singaporean registry.

Data on clinical tumor characteristics included tumor size, lat-erality of tumor (right, left, bilateral), lymph node involvement (clinical staging: N0-N3), presence of distant metastasis (yes/no), and metastatic site. Pathological tumor characteristics included number of lymph nodes resected, number of lymph nodes involved, tumor histology, tumor grade (Scarff-Richardson-Bloom classifica-tion; grade 1 (lowest) e well-differentiated cells, grade 2 e moder-ately-differentiated cells, grade 3 (highest) e poorly-differentiated

cells) as well as estrogen receptor (ER) status, and progesterone (PR) receptor status. Hormonal receptor status (ER and PR) was deter-mined via immunohistochemical staining and deemed positive when >10% of cells stained positive. In both registries, analysis of ER and PR hormone receptor status was not routinely assessed in the early 1990s. HER2/neu status was only available in patients diag-nosed since mid 2000. All breast cancers diagnosed in 2002 and before were staged according to the 5th edition of TNM classification by American Joint Committee on Cancer (AJCC), while cancers diagnosed after 2002 were staged according to the 6th edition of AJCC.

Treatment data consisted of type of initial treatment (surgery, chemotherapy, radiotherapy, hormone therapy), surgery (yes/no), type of surgery (mastectomy, breast conserving surgery [BCS]), chemotherapy (yes/no), chemotherapy regime, radiotherapy (yes/ no), hormone therapy (yes/no), and type of hormone therapy.
Both the databases were synchronized into a standard template and subsequently merged. Quality checks were carried out where results were cross-checked between the individual registries and the SMBCR to ensure uniformity. In July 2010, the SMBCR consisted of 4058 patients who were newly diagnosed with primary breast cancer between 1990 and 2007. Prospective registration is currently ongoing.

Overall, histological characteristics were missing in 2% (lymph node staging) to 41% (PR status) of the cases, whereas treatment data was missing in 3e5% of patients. The vital status of 0.1% of patients in Singapore and 8.6% in Malaysia could not be deter-mined. In both registries, cause of death, as well as data on local or systemic recurrences were not available to a large extent.

Statistical analysis

All categorical variables were described by proportions and compared using the Chi square test. Continuous variables were expressed in medians and compared using the KruskaleWallis test. KaplaneMeier analyses were conducted to estimate overall survival (OS) and compared by log-rank test. Two-tailed P value <0.05 was considered as statistically significant. All statistical analyses were performed using SPSS for Windows version 16.0 (SPSS Inc., Chicago, Illinois, USA).

Results

In this cohort of Southeast Asian women with breast cancer, the age at diagnosis ranged between 21 and 94 years. Approximately half of the patients were diagnosed before the age of 50 years (median ¼ 49 years). Fifteen percent of patients were aged younger than 40 years at presentation. The majority of patients were of Chinese ethnicity (72%), followed by Malays (16%), Indians (8%), and other races (4%).

Median tumor size at presentation was 26 mm and there was a decrease with calendar time from 40 mm in patients diagnosed from 1990 to 1994 to 20 mm in those diagnosed in 2005 onwards (P < 0.001, Fig. 1). A quarter of the patients presented with advanced stage disease, including 15% with stage III and 10% with stage IV disease. Only 7% of patients presented with ductal carci-noma in situ (DCIS) and 21% with stage I disease. Forty-three percent of patients presented with stage II. While the proportion of patients presenting with early stage disease (DCIS and stage I) increased over the years (P < 0.001), there was no decrease in the proportion of patients presenting with advanced stages (stage III and IV) over time (P ¼ 0.56). Fig. 2 shows that even though the proportion of stage IV had decreased with time, the proportion of patients with stage III breast cancer seems to have increased.

N. Bhoo Pathy et al. / The Breast 20 (2011) S75eS80 | | | S77 | | | | | Table 1 | | | | | | | | Distribution of histological tumor characteristics in 4058 patients with | | | | | breast cancer. | | | | | | | | | | | | | | | | Histological Tumor Characteristic | n (%) | | | | | | | | | | | | | Pathological lymph node staging | | | | | | | | N0 | 2256 (57) | | | | | | N1 | 1041 (26) | | | | | | N2 | 425 (11) | | | | | | N3 | 236 (6) | | | | | | Unknown | 100 | | | | | | | ER status | | | | | | | | Positive | 1706 (57) | | | | | | Negative | 1301 (43) | | | | | | Unknown | 1051 | | | | | | PR status | | | | | | | | Positive | 1315 (54) | | | | | | Negative | 1120 (46) | | | | | | Unknown | 1623 | | | | | | ER/PR combination | | | | | | | | ERþ/PRþ | 1071 (44) | | | | | | ERþ/PR_ | 292 (12) | | | | | | ER_/PRþ | 244 (10) | | | | | | ER_/PR_ | 828 (34) | | | | | | Unknown | 1623 | | | | | | Histologic grade | | | | | | | | Grade 1 | 383 (13) | | | Fig. 1. Breast cancer tumor size at diagnosis for the four study periods. | | Grade 2 | 1345 (47) | | | | | Grade 3 | 1153 (40) | | | | | | | | | | | | | Unknown | 1177 | | | Forty-three percent of patients had lymph node positive | | Lymphovascular invasion | | | | | | | Present | 2102 (52) | | | disease, and 40% of tumors were poorly differentiated (Table 1). A | | Absent/Unknown | 1956 (48) | | | great majority of tumors were of invasive ductal histology (87%) | | | | | | | while invasive lobular cancers made up 4%, and another 9% of | | | | | | | tumors were of other histological types. Overall, 43% of patients had | | | | | | | ER negative and 46% had PR negative cancer. Fifty-two percent of | Table 2 | | | | | patients had tumors exhibiting lymphovascular invasion. | | | | | | | Treatment distribution and patterns in 4058 Southeast Asian Women with breast | | Overall, 97% of patients were treated either with loco-regional, | | | | cancer. | | | | | systemic or both types of treatment while 3% of patients did not | | | | | | | | Treatment | | n (%) | | receive any therapy. Patients who did not receive any treatment were | | | | | | | | | | | | | | more likely to be older (median age ¼ 62 years), and have larger | Received surgerya | | | | | | Yes | 3355 (98) | | tumor size at diagnosis (median ¼ 45 mm). A vast majority of | No | 67 (2) | | | patients (98%) with non-metastatic breast cancer (stage 0 to stage III) | Unknown | 77 | | | received surgical intervention (Table 2). Seventy percent of them | Type of surgerya,b | | | | | | | Mastectomy | 2360 (70) | | | | Breast conservation surgery | 995 (30) | | | | Received radiotherapya | | | | | | | Overall | | | | | | | | Yes | 1858 (55) | | | | | No | 1508 (45) | | | | | Unknown | 133 | | | | | By surgical status | | | | | | | Yes, after breast conserving surgery | 849 (86) | | | | Yes, after mastectomy | 1000 (43) | | | | Yes, with no surgery/unknown surgical status | 9 (1) | | | | | Received chemotherapy | | | | | | | Overall | | | | | | | | Yes | 2167 (56) | | | | | No | 1719 (44) | | | | | Unknown | 172 | | | | | ER negative and lymph node positive disease | | | | | | | Yes | 488 (85) | | | | No | 87 (15) | | | | | Unknown | 6 | | | | | Received hormone therapy | | | | | | | Overall | | | | | | | | Yes | 2319 (60) | | | | | No | 1573 (40) | | | | | Unknown | 166 (4) | | | | | By ER status | | | | | | | ER positive | 1436 (85) | | | | ER negative | 447 (35) | | | | ER status unknown | 436 (46) | | | | | | | | | | | a | | | | | Fig. 2. Percentage of patients with different TNM stage (0eIV) at presentation for the | b Excluding patients with stage IV breast cancer (n ¼ 387). | | | | | four study periods. | | Confined to those who were subjected to surgery. | | | | |

S78 N. Bhoo Pathy et al. / The Breast 20 (2011) S75eS80

received mastectomy while another 30% received breast conserving surgery (BCS) (Fig. 3). Eighty-six percent of patients treated with BCS received radiotherapy post surgery.

Overall, 56% of patients received chemotherapy. Most (85%) patients with ER negative and lymph node positive disease were given chemotherapy. Sixty percent of women were given hormonal therapy, where 85% of those with ER positive tumors received hormone treatment.

Of 745 patients who did not receive any form of systemic therapy (i.e., 20% of the study patients), 56% were either in stage 0 or stage I disease. Twelve percent of patients received neo-adjuvant chemotherapy. Median tumor size at diagnosis in these patients was 80 mm.

A total of 1165 deaths occurred in 16,795 person-years of observation with a 5-year overall survival of 67.6% (65.8e69.4%). In patients with TNM stage 0 to stage II cancer, 5-year overall survival was 82.5% (95% CI: 80.7e84.3%), and 30.2% (95% CI: 26.7e33.7%) in those with later stages. Table 3 shows the 2-year and 5-year survival of patients by stages of breast cancer.

Discussion

The results of this study indicate that the presentation of breast cancer of women in Asian settings may indeed be different from the Caucasian/Western settings. Approximately 50% of Asian women in our study were diagnosed before the age of 50 years. This is in contrast to the Western settings where breast cancers in women aged younger than 50 years accounts for about 23% of the total breast cancer incidence.9 Previous studies have suggested that younger age at onset may be attributed to the relatively young population in Asian countries as well as birth cohort effect8,10 and this may well explain our findings. Breast cancer in young women is exceptionally impactful, since these women may still have young children, a wish to conceive, and may be in the mid-stage of their career life.

Compared to the West, our patients presented with larger tumors, a finding similar to a previous Asian study conducted in Hong Kong, India and Malaysia.11 We also observed a decreasing trend in tumor size, which may be associated with increasing breast cancer awareness in the population and, to a certain extent, with the introduction of the mammographic breast screening

Fig. 3. Type of surgery (mastectomy or breast conserving surgery) by TNM stage (0eIII) in women with non-metastatic breast cancer.

program in Singapore since 2002. This trend was complemented with an increasing proportion of patients presenting with DCIS and stage I disease over time. Even though, in aggregate, the proportion of patients presenting with advanced stages (stage III and IV) did not decrease, the proportion of those presenting with metastatic breast cancer had declined over time. Overall, 10% of patients had metastatic breast cancer at initial presentation as opposed to 3e6% in the Western settings.12

We observed that the proportion of poorly differentiated tumors (40%) was similar to Caucasian (41%), and lower than Afri-caneAmerican populations (57%).13 As in the Western settings, invasive ductal carcinomas were the main histological type of breast cancer, but lobular cancers were far less common in our Asian setting (only 4% versus 12e18% in Western settings).13 Previous studies have suggested a positive association between postmenopausal hormone replacement therapy (HRT) and the incidence of lobular breast cancers.14,15 Therefore, the lower use of

postmenopausal HRT in Asian versus Western populations (less than 20% use of HRT versus up to 60%, respectively),16,17 in

combination with the higher proportion of premenopausal cases, could explain the lower incidence of lobular-type breast cancers. Compared to women registered in the Surveillance, Epidemiology, and End Results (SEER) database in the USA, the proportion of patients with ERþ/PRþ tumors in our study was lower (63% versus 44%) whereas the proportion of those with ER_/PR_ tumors was higher (21% versus 34%).18 This may be related to the younger age of our patients since it has been previously shown that the incidence of ERþ/PRþ tumors is positively associated with age.19 In addition, lower HRT use in our postmenopausal women may also explain the above finding whereby HRT use has been associated with devel-opment of ERþ/PRþ tumors.20

Besides describing the clinical and histological tumor charac-teristics of the patients, this study was conducted to shed light into the management and overall survival of patients following the diagnosis of breast cancer in an Asian setting. Compared to patients in the West, the overall mastectomy rates in our population were higher (71% versus 31e45%),21 whereas BCS rates for stage I patients were lower (48% versus 60%).22 This may be due to the larger tumor size at presentation,11 smaller breast volume in Asian patients,23 patients’ decision, and preferences of physicians. Patients eligible for BCS may opt to undergo mastectomy to feel safer and reduce the risk of loco-regional recurrence,24e26 to avoid radiotherapy,26 as well as for financial reasons and convenience as BCS followed by radiotherapy requires more intense follow-up and frequent commuting to the hospital.24

The overall proportion of patients receiving chemotherapy was 56%, which is higher than in countries like Australia (32e49%), Canada (40e42%), Sweden (30e40%), United Kingdom (29%) and USA (40%).27 A possible explanation for this is the higher proportion of ER negative tumors and more advanced disease in our patients. A majority of patients with ER positive tumors (85%) were given hormonal treat-ment. Prior to the era of routine hormonal receptor assessment at UMMC, the treatment policy was routine prescription of tamoxifen to patients deemed clinically eligible by the treating physicians.

The proportion of patients not treated (loco-regional, systemic or both), or receiving incomplete treatment may well be a reflec-tion of patient choice and not a consequence of management policies, as it is not uncommon for Asian breast cancer patients to decline treatment or follow-up in order to seek alternative or traditional treatment.11,24,28e30 Studies in Malaysia have shown

that approximately 5% of patients with breast cancer attending the Kuala Lumpur Hospital decline further treatment.31 In an East Malaysian hospital, 55% of patients who did not adhere to treat-ment refused surgical intervention, followed by non-adherence to chemotherapy (29%), and non-adherence to radiotherapy (13%).24

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Table 3

Survival estimates (median survival (months), 2-year survival, 5-year survival) by stages of breast cancer.

| Stage 0 | Stage I | Stage II | Stage III | Stage IV | | | | | | | | | | Median survival, mos (95% CI) | * | | * | 164 (*) | 53 | (47e59) | 17 | (15e19) | 2-yr survival % (95% CI) | 99.5 | (98.5e100.0) | 98.9 (98.1e99.7) | 94.0 (92.8e95.2) | 77.9 | (74.4e81.4) | 36.3 | (33.7e44.7) | 5-yr survival % (95% CI) | 95.6 | (91.7e99.5) | 93.6 (91.4e95.8) | 76.0 (73.5e78.5) | 44.1 | (39.2e49.0) | 9.3 | (5.8e12.8) | | | | | | | | | |

* Data unavailable.

The rate of non-adherence in the current study is higher than the reported rate among patients with non-metastatic breast cancer in Geneva, Switzerland where 1.3% of women refused surgery.32 However, our patients who declined treatment were also older and had bigger tumors similar to the study in Geneva.

After stratifying for stage, our patients with early breast cancer (carcinoma in situ and stage I) had similar 5-year overall survival as patients registered in the National Cancer Database in the United States (accession year 1999); stage 0 (96% versus 97%), stage I (94% versus 90%) [http://www.gundluth.org/?id¼885&sis¼1]. However, Asian patients with more advanced stages had worse 5-year overall survival rates than their counterparts in the United States: stage II (76% versus 85%), stage III (44% versus 55%), and stage IV (9% versus 13%). This may be due to a combination of disparities in treatment options, more severe metastatic profile at presentation in Asian women,11 as well as lower treatment uptake or adherence rates related to the health behavior of patients.

To our knowledge, this is one of the largest multi-ethnic collabo-rative studies in Asia assessing the presentation, management and survival following breast cancer among Asian women. However, we do acknowledge that this study suffers from limitations. While Malaysia is an upper-middle income nation, Singapore is a high income nation, making populations heterogeneous from socio-economic perspectives. However, the two hospitals in this study are tertiary academic centers with fairly comparable diagnostic and therapeutic facilities. On the other hand, since UMMC is a tertiary center and serves a predominantly middle income urban population, our findings may not necessarily reflect the overall situation of breast cancer in Malaysia. The presentation of breast cancer in the rural Malaysian settings for instance, may be more advanced than in our study. However, our results may be regarded as the best available information to date. Another limitation of our study is that some prognostic factors, such as body mass index (BMI), lifestyle, HER2/neu status, and local/systemic recurrence were largely missing. Missing data on histological characteristics and recurrence were not at random. Histological datawas missing largely inpatients who refused surgery and to a certain extent due to lack of routine assessment for hormonal receptor status in the early 1990s. Recurrence is difficult to capture in a hospital-based registry as patients may subsequently decide to seek treatment in other hospitals. The authors had limited information on existing comorbidities of the patients and were also unable to estimate breast cancer specific survival as cause of death of a majority of our patients was not available.

Based on this study, we conclude that late stage at presentation remains a problem in Asianwomen and poses a challenge to the health care community in this region. Our patients are also more often diag-nosed at a younger age when family and professional commitments hold major importance in their life. In order to reduce the burden of breast cancer in this part of the world, a multi-sectoral approach is required. Evidence-based cancer control strategies aiming at early detection and effective management may be the best way forward.

Contributors statement

NB, CHY, MH, and HMV contributed to study design, data collection, and statistical analyses. NAT contributed to study design

and data collection; NS and SCL contributed to data collection. All authors contributed to interpretation of results and manuscript writing: NB, CHY, NAT, MH, HMV, NS, PI, SCL, AMB, SEL, and JELW.

Conflict of interest and funding statement

All authors reported that they had no conflict of interest. Nirmala Bhoo Pathy was financially supported by the European Union, AsiaLink program MY/AsiaLink/044 (128-713).

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