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Breast cancer research in Asia: Adopt or adapt Western knowledge?
European Journal of Cancer (2013) 49, 703– 709
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Review
Breast cancer research in Asia: Adopt or adapt Western knowledge? Nirmala Bhoo-Pathy a,b,c,⇑, Cheng-Har Yip d, Mikael Hartman e, Cuno S.P.M. Uiterwaal c, Beena C.R. Devi f, Petra H.M. Peeters c, Nur Aishah Taib d, Carla H. van Gils c, Helena M. Verkooijen e a
National Clinical Research Centre, Level 3, Dermatology Block, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia Julius Center, Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia c Julius Center for Health Sciences and Primary Care, University Medical Center, PO Box 85500, 3508 GA Utrecht, The Netherlands d Department of Surgery, Faculty of Medicine, University of Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia e Saw Swee Hock School of Public Health, National University of Singapore, MD3, 16 Medical Drive, Singapore 117597, Republic of Singapore f Department of Radiotherapy, Oncology & Palliative Care, Sarawak General Hospital, Jalan Hospital, 93586 Kuching, Sarawak, Malaysia b
Available online 2 October 2012
KEYWORDS Breast cancer Asia Asian Clinical research
The incidence and mortality of breast cancer continues to rise rapidly in Asian countries. However, most of our current knowledge on breast cancer has been generated in Western populations. As the socio-economic profile, life style and culture of Asian and Western women are substantially different, and genetic backgrounds vary to some extent, we need to answer the question on whether to ‘adopt’ or ‘adapt’ Western knowledge before applying it in the Asian setting. It is generally accepted that breast cancer risk factors, which have mainly been studied in Western populations are similar worldwide. However, the presence of gene–environment or gene–gene interactions may alter their importance as causal factors across populations. Diagnostic and prognostic study findings, including breast cancer prediction rules, are increasingly shown to be ‘setting specific’ and must therefore be validated in Asian women before implementing them in clinical care in Asia. Interventional research findings from Caucasian patients may not be applicable in patients in Asia due to differences in tumour biology/profiles, metabolism of drugs and also health beliefs which can influence treatment acceptance and adherence. While breast cancer research in Asia is warranted in all domains of medical research, it is felt that for Asian breast cancer patients, needs are highest for diagnostic and prognostic studies. International clinical trials meanwhile need to include breast cancer patients from various Asian settings to provide an insight into the effectiveness of new treatment modalities in this part of the world. Ó 2012 Elsevier Ltd. All rights reserved. Abstract
⇑ Corresponding author: Address: National Clinical Research Centre, Level 3, Dermatology Block, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia. Tel.: +603 40443060/70. E-mail address: [email protected] (N. Bhoo-Pathy).
0959-8049/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2012.09.014
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1. Introduction In the past few decades, Asia has seen rapid economic growth resulting in increasing life expectancy, declining mortality from communicable diseases and westernisation of lifestyle.1 While these developments are overall beneficial, they come with a price. Breast cancer incidence is rapidly increasing in Asian populations. In China and India, incidence rates have increased by up to 30% over the last 10 years, whereas in Japan, Korea and Singapore, the rates have doubled or even tripled in the past few decades.2 The age-standardised incidence of breast cancer in Singapore, for instance, had increased from 20.2 per 100,000/year between 1968 and 1972,3 to 60.7 per 100,000/year between 2006 and 2010,4 where much of this is attributed to the decline in parity and delayed first childbirth in Singaporean women.5 While the incidence of breast cancer in Asian women is currently still lower than in their Western counterparts across all age groups (Fig. 1),6 the dramatic increase of incidence rates in Asian populations renders it conceivable that in the near future, the majority of breast cancer patients worldwide will be of Asian ethnicity. Most of our current knowledge on breast cancer has been generated from studies conducted in Western populations. Hence, diagnostic and treatment guidelines in Asia are largely based on Western knowledge. For instance, the recent consensus guideline on the management of HER2-positive breast cancer in Asia was based only on studies conducted in non-Asian populations.7
The question is whether we can simply adopt current Western knowledge in Asia, whether we have to adapt it before implementation, or whether we need new evidence. Central to this issue is that Asian women are substantially different from Western women from many perspectives, including genetic background, socio-economic profile, lifestyle, culture and health beliefs, all of which play an important role in breast cancer incidence and prognosis.8 Below, we use some research examples to support our views on which areas require adopted, adapted or de novo Asian breast cancer research. 2. Aetiological breast cancer research While it is generally accepted that the aetiology of breast cancer is similar worldwide, differences in genetic make-up of Asian women may cause different interactions with environmental exposures (e.g. reproductive, dietary), altering their susceptibility to the beneficial or harmful effects of these exposures. A meta-analysis investigating the association between soy intake and breast cancer risk had shown that the protective effect of soy was observed only in women of Asian ethnicity (Asian or Asian Americans), whereas soy intake was unrelated to breast cancer risk in Western women.9 A nested case control study within the Singapore Chinese Health Study cohort revealed that the protective effect of dietary soy isoflavones on postmenopausal breast cancer was restricted to women who were homozygous for the high activity murine double minute 2 (MDM2) allele
Fig. 1. Age-specific breast cancer incidence rates in selected cancer registries. Source: Bray et al.6 (Reproduced with permission from Freddie Bray, International Agency for Research on Cancer).
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(GG genotype).10 Interestingly, it has been previously demonstrated that genetic polymorphisms of MDM2 is a risk factor for breast cancer in Chinese women but not in non-Chinese women.11 Furthermore, the exposure levels or prevalence of established aetiological factors may be different in Asia. Hence, the relevance or (population) attributable risks of certain risk factors may substantially differ between the Western and Asian populations. For instance, alcohol consumption and hormone replacement therapy (HRT) intake have been consistently shown to increase breast cancer risk in Caucasian women.12–14 In Asia, the prevalence of alcohol consumption and use of HRT15 is low and these factors will thus only make a small contribution to breast cancer incidence. Similarly, the importance of genetic risk factors depends not only on the actual relative risk of breast cancer conferred by the marker but also on its allele frequency which is known to vary across population.16 A study assessing 13 single nucleotide polymorphisms associated with breast cancer risk in European populations showed that these genetic markers confer different population risks in Chinese, Malay and Indian populations due to variations in the frequency of the risk alleles.17 There are differences in exposure levels of breast cancer risk factors and in breast cancer specific genetic susceptibilities between Asian and Western women. New Asian aetiologic studies should adopt current knowledge and aim at finding new causes of breast cancer, some of which may be specific for Asian women.
since the incidence of breast cancer among Asian women is still relatively lower than their Western counterparts. Therefore, the implementation of population based screening mammography in Asia has been considered by some as misappropriation of resources, even in high income Asian settings.19 In low and middle income Asian countries, it seems wise to channel available resources to improve breast cancer awareness and encourage women with breast lumps or symptoms to seek treatment.25 In these settings, clinical breast examination (CBE) has been proposed to improve breast cancer detection in treatable stages. For instance, in East Malaysia, the proportion of patients presenting with stage III and stage IV breast cancer was substantially reduced following execution of a training programme for nurses from rural districts in the state of Sarawak between1994 and 1999.26 However, there seems to be a knowledge gap on whether CBE is effective in reducing mortality from breast cancer in Asian patients.27 This is currently being addressed by a large scale randomised trial involving approximately 150,000 women living within the slums of Mumbai, India which aims to determine the efficacy and costeffectiveness of CBE as a screening method to reduce breast cancer mortality in limited resource settings.28 Furthermore, diagnostic breast cancer research in Asian settings is extremely scarce. As this type of research is setting specific,29 this is probably the domain that really requires not adoption but either adaption or new research questions.
3. Diagnostic breast cancer research
4. Prognostic breast cancer research
A large proportion of breast cancer patients in Asia present with advanced stages, and up to 25% percent have distant metastases at initial presentation.18 There have been demands for the introduction of population based mass screening mammography in Asian women over the recent years.19 However, there is little evidence that breast cancer screening via mammography would be effective in the Asian setting.20 In addition to cultural, economic and logistic barriers,21 which are thought to be the reasons for the low participation rates in Asian countries with screening programmes (i.e. Hong Kong, Singapore),19,20 there may be additional problems with mammography as a screening tool. Approximately 50% of Asian women are diagnosed with breast cancer before the age of 50 years,22 suggesting that age limits may need to be adapted. However, the diagnostic performance of mammography is poor in women under the age of 50 years.23 Moreover, Asian women generally have small-volume breasts and relatively dense parenchymal breast tissue which may obscure detection of early and small breast tumours.24 In addition, the positive predictive value of screening mammography is currently expected to be a lot lower in Asia than in the West
Accurate prognostication of breast cancer is crucial as it ensures accurate information for patients, and allows for adequate treatment decisions and risk stratification. Prognostic research findings from Western countries are used in Asian breast cancer patients, in order to predict an individual woman’s disease outcome, which is based on personal as well as disease characteristics, i.e. TNM stage, grade and receptor status. Microarray gene expression based prognostic tests for breast cancer such as Oncotype-Dx30 and Mammaprint31 are steadily gaining popularity in Western oncology practice settings as tools in risk stratification, and selection and optimisation of drug regimens for women with early breast cancer.32 However, in most Asian settings, the above assays are not only economically unfeasible, but their clinical utility remains both unclear, given the higher incidence of oestrogen receptor negative breast cancers22,33 where gene arrays have limited added value, and unproven, given the absence of validation in Asian patients. Since multigene assays are not feasible in most of Asia, web-based prognostication tools such as Adjuvant! Online may be valuable in clinical practice. Adjuvant! Online which was developed in the United States
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based on data from the Surveillance, Epidemiology and End Results registry,34 is also widely used in Europe35,36 and Asia37 as a tool to aid patient counselling and clinical decision making in the management of women with early breast cancer following receipt of loco-regional treatment. However, a recent study conducted in a multiethnic Asian setting found that Adjuvant! Online significantly overestimated survival in Asian breast cancer patients especially in women aged less than 40 years, as well as in patients of Malay ethnicity.38 This study underscores the need to validate Western derived prognostic models in Asian patients, and adapting them to improve their predictive capacity. It may even be necessary to build new ‘Asia-specific’ prediction models using a large cohort of Asian breast cancer patients. 5. Intervention research in breast cancer Interventions and treatments that are developed and shown to be effective in Caucasian populations may not necessarily be effective in Asian women. There are several reasons why findings from clinical intervention trials conducted in Western settings may not apply to Asian populations. The metabolism of anticancer drugs for instance may differ between individuals due to presence of underlying genetic variations.39 A recent review looking at differences in toxicity and clinical outcome following treatment with anticancer drugs highlighted that there may be ethnic differences in tolerability and response to hormonal treatment and cytotoxic chemotherapy in breast cancer suggesting that anti-cancer drugs may be more effective in certain ethnic groups.40 The presence of underlying pharmacogenomic differences in drug metabolism and response,41,42 may also lead to differential tolerance to chemotherapy with higher occurrences of acute toxicities to chemotherapy. In addition, body mass index is also inversely associated with chemotherapy related toxicities.43 In a multicentre international study, Asian breast cancer patients were shown to be significantly more likely to experience grade 3 haematologic toxicities from FEC 100 chemotherapy than their Caucasian, African American and Hispanic counterparts.43 This was however, fully explained by the fact that the Asian patients were significantly less likely to be overweight or obese compared to the nonAsians in this study. Based on the above factors, it is conceivable that the dose intensity/density in Asian patients may be compromised due to lower tolerance to chemotherapy, leading to administration of lower doses of chemotherapy than the recommended dose e.g. the FEC 75 regime.38 Anticancer drugs therefore need to be evaluated in multiethnic Asian populations before claims on the potential benefits of the new treatment can be made. The Korea Food and Drug Administration for instance pay considerable importance to ethnic equivalence in
drug safety and efficacy data generated in Western populations.44 In China, the State Food and Drug Administration requires that local pharmacokinetic studies are conducted in Chinese patients, and a minimum of 100 Chinese patients per intervention arm are included in international Phase III trials, before a new drug gets approval for marketing in China.44 As only five percent of global spending on cancer is in developing countries, most current strategies for breast cancer treatment in affluent Western countries are not applicable in a major part of Asia.45 Poor compliance to (expensive) cancer treatment due to social, financial and cultural factors may also hamper breast cancer outcomes and needs to be taken into account when translating the treatment impact of a particular intervention in Asian patients.46 It is felt that large scale international clinical trials must include a sufficient number of breast cancer patients from different Asian settings to enable appropriate conclusions to be made on the effectiveness of new anticancer therapies in Asians. In instances where recruiting a large number of Asian patients are not feasible, meta-analyses of large trials should include Asianspecific analyses. 6. Need for breast cancer research in Asia While breast cancer mortality has decreased in many European and North American countries,47 mortality rates continue to rise in many Asian countries48 resulting in discrepancies in the ratio of breast cancer mortality versus the incidence, between the Western and Asian settings. Experts have warned that most of the developing nations are ill prepared as they do not have the infrastructure in place to prevent cancer, diagnose the disease in an early stage or provide long-term treatment.49 While some international expert groups such as the Breast Health Global Initiative50 and CanTreat International49 have been lobbying to improve cancer prevention and control in developing countries, Asian governments also need to proactively take actions to combat cancer. Breast cancer should not be regarded as ‘low priority’ to merit the allocation of precious health care dollars.8,51 This would otherwise lead to a vicious cycle where deficient funding leads to inadequate infra-structure with inaccessible cancer diagnostic and therapeutic facilities, lack of manpower (e.g. oncologists, pathologists and epidemiologists) and lack of reliable cancer registration. What is striking in Asia is that less than one in three countries collect data on cancer incidence, and only one in six countries monitor cancer mortality.49 This in return makes knowledge on breast cancer reprehensibly scarce, and causes difficulties in objectively ascertaining the magnitude of the problem in Asia. Cancer registration is therefore vital and what
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is required for it to succeed in Asia, among others include adequate professional staffing, sustainable funding and continuous support from the medical community as well as the policy makers.52 In Asian countries where there is an absence of reliable population based cancer registries, predicting rises of breast cancer incidence based on changes in simple parameters such as total fertility rate and age at first childbirth is not only useful for planning capacity, but may also stimulate the development of high quality cancer registries. In these settings, study findings from well conducted hospital based registries will additionally provide valuable knowledge and insight to aid health care professionals and policy makers, in making strategic plans and taking affirmative actions to improve breast cancer outcomes.
8. Conclusion
7. Asian breast cancer patients living in the Western settings
Conflict of interest statement
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While breast cancer research in Asia is warranted in all domains of medical research, it is felt that for Asian breast cancer patients, needs are highest for diagnostic and prognostic studies. International clinical trials meanwhile need to include breast cancer patients from various Asian settings to provide an insight into the effectiveness of new treatment modalities in this part of the world. Contributors Conception of the study was by N.B., C.U. and H.M.V. All authors contributed in writing, editing and reviewing the manuscript.
None declared. As a result of international migration, an increasing proportion of Asian women are living in Western settings for instance in the United States, United Kingdom, Australia and Western Europe. The incidence of breast cancer among Asian women who migrate to these settings have been reported to escalate with time, approximating the rates of Caucasian women, as they gradually undergo acculturation and adopt a Westernised lifestyle.53,54 This phenomenon firmly supports the contribution of environmental and nongenetic factors in breast carcinogenesis. Some recent evidence show that women of Asian descent who were born in Western settings, may in fact experience a higher risk of breast cancer than Caucasians,55,56 suggesting additional gene–environment interplay. A recent population based study in California highlighted that the Korean, Vietnamese and Chinese women had substantially higher incidence of HER2positive breast cancers compared to the non-Hispanic whites. The incidence of triple negative breast cancers meanwhile was significantly lower in the Chinese and Filipino women compared to the non-Hispanic whites.57 A number of studies have also found that breast cancer screening participation rate is less than optimal among Asian women living in the United States,58 United Kingdom,59 and Australia.60 Interestingly, it has been shown that breast cancer survival in Asian women living in Western countries is higher than that of women of other ethnicities, both in the United Kingdom61 and United States.62 These findings serve to highlight that further research is required in Asian breast cancer patients, as their differences in genetic make-up, health beliefs and behaviours and tumour biology compared to Caucasian women, seem to substantially impact their risk, as well as outcome of breast cancer.
Acknowledgement Nirmala Bhoo Pathy was financially supported by the European Union, AsiaLink programme MY/AsiaLink/ 044 (128-713). This study was supported by a High Impact Research Grant (UM.C/HIR/MOHE/06) from the Ministry of Higher Education, Malaysia. The funders did not play any role in the conception, design or writing of this study. References 1. Editorial. Scaling up cancer diagnosis and treatment in developing countries: what can we learn from the HIV/AIDS epidemic? Ann Oncol 2010;21:680–2. 2. Coughlin SS, Ekwueme DU. Breast cancer as a global health concern. Cancer Epidemiol 2009;33:315–8. 3. Seow A, Duffy SW, McGee MA, Lee J, Lee HP. Breast cancer in Singapore: trends in incidence 1968–1992. Int J Epidemiol 1996;25:40–5. 4. Singapore Cancer Registry. Interim annual registry report. Trends in cancer incidence in Singapore 2006–2010. Available from: http://www.nrdo.gov.sg/uploadedFiles/NRDO/Cancer_Trends_ Report_06-10_final2.pdf. 5. Chia KS, Reilly M, Tan CS, et al. Profound changes in breast cancer incidence may reflect changes into a Westernized lifestyle: a comparative population-based study in Singapore and Sweden. Int J Cancer 2005;113:302–6. 6. Bray F, McCarron P, Parkin DM. The changing global patterns of female breast cancer incidence and mortality. Breast Cancer Res 2004;6:229–39. http://dx.doi.org/10.1186/bcr932. 7. Wong NS, Anderson BO, Khoo KS, et al. Management of HER2-positive breast cancer in Asia: consensus statement from the Asian Oncology Summit 2009. Lancet Oncol 2009;10: 1077–85. 8. Agarwal G, Pradeep PV, Aggarwal A, Yip CH, Cheung PS. Spectrum of breast cancer in Asian women. World J Surg 2007;31:1031–104. 9. Wu AH, Yu MC, Tseng CC, Pike MC. Epidemiology of soy exposures and breast cancer risk. Br J Cancer 2008;98:9–14.
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Available at www.sciencedirect.com
journal homepage: www.ejcancer.info
Review
Breast cancer research in Asia: Adopt or adapt Western knowledge? Nirmala Bhoo-Pathy a,b,c,⇑, Cheng-Har Yip d, Mikael Hartman e, Cuno S.P.M. Uiterwaal c, Beena C.R. Devi f, Petra H.M. Peeters c, Nur Aishah Taib d, Carla H. van Gils c, Helena M. Verkooijen e a
National Clinical Research Centre, Level 3, Dermatology Block, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia Julius Center, Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia c Julius Center for Health Sciences and Primary Care, University Medical Center, PO Box 85500, 3508 GA Utrecht, The Netherlands d Department of Surgery, Faculty of Medicine, University of Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia e Saw Swee Hock School of Public Health, National University of Singapore, MD3, 16 Medical Drive, Singapore 117597, Republic of Singapore f Department of Radiotherapy, Oncology & Palliative Care, Sarawak General Hospital, Jalan Hospital, 93586 Kuching, Sarawak, Malaysia b
Available online 2 October 2012
KEYWORDS Breast cancer Asia Asian Clinical research
The incidence and mortality of breast cancer continues to rise rapidly in Asian countries. However, most of our current knowledge on breast cancer has been generated in Western populations. As the socio-economic profile, life style and culture of Asian and Western women are substantially different, and genetic backgrounds vary to some extent, we need to answer the question on whether to ‘adopt’ or ‘adapt’ Western knowledge before applying it in the Asian setting. It is generally accepted that breast cancer risk factors, which have mainly been studied in Western populations are similar worldwide. However, the presence of gene–environment or gene–gene interactions may alter their importance as causal factors across populations. Diagnostic and prognostic study findings, including breast cancer prediction rules, are increasingly shown to be ‘setting specific’ and must therefore be validated in Asian women before implementing them in clinical care in Asia. Interventional research findings from Caucasian patients may not be applicable in patients in Asia due to differences in tumour biology/profiles, metabolism of drugs and also health beliefs which can influence treatment acceptance and adherence. While breast cancer research in Asia is warranted in all domains of medical research, it is felt that for Asian breast cancer patients, needs are highest for diagnostic and prognostic studies. International clinical trials meanwhile need to include breast cancer patients from various Asian settings to provide an insight into the effectiveness of new treatment modalities in this part of the world. Ó 2012 Elsevier Ltd. All rights reserved. Abstract
⇑ Corresponding author: Address: National Clinical Research Centre, Level 3, Dermatology Block, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia. Tel.: +603 40443060/70. E-mail address: [email protected] (N. Bhoo-Pathy).
0959-8049/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2012.09.014
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1. Introduction In the past few decades, Asia has seen rapid economic growth resulting in increasing life expectancy, declining mortality from communicable diseases and westernisation of lifestyle.1 While these developments are overall beneficial, they come with a price. Breast cancer incidence is rapidly increasing in Asian populations. In China and India, incidence rates have increased by up to 30% over the last 10 years, whereas in Japan, Korea and Singapore, the rates have doubled or even tripled in the past few decades.2 The age-standardised incidence of breast cancer in Singapore, for instance, had increased from 20.2 per 100,000/year between 1968 and 1972,3 to 60.7 per 100,000/year between 2006 and 2010,4 where much of this is attributed to the decline in parity and delayed first childbirth in Singaporean women.5 While the incidence of breast cancer in Asian women is currently still lower than in their Western counterparts across all age groups (Fig. 1),6 the dramatic increase of incidence rates in Asian populations renders it conceivable that in the near future, the majority of breast cancer patients worldwide will be of Asian ethnicity. Most of our current knowledge on breast cancer has been generated from studies conducted in Western populations. Hence, diagnostic and treatment guidelines in Asia are largely based on Western knowledge. For instance, the recent consensus guideline on the management of HER2-positive breast cancer in Asia was based only on studies conducted in non-Asian populations.7
The question is whether we can simply adopt current Western knowledge in Asia, whether we have to adapt it before implementation, or whether we need new evidence. Central to this issue is that Asian women are substantially different from Western women from many perspectives, including genetic background, socio-economic profile, lifestyle, culture and health beliefs, all of which play an important role in breast cancer incidence and prognosis.8 Below, we use some research examples to support our views on which areas require adopted, adapted or de novo Asian breast cancer research. 2. Aetiological breast cancer research While it is generally accepted that the aetiology of breast cancer is similar worldwide, differences in genetic make-up of Asian women may cause different interactions with environmental exposures (e.g. reproductive, dietary), altering their susceptibility to the beneficial or harmful effects of these exposures. A meta-analysis investigating the association between soy intake and breast cancer risk had shown that the protective effect of soy was observed only in women of Asian ethnicity (Asian or Asian Americans), whereas soy intake was unrelated to breast cancer risk in Western women.9 A nested case control study within the Singapore Chinese Health Study cohort revealed that the protective effect of dietary soy isoflavones on postmenopausal breast cancer was restricted to women who were homozygous for the high activity murine double minute 2 (MDM2) allele
Fig. 1. Age-specific breast cancer incidence rates in selected cancer registries. Source: Bray et al.6 (Reproduced with permission from Freddie Bray, International Agency for Research on Cancer).
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(GG genotype).10 Interestingly, it has been previously demonstrated that genetic polymorphisms of MDM2 is a risk factor for breast cancer in Chinese women but not in non-Chinese women.11 Furthermore, the exposure levels or prevalence of established aetiological factors may be different in Asia. Hence, the relevance or (population) attributable risks of certain risk factors may substantially differ between the Western and Asian populations. For instance, alcohol consumption and hormone replacement therapy (HRT) intake have been consistently shown to increase breast cancer risk in Caucasian women.12–14 In Asia, the prevalence of alcohol consumption and use of HRT15 is low and these factors will thus only make a small contribution to breast cancer incidence. Similarly, the importance of genetic risk factors depends not only on the actual relative risk of breast cancer conferred by the marker but also on its allele frequency which is known to vary across population.16 A study assessing 13 single nucleotide polymorphisms associated with breast cancer risk in European populations showed that these genetic markers confer different population risks in Chinese, Malay and Indian populations due to variations in the frequency of the risk alleles.17 There are differences in exposure levels of breast cancer risk factors and in breast cancer specific genetic susceptibilities between Asian and Western women. New Asian aetiologic studies should adopt current knowledge and aim at finding new causes of breast cancer, some of which may be specific for Asian women.
since the incidence of breast cancer among Asian women is still relatively lower than their Western counterparts. Therefore, the implementation of population based screening mammography in Asia has been considered by some as misappropriation of resources, even in high income Asian settings.19 In low and middle income Asian countries, it seems wise to channel available resources to improve breast cancer awareness and encourage women with breast lumps or symptoms to seek treatment.25 In these settings, clinical breast examination (CBE) has been proposed to improve breast cancer detection in treatable stages. For instance, in East Malaysia, the proportion of patients presenting with stage III and stage IV breast cancer was substantially reduced following execution of a training programme for nurses from rural districts in the state of Sarawak between1994 and 1999.26 However, there seems to be a knowledge gap on whether CBE is effective in reducing mortality from breast cancer in Asian patients.27 This is currently being addressed by a large scale randomised trial involving approximately 150,000 women living within the slums of Mumbai, India which aims to determine the efficacy and costeffectiveness of CBE as a screening method to reduce breast cancer mortality in limited resource settings.28 Furthermore, diagnostic breast cancer research in Asian settings is extremely scarce. As this type of research is setting specific,29 this is probably the domain that really requires not adoption but either adaption or new research questions.
3. Diagnostic breast cancer research
4. Prognostic breast cancer research
A large proportion of breast cancer patients in Asia present with advanced stages, and up to 25% percent have distant metastases at initial presentation.18 There have been demands for the introduction of population based mass screening mammography in Asian women over the recent years.19 However, there is little evidence that breast cancer screening via mammography would be effective in the Asian setting.20 In addition to cultural, economic and logistic barriers,21 which are thought to be the reasons for the low participation rates in Asian countries with screening programmes (i.e. Hong Kong, Singapore),19,20 there may be additional problems with mammography as a screening tool. Approximately 50% of Asian women are diagnosed with breast cancer before the age of 50 years,22 suggesting that age limits may need to be adapted. However, the diagnostic performance of mammography is poor in women under the age of 50 years.23 Moreover, Asian women generally have small-volume breasts and relatively dense parenchymal breast tissue which may obscure detection of early and small breast tumours.24 In addition, the positive predictive value of screening mammography is currently expected to be a lot lower in Asia than in the West
Accurate prognostication of breast cancer is crucial as it ensures accurate information for patients, and allows for adequate treatment decisions and risk stratification. Prognostic research findings from Western countries are used in Asian breast cancer patients, in order to predict an individual woman’s disease outcome, which is based on personal as well as disease characteristics, i.e. TNM stage, grade and receptor status. Microarray gene expression based prognostic tests for breast cancer such as Oncotype-Dx30 and Mammaprint31 are steadily gaining popularity in Western oncology practice settings as tools in risk stratification, and selection and optimisation of drug regimens for women with early breast cancer.32 However, in most Asian settings, the above assays are not only economically unfeasible, but their clinical utility remains both unclear, given the higher incidence of oestrogen receptor negative breast cancers22,33 where gene arrays have limited added value, and unproven, given the absence of validation in Asian patients. Since multigene assays are not feasible in most of Asia, web-based prognostication tools such as Adjuvant! Online may be valuable in clinical practice. Adjuvant! Online which was developed in the United States
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based on data from the Surveillance, Epidemiology and End Results registry,34 is also widely used in Europe35,36 and Asia37 as a tool to aid patient counselling and clinical decision making in the management of women with early breast cancer following receipt of loco-regional treatment. However, a recent study conducted in a multiethnic Asian setting found that Adjuvant! Online significantly overestimated survival in Asian breast cancer patients especially in women aged less than 40 years, as well as in patients of Malay ethnicity.38 This study underscores the need to validate Western derived prognostic models in Asian patients, and adapting them to improve their predictive capacity. It may even be necessary to build new ‘Asia-specific’ prediction models using a large cohort of Asian breast cancer patients. 5. Intervention research in breast cancer Interventions and treatments that are developed and shown to be effective in Caucasian populations may not necessarily be effective in Asian women. There are several reasons why findings from clinical intervention trials conducted in Western settings may not apply to Asian populations. The metabolism of anticancer drugs for instance may differ between individuals due to presence of underlying genetic variations.39 A recent review looking at differences in toxicity and clinical outcome following treatment with anticancer drugs highlighted that there may be ethnic differences in tolerability and response to hormonal treatment and cytotoxic chemotherapy in breast cancer suggesting that anti-cancer drugs may be more effective in certain ethnic groups.40 The presence of underlying pharmacogenomic differences in drug metabolism and response,41,42 may also lead to differential tolerance to chemotherapy with higher occurrences of acute toxicities to chemotherapy. In addition, body mass index is also inversely associated with chemotherapy related toxicities.43 In a multicentre international study, Asian breast cancer patients were shown to be significantly more likely to experience grade 3 haematologic toxicities from FEC 100 chemotherapy than their Caucasian, African American and Hispanic counterparts.43 This was however, fully explained by the fact that the Asian patients were significantly less likely to be overweight or obese compared to the nonAsians in this study. Based on the above factors, it is conceivable that the dose intensity/density in Asian patients may be compromised due to lower tolerance to chemotherapy, leading to administration of lower doses of chemotherapy than the recommended dose e.g. the FEC 75 regime.38 Anticancer drugs therefore need to be evaluated in multiethnic Asian populations before claims on the potential benefits of the new treatment can be made. The Korea Food and Drug Administration for instance pay considerable importance to ethnic equivalence in
drug safety and efficacy data generated in Western populations.44 In China, the State Food and Drug Administration requires that local pharmacokinetic studies are conducted in Chinese patients, and a minimum of 100 Chinese patients per intervention arm are included in international Phase III trials, before a new drug gets approval for marketing in China.44 As only five percent of global spending on cancer is in developing countries, most current strategies for breast cancer treatment in affluent Western countries are not applicable in a major part of Asia.45 Poor compliance to (expensive) cancer treatment due to social, financial and cultural factors may also hamper breast cancer outcomes and needs to be taken into account when translating the treatment impact of a particular intervention in Asian patients.46 It is felt that large scale international clinical trials must include a sufficient number of breast cancer patients from different Asian settings to enable appropriate conclusions to be made on the effectiveness of new anticancer therapies in Asians. In instances where recruiting a large number of Asian patients are not feasible, meta-analyses of large trials should include Asianspecific analyses. 6. Need for breast cancer research in Asia While breast cancer mortality has decreased in many European and North American countries,47 mortality rates continue to rise in many Asian countries48 resulting in discrepancies in the ratio of breast cancer mortality versus the incidence, between the Western and Asian settings. Experts have warned that most of the developing nations are ill prepared as they do not have the infrastructure in place to prevent cancer, diagnose the disease in an early stage or provide long-term treatment.49 While some international expert groups such as the Breast Health Global Initiative50 and CanTreat International49 have been lobbying to improve cancer prevention and control in developing countries, Asian governments also need to proactively take actions to combat cancer. Breast cancer should not be regarded as ‘low priority’ to merit the allocation of precious health care dollars.8,51 This would otherwise lead to a vicious cycle where deficient funding leads to inadequate infra-structure with inaccessible cancer diagnostic and therapeutic facilities, lack of manpower (e.g. oncologists, pathologists and epidemiologists) and lack of reliable cancer registration. What is striking in Asia is that less than one in three countries collect data on cancer incidence, and only one in six countries monitor cancer mortality.49 This in return makes knowledge on breast cancer reprehensibly scarce, and causes difficulties in objectively ascertaining the magnitude of the problem in Asia. Cancer registration is therefore vital and what
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is required for it to succeed in Asia, among others include adequate professional staffing, sustainable funding and continuous support from the medical community as well as the policy makers.52 In Asian countries where there is an absence of reliable population based cancer registries, predicting rises of breast cancer incidence based on changes in simple parameters such as total fertility rate and age at first childbirth is not only useful for planning capacity, but may also stimulate the development of high quality cancer registries. In these settings, study findings from well conducted hospital based registries will additionally provide valuable knowledge and insight to aid health care professionals and policy makers, in making strategic plans and taking affirmative actions to improve breast cancer outcomes.
8. Conclusion
7. Asian breast cancer patients living in the Western settings
Conflict of interest statement
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While breast cancer research in Asia is warranted in all domains of medical research, it is felt that for Asian breast cancer patients, needs are highest for diagnostic and prognostic studies. International clinical trials meanwhile need to include breast cancer patients from various Asian settings to provide an insight into the effectiveness of new treatment modalities in this part of the world. Contributors Conception of the study was by N.B., C.U. and H.M.V. All authors contributed in writing, editing and reviewing the manuscript.
None declared. As a result of international migration, an increasing proportion of Asian women are living in Western settings for instance in the United States, United Kingdom, Australia and Western Europe. The incidence of breast cancer among Asian women who migrate to these settings have been reported to escalate with time, approximating the rates of Caucasian women, as they gradually undergo acculturation and adopt a Westernised lifestyle.53,54 This phenomenon firmly supports the contribution of environmental and nongenetic factors in breast carcinogenesis. Some recent evidence show that women of Asian descent who were born in Western settings, may in fact experience a higher risk of breast cancer than Caucasians,55,56 suggesting additional gene–environment interplay. A recent population based study in California highlighted that the Korean, Vietnamese and Chinese women had substantially higher incidence of HER2positive breast cancers compared to the non-Hispanic whites. The incidence of triple negative breast cancers meanwhile was significantly lower in the Chinese and Filipino women compared to the non-Hispanic whites.57 A number of studies have also found that breast cancer screening participation rate is less than optimal among Asian women living in the United States,58 United Kingdom,59 and Australia.60 Interestingly, it has been shown that breast cancer survival in Asian women living in Western countries is higher than that of women of other ethnicities, both in the United Kingdom61 and United States.62 These findings serve to highlight that further research is required in Asian breast cancer patients, as their differences in genetic make-up, health beliefs and behaviours and tumour biology compared to Caucasian women, seem to substantially impact their risk, as well as outcome of breast cancer.
Acknowledgement Nirmala Bhoo Pathy was financially supported by the European Union, AsiaLink programme MY/AsiaLink/ 044 (128-713). This study was supported by a High Impact Research Grant (UM.C/HIR/MOHE/06) from the Ministry of Higher Education, Malaysia. The funders did not play any role in the conception, design or writing of this study. References 1. Editorial. Scaling up cancer diagnosis and treatment in developing countries: what can we learn from the HIV/AIDS epidemic? Ann Oncol 2010;21:680–2. 2. Coughlin SS, Ekwueme DU. Breast cancer as a global health concern. Cancer Epidemiol 2009;33:315–8. 3. Seow A, Duffy SW, McGee MA, Lee J, Lee HP. Breast cancer in Singapore: trends in incidence 1968–1992. Int J Epidemiol 1996;25:40–5. 4. Singapore Cancer Registry. Interim annual registry report. Trends in cancer incidence in Singapore 2006–2010. Available from: http://www.nrdo.gov.sg/uploadedFiles/NRDO/Cancer_Trends_ Report_06-10_final2.pdf. 5. Chia KS, Reilly M, Tan CS, et al. Profound changes in breast cancer incidence may reflect changes into a Westernized lifestyle: a comparative population-based study in Singapore and Sweden. Int J Cancer 2005;113:302–6. 6. Bray F, McCarron P, Parkin DM. The changing global patterns of female breast cancer incidence and mortality. Breast Cancer Res 2004;6:229–39. http://dx.doi.org/10.1186/bcr932. 7. Wong NS, Anderson BO, Khoo KS, et al. Management of HER2-positive breast cancer in Asia: consensus statement from the Asian Oncology Summit 2009. Lancet Oncol 2009;10: 1077–85. 8. Agarwal G, Pradeep PV, Aggarwal A, Yip CH, Cheung PS. Spectrum of breast cancer in Asian women. World J Surg 2007;31:1031–104. 9. Wu AH, Yu MC, Tseng CC, Pike MC. Epidemiology of soy exposures and breast cancer risk. Br J Cancer 2008;98:9–14.
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