There is a paucity of data regarding Breast cancer (BC) in the developing world. We have previously reported on the BC characteristics from women residing in Africa, the Middle East, Eastern Europe, Mexico, the Caribbean and South America [1]. Here we present the results for the Asian Subcontinent and South East Asia.

The methods and search strategy employed was the same as described in the first paper of this series [1].

A flow diagram (QUROUM statement) outlining the process by which papers were selected for further evaluation is presented in the first manuscript of this series [1].

An overview of the biological features of BC within Pakistan, India and Sri Lanka is presented in Table 1.

This review has shown that females with BC in the developing world have an early peak age at presentation with large and aggressive tumours. Distant metastases are frequently present at the time of diagnosis. Over half the women from the Asian subcontinent have lymph node metastases at first presentation with most cases having either grade two or three tumours. The rise in BC incidence amongst South East Asian countries exceeds that of the western world, with women from Malaysia and Philippines frequently presenting with stage three or four cancer. African women have a higher frequency of triple negative tumours. Over half of Middle Eastern women have lymph node involvement at the time of diagnosis. Despite experiencing a lower incidence compared to the Ashkenazi Jewish population, Palestinian women have poorer five-year survival outcomes. The majority of women from Mexico and South America have stage two or three disease whilst over sixty percent of women from Eastern Europe have either stage one or stage two diseases.

BC has long been considered a disease predominantly affecting affluent nations with the highest incidence rates reported in North America and Western Europe [48,49]. This is thought to be, at least partly, related to a greater prevalence of BC risk factors and the detection of early stage cancer through breast screening programmes [49,50]. Conversely, a lower incidence pattern is reported in developing nations such as those in Asia and Africa [48,49]. This is probably partially related to an under-reporting of cases due to the absence of cancer registries as well as a lower prevalence of risk factors for the development of BC [49,50]. Despite this the majority of BC deaths are reported in developing countries which have a higher mortality-to-incidence ratio [37,48]. For example the incidence to mortality ratio in South East Asia is 0.46 compared to 0.19 in North America [49].

In 2002, there were approximately 1.38 million new cases of BC worldwide and by 2020 this is expected to escalate to 1.7 million [48,51]. Furthermore, a projected 50% increase in BC mortality is anticipated worldwide, however this value is expected to be higher (58%) in developing nations [50]. Increasing life expectancy as well as changes in BC risk factor profile amongst developing nations are thought to contribute to the overall rise in BC incidence in the future.[50]. In urban Shanghai, the incidence of BC has increased by 50% [52]. In Mexico, BC is the leading cause of female cancer death whilst amongst the urban centres of India, it has surpassed cervical cancer as the leading female cancer [12,53]. The impact of ‘westernisation’ whereby a previously unexposed population are exposed to changes in risk profile (cohort effect) may partially be responsible for the increased BC risk observed [54]. Evidence to support this originates from migration studies which show a higher risk of BC in women who had migrated from Japan to Northern America [55]. Furthermore, data from the Shanghai BC study have identified similar hormonal and reproductive risk factors for the development of BC to that observed in the developed world which included earlier age at menarche, nulliparity later age at first live pregnancy and menopause and a lack of breastfeeding to be prevalent amongst affected cases [56,57]. Similar patterns have also been observed in Malaysia and other parts of the developing world [58,59].

The advanced nature of BC in the developing world has largely been attributed to the delays in seeking medical attention [60,61]. The reasons for this are multi factorial and include a lack of breast screening services combined with socioeconomic, cultural and political factors that underpin a propensity for women to present with advanced cancer [61,62]. Thongsuksai et al. had reported that 25% of BC patients from Thailand had waited 12 weeks from the recognition of symptoms before seeking medical advice, with similar patterns of behaviour observed amongst women from Iran (43%), Columbia (20%) and Peru (67%) [63-66]. Fears amongst patients and their families were identified as barriers to preventing timely access to early detection methods in Mexico [67]. Amongst Iranian women, a lack of knowledge regarding the necessity of such visits, fear, negligence, lack of access to physicians, and poverty were cited as the main reasons for delay [64]. The lack of BC education and the presence of other competing causes of morbidity and mortality means the community knowledge of BC is relatively limited [68]. Cultural factors are also influential, with affected cases only presenting to medical services once homeopathic and alternate therapies have been exhausted [25]. For example, Ajekigbe et al. identified preference for prayer houses or spiritual healing homes in 14% of cases with delayed presentation [69]. Errico et al. have shown that some women describe a sense of guilt of bringing “bad genes” into the family and are made to feel isolated by their communities over fears of ‘spreading’ their illness [70]. Women also carry fears over BC treatment. Ajekigbe et al. found that amongst Nigerian women, the most common reason for delayed presentation (45%) was fear of mastectomy with similar reasons identified by women from Pakistan [69,71].

The quality of treatment for BC in the developing world is highly variable. Agarawal et al. has described reoperation rates of up to 40% in certain sites in India following suboptimal surgery [68]. Furthermore, imperfections in pathological reporting of tumours have also been reported [72]. Inadequate tissue fixation has important consequences on the interpretation of hormone receptor status and hence treatment with hormonal type therapies [39]. In addition the ability to offer breast conserving surgery in developing countries is limited by the advanced nature of disease combined with a lack of radiotherapy services. A study from Delhi found only 11% of patients underwent breast conserving surgery due to the lack of radiotherapy services [73]. El Saghir et al. reported a total of 84 radiation therapy centres amongst all Arab countries combined compared to 1875 in the USA, despite the population numbers for the two areas being equivalent (approx 300 million) [74]. Finally, the financial costs also influence a women's decision to proceed with treatment as the costs of clinical visits and treatments have to be self funded.

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 [75]. Gukas et al. reported that only 5% of the Nigerian population were greater than 60 years of age compared to 21% of the British population [76]. Furthermore, the age standardised rate of BC was not higher amongst the Nigerian population. In fact, for both populations the age standardised rate was greater for women above the age of 50 [76]. In addition, it is well known that BC amongst premenopausal women tends to display poorer tumour characteristics [77,78]. Thus the earlier mean peak age at presentation may partially account for the aggressive pattern of cancer observed in much of the developing world.

Although increased parity has typically been associated with reduced risk of BC, Palmer et al. described the ‘dual effect of pregnancy’ and found African American women who had more than four children prior to the age of 45 years had a greater risk of BC and this was associated with a protective effect in women greater than 45 [79]. The role of increased parity (>3 live births) and increased BC risk amongst younger African women (but not white American women) was also noted by Hall et al., although the results were deemed not significant [80]. Okobia et al. found increased parity (>4) carried an overall protective effect in a case control study of 250 Nigerian women with BC where the mean age of cases and controls was 46 and 47 respectively [81]. In contrast, Adebamowo et al. found a significant difference in the mean number of pregnancies in affected cases compared to controls also amongst Nigerian women [59].

A number of studies from Africa and the Middle East report a greater frequency of triple negative tumours. This has previously been related to poor tissue preservation [82]. Uy et al. reported a 10% increase in the number of hormone receptor positive tumours at the Philippines General Hospital after specific tissue fixation procedures were implemented [39]. Adawambabo et al. found no difference between ER/PR receptor status and age of Nigerian BC patients, although Awadelkarim et al. found a mean difference of 12 years between Sudanese and Italian cases positive for ER [60,82]. The Californian BC study showed premenopausal African American women had a greater frequency of basal like tumours (triple negative tumours) compared to non-African American women of any age [83]. Thus the lower frequency of hormone positive receptors reported amongst women living in Africa or other developing countries may reflect a combination of poor tissue fixation, patient age and possible differences in biology.

The aim of this study was to summarise the biological features of BC form developing countries. Due to the amount of detail already presented in this series we did not compare these findings to first world countries. For the same reason we did not elaborate on the management and treatment of BC in developing countries as discussion on this topic can be found elsewhere [50]. There were however some limitations to this report. A number of studies were based on the findings from single institutions within each country's largest city. Thus the BC characteristics of the country were inferred based on the results from a single study which reflect cases that, on average, have the highest standard of living. This is also a limitation of some National Cancer registries as the true BC incidence, mortality and biological characteristics from many of the smaller towns and villages remain largely unknown. As such we have incorporated the findings from World Health Organisation GLOBOCAN database which provides an estimate of BC incidence and mortality around the world including developing countries. One of the limitations that hindered valid comparisons between developing counties related to a lack of standardised reporting of data of BC characteristics. For example, some centres reported on tumour size and cancer stage based on clinical rather than pathological values while not all centres had reported on hormone receptor status. As a consequence some of the outcomes reported in this review were incomplete due to the variability in the data recorded. There are a limited number of studies which have assessed the contribution of genetic mutations to the development of BC within the context of the developing world. The lack of specialised laboratories, genetic reporting services and personnel amongst the developing world renders it difficult to elicit whether true genetic differences exist within ethnic groups. The role of socioeconomic factors is associated with poor prognosis and was not accounted for in this study. Finally, we were only able to review studies and abstracts written in English.

The global BC health initiative group have devised guidelines aimed at risk factor modification, early diagnosis, treatment and management of BC for developing countries [50]. With an increasing lifespan amongst individuals living in the developing world coupled with changes in risk factor profiles such as obesity and child bearing practises, BC incidence rates will continue to climb and a shifting trend from pre to post menopausal BC may occur [50,54]. Mammography remains the gold standard for early detection of BC [84]. However, the cost of establishing and maintaining such a programme may not be feasible in much of the developing world. Furthermore, mammography screening amongst pre menopausal women and the associated risks of high false positive tests would impose difficulties amongst developing countries. While alternative screening approaches such as self breast examinations have not been shown to reduce mortality in two randomised trials, the use of clinically trained professionals in performing clinical breast examinations in Egypt and India has shown encouraging results [85-89]. The importance of educating women of the symptoms, risk factors as well as addressing perceptions/misconceptions in a culturally sensitive manner remains essential [90].

BC in the developing world is characterised by an early peak age of onset with aggressive biological characteristics. There are a limited number of detailed studies in this field with significant variability of outcomes reported. Further research into the molecular and biological features as well as genetic determinants into BC development is certainly warranted. Importantly, public health initiatives that improve BC awareness address amenable risk factors and allow for the early detection of BC will be essential in addressing the outcome inequalities that currently exist.