Epidemiology of breast cancer in Indian women

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1 Asia-Pacific Journal of Clinical Oncology 2017; 13: doi: /ajco REVIEW ARTICLE Epidemiology of breast cancer in Indian women Shreshtha MALVIA, 1 Sarangadhara Appalaraju BAGADI, 1 Uma S. DUBEY 2 and Sunita SAXENA 1 1 National Institute of Pathology (ICMR), Safdarjung Hospital Campus, New Delhi 2 Birla institute of Technology, Pilani, Rajasthan, India Abstract Breast cancer has ranked number one cancer among Indian females with age adjusted rate as high as 25.8 per 100,000 women and mortality 12.7 per 100,000 women. Data reports from various latest national cancer registries were compared for incidence, mortality rates. The age adjusted incidence rate of carcinoma of the breast was found as high as 41 per 100,000 women for Delhi, followed by Chennai (37.9), Bangalore (34.4) and Thiruvananthapuram District (33.7). A statistically significant increase in age adjusted rate over time ( ) in all the PBCRs namely Bangalore (annual percentage change: 2.84%), Barshi (1.87%), Bhopal (2.00%), Chennai (2.44%), Delhi (1.44%) and Mumbai (1.42%) was observed. Mortality-to-incidence ratio was found to be as high as 66 in rural registries whereas as low as 8 in urban registries. Besides this young age has been found as a major risk factor for breast cancer in Indian women. Breast cancer projection for India during time periods 2020 suggests the number to go as high as Better health awareness and availability of breast cancer screening programmes and treatment facilities would cause a favorable and positive clinical picture in the country. Key words: breast, cancer, early age, India, PBCR, trends INTRODUCTION Breast cancer is the most common female cancer worldwide representing nearly a quarter (25%) of all cancers with an estimated 1.67 million new cancer cases diagnosed in Women from less developed regions ( cases) have slightly more number of cases compared to more developed ( ) regions. 1 In India, although age adjusted incidence rate of breast cancer is lower (25.8 per ) than United Kingdom (95 per ) but mortality is at par (12.7 vs 17.1 per ) with United Kingdom. 2 There is a significant increase in the incidence and cancer-associated morbidity and mortality in Indian subcontinent as described in global and Indian studies. 3 7 Earlier cervical cancer was most common cancer in Indian woman but now the incidence of breast cancer has surpassed cervical cancer and Correspondence: Dr Sunita Saxena, Director Scientist-G, National Institute of Pathology (Indian Council of Medical Research), Safdarjung Hospital Campus, New Delhi , India. sunita_saxena@yahoo.com Accepted for publication 3 December First published 9 February 2017 is leading cause of cancer death, although cervical cancer still remains most common in rural India. 8 To plan and formulate sound cancer control strategies based on scientific and empirical bases, authorities and policy makers need correct and complete knowledge of epidemiology. Although many epidemiologic studies have been conducted previously in cancers as prostate, gastric, oral including breast cancer 9 12 but this systematic review was conducted from evidences available on epidemiologic correlates of breast cancer addressing incidence, prevalence, and associated factors like age, time trends and other risk factors to understand disease burden and pattern in India. The objective of this review article is to bring together the information scattered in different Indian registries and studies to see a broader picture of breast cancer epidemiology in Indian subcontinent. METHODS Multiple sources from literature were used for gathering information and analysis of breast cancer. Information on crude rate (CR) and age adjusted rate (AAR) per 100,000 population was collected from National

2 290 S Malvia et al Table 1 Ranking and rates for breast cancer Breast % R CR per AAR φ per Mumbai Bangalore Chennai Thiruvanantha puram Dibrugarh New Delhi Barshi Rural Relative proportion. Rank. Crude rate. φ Age adjusted rate. Cancer Registry Program reports and twenty-five population-based cancer registries (PBCRs) across India (Bangalore, Barshi rural and expanded, Bhopal, Chennai, Delhi, Mumbai, Ahmedabad rural and urban, Aurangabad, Thiruvananthpuram) including North-East states (Cachar District, Aizawl District, Dibrugarh District, Kamrup Urban District, Manipur State, Mizoram State, Imphal). 13 National Cancer Registry Program reports on time trends in cancer incidence rates ( ) from 13 PBCRs (Bangalore, Bhopal, Chennai, Delhi, Mumbai, Barshi, Thiruvananthapuram, Dibrugarh, Kamrup Urban District, Imphal West District, Ahmedabad Rural District and the states of Mizoram and Sikkim) were also used for projection of annual percentage change (APC) in burden of breast cancer. Besides many review articles were also screened for the filtering out of the data regarding epidemiology of breast cancer in Indian women. Burden of breast cancer in Indian population According to Globocan 2012, India along with United States and China collectively accounts for almost one third of the global breast cancer burden. India is facing challenging situation due to 11.54% increases in incidence and 13.82% increase in mortality due to breast cancer during ,14 The main reasons for this observed hike in mortality is due to lack of inadequate breast cancer screening, diagnosis of disease at advanced stage and unavailability of appropriate medical facilities. Breast cancer attains top rank even in individual registries (Mumbai, Bangalore, Chennai, New Delhi and Dibrugarh) in females during the period of (Table 1). The relative proportion of breast cancer in different registries varied from 30.7% in Chennai to 19% in Dibrugarh (Table 1). 13 Increasing urbanization and westernization associated with changing lifestyle and food habits has lead breast cancer to attain top position in all major urban registries, whereas in Barshi rural registry still cervical cancer is at top position in females and cancer of breast holds second position. Breast cancer crude rate (CR) among different registries showed highest rate in Thiruvananthapuram 43.9 (per ) followed by Chennai (40.6), New Delhi (34.8) and Mumbai (33.6). Among all the PBCR s top four places were occupied by Delhi with AAR 41.0 (per 100,000), Chennai 37.9, Bangalore 34.4 and Thiruvananthapuram District 33.7 (Table 1 and Fig. S1). A total district wise minimum age adjusted incidence rate per for India is shown in Fig. S2. AAR more than 20 per has been reported for districts Chandigarh (39.5), Panchkula (34.6), Aizwal (36.2) and Goa (36.8). 13 Mortality/incidence ratio (MIR) is another novel measure to evaluate cancer mortality in relation to incidence. It is used to identify whether a region has a higher mortality than might be expected based on its incidence. Barshi rural has MIR as high as 66.3 projecting a very high mortality rate inspite of low incidence of breast cancer in rural India (Table S1). 13 However, Delhi registry had a low MIR of 8.0 despite having high incidence (28.6%), possibly due to high literacy, more awareness and availability of better medical facilities in metropolitan cities. 13 In rural areas, cancer patients are diagnosed at late or advanced stages of disease with a higher proportion of them having widespread metastasis suggesting for need of more attention in terms of awareness, treatment and facilities for early diagnosis. Agewise breast cancer trends The survey carried out by Indian Council of Medical Research (ICMR) in the metropolitan cities during 1982 to 2005 has shown that incidence of breast cancer has almost doubled. 5 Indian women having breast cancer are found a decade younger in comparison to western women suggesting that breast cancer occurs at a younger premenopausal age in India Cancers in the young tend to be more aggressive. Studies from various registries have revealed increasing AAR for the breast cancer patients with age intervals (viz , 35 44, 45 54, 55 64, and >64 years). The youngest age group consisting of years had an APC of 4.24%, 1.60% and 0.80% in Nagpur, Mumbai and Chennai, respectively. For age group, the APC ranged from 0.37% to 2.97% in these registries. However, oldest age group comprising of patients >64 years, the APC ranged from 0.53% to Asia-Pac J Clin Oncol 2017; 13:

3 Breast cancer epidemiology 291 Figure 1 Trends for 5-year age distribution among different Indian registries. (Adapted from NCRP ). [Colour figure can be viewed at wileyonlinelibrary.com] 2.64%. 19 Studies suggest that the disease peaks at years in Indian women. 20 Many of these cancers are HER2 positive and ER/PR negative, or HER2/ER/PR all three negative, and have a poor prognosis. Trends for 5-year age distribution among different registries showed a peak relative proportion between 45 and 49 years in all registries except in north eastern registries where the peak is seen in even 10-year younger age group (Fig. 1). 21 In India, majority of patients present at locally advanced or at metastatic stages at the time of diagnosis. According to various studies, majority of carcinoma breast cases in the west report in stages I and II of disease, whereas in India 45.7% report in advanced stages. 18,22 Disease presentation in such conditions results in increased mortality in India. Data from UK cancer registry showed an increasing trend for breast cancer from age 30 to 35 achieving highest peak during age years (Fig. 2), suggesting that an average woman in India under the age of 40 has a considerably higher chance of developing the disease unlike United Kingdom. 21 Risk factors Several studies have reported association of various risk factors with breast cancer in Indian women. Women from north India has revealed strong association of risk factors like breast-feeding, location (urban/rural) and increased BMIwithbreastcancer(P < 0.05). 23 Increased breastfeeding and physical activity were in general protective for both ER + and ER breast cancer. 24 Lifetime duration Figure 2 Trends for age distribution among UK cancer registry. (Adapted from Cancer Research UK). [Colour figure can be viewed at wileyonlinelibrary.com] of breastfeeding was inversely associated with breast cancer risk among premenopausal women. 25 Living in rural areas decreases the risk for breast carcinoma as compared to urban counterparts mainly due their adherence to rural lifestyle. 26 Waist-to-hip ratio of 0.95 compared to ratio 0.84 was found strongly associated with risk of BC in both rural and urban populations (OR urban = 4.10, 95% CI, ; OR rural = 3.01, 95% CI, ). 27 Though increased anthropometric measures like larger body size and obesity determines breast cancer risk in India however it does not contribute appreciably to the urban rural breast cancer differences. 28 Western and South India females faced increased risk with Asia-Pac J Clin Oncol 2017; 13:

4 292 S Malvia et al increasing age, low parity (three or more pregnancies getting associated with a 40 50% reduction in risk (P < 0.01) and obesity Household activities also played a role among urban and rural women in the development of BC. The more time spent on household activities further reduced the breast cancer risk. It was found that ORs for 5 6 h activity/day was 0.48 (95% CI, ) in premenopausal and 0.49 (95% CI, ) in postmenopausal women compared to ORs for 6 or more hours/day which was found to be 0.70 (95% CI, ) and 0.51 (95% CI, ), respectively. 32 Women who were unmarried (OR = 3.31; 95% CI, ), widowed/ divorced (OR = 1.46; 95% CI, ), with lower education (OR = 2.72; 95% CI, for illiterate women and OR = 2.32; 95% CI, for women with primary school education and OR = 2.07; 95% CI, for women with middle school education) and postmenopausal women (OR = 1.45; 95% CI, ) possessed elevated risks for the disease and presented themselves at late stages. 33 Breast cancer ranks top in north east India and has significant association with the factors as betel quid and tobacco chewing habits (P = 0.003), number of children (P = 0.080), age at marriage (P = 0.014), age at first child birth (P = 0.007), age at menarche (P = 0.010) Women menstruating at age <12 years have increased risk of developing breast than those mensurating above 12 years. Similarly, women achieving menopause after 55 years have increased risk since their longer period of menstruation leads them to higher lifetime exposure of hormones estrogen and progesterone. 19,37 Although the probability of developing breast cancer rises with increasing age, but in India incidence of breast cancer is increasing in younger people. 20 Early-onset breast cancer tends to be more aggressive than late-onset, with higher stage and grade at presentation with more estrogen receptornegative or triple-negative subtypes. 38 Young females below 40 years have more denser breast tissue which makes them less amenable to routine screening programs making women in this age group more likely to present with a palpable mass with a tumor which tends to be larger and are more likely to have nodal involvement at the time of presentation. 16,39 Younger aged patients tends to be triple negative which is a significant poor prognostic factor. 40 Prevalence of TNBC in India is considerably higher compared with that seen in Western populations as suggested by various meta-analysis studies. 41,42 TNBC tumors are significantly larger with majority of patients presenting as locally advanced stage breast cancer which is histologically more aggressive (grade 3) compared to other groups. 43,44 Survival studies have revealed the fact that two-third of patients at time of disease presentation are in advanced-stage which account for the poor overall survival. 45 Environmental compounds and their exposure also increase breast cancer risk as India is topmost polycyclic aromatic hydrocarbons PAH emitting countries. PAHs are lipophilic (fat-seeking) and are stored in the fat tissue of the breast and they interact with the cellular estrogen receptor In 5% of breast cancer cases, there is a strong inherited familial risk. Genetic factors play a major role in promoting breast cancer like mutations in BRCA1, BRCA2 gene inherited from parents. 49 The frequency of BRCA1/2 genetic mutations was reported in many studies to range from 2.9% to 24.0% among Indian familial breast cancer patients. 50 Furthermore, 2.8% of early-onset breast cancer patients in the Indian population were found to have BRCA1/2 mutations. Notably, the occurrence rates of BRCA2 mutations were lower than those of BRCA1 in India. 51 Although most of studies have shown distinct sequence variants both in BRCA1 and BRCA2, some of them being unique to Indian population however 185delAG founder mutation reported in Ashkenazi Jews has been reported by many Indian studies. 49,52 55 Other gene mutations like ATM, TP53, CHEK2, PTEN, CDH11 and STK11 are also associated with breast cancer Community level breast cancer survey was also conducted which highlighted the fact that 53.4% women were aware about various aspects of breast cancer while 49.1% women believed that breast cancer was incurable. 40.5% women had higher awareness, which was associated with socioeconomic status. 59 Time trends of various cancer registries Study on time trends for incidence of breast cancer over three decades from 1982 to 2012 form six major PBCRs showed statistically significant increase in AARs per 100,00 over time (Fig. 3). The AARs of breast cancer in five PBCRs Bangalore, Barshi, Bhopal, Chennai, Delhi and Mumbai are mentioned in Table S2(a) for each calendar year with statistical significance measured using slope and p-value based on simple linear regression. The AARs for breast cancer showed almost consistent increase over the time ( ) for all PBRCs. Joinpoint Regression Model Graphs has also been depicted for the same registries. A statistically significant increase in AARs over time in PBCRs namely Bangalore (APC: 2.84%), Barshi (1.87%), Bhopal (2.00%), Chennai (2.44%), Delhi (1.44%) and Mumbai (1.42%) was observed (Table S2(b)). 13 All the PBCRs except Barshi showed a significant increase for annual average of AARs for both 3 and 5 years. Barshi showed an increase in only Asia-Pac J Clin Oncol 2017; 13:

5 Breast cancer epidemiology 293 Figure 3 Five-year trends of breast cancer among registries. (Adapted from NCRP ). [Colour figure can be viewed at wileyonlinelibrary.com] 3 years trend (Table S2(a)). 13 Initial APC for Bhopal was 1.35% for years , which rose to 5.64% for the period of Similarly, initial APC for Chennai was 1.51% for , which rose to 2.83% for the period For Delhi, the initial APC was 0.91% for period , which hiked to 5.31% for the period (Table S2(b)). 13 Projection of burden of breast cancer Cancer projections are useful especially in a developing country like India, where there is an urgent need to plan and prioritize health care services including both diagnostic and treatment facilities. Breast cancer projection for India during time periods 2020 suggests the number to go as high as with its approximately relative percentage remaining same 10% among all the cancers. 13 CONCLUSION Breast cancer is the major cause of morbidity and mortality among females ranking number one among females in Indian metropolitan cities like Delhi, Kolkatta, Pune and Thi puram, Bangalore and Mumbai and in Northeast, whereas in rural areas such as Barshi it still hold a second position. Epidemiology of breast cancer across different PBCRs in India shows increasing trends for incidence and mortality mainly due to rapid urbanization, industrialization, population growth and ageing affecting almost all parts of India. Factors as marital status, location (urban/rural), BMI, breast feeding, waist to hip ratio, low parity, obesity, alcohol consumption, tobacco chewing, smoking, lack of exercise, diet, environmental factors were major risk factors in India leading to increasing incidence cancer; however, the reason for high incidence of breast cancer in younger women are not well known. Delayed disease presentation due to illiteracy, lack of awareness, financial constrains in some regions of India leads to late diagnosis, which in turn increases mortality rate. Lack of organized breast cancer screening program, paucity of diagnostic aids, and general indifference toward the health of females in the predominantly patriarchal Indian society are also the drawbacks leading to increased breast cancer incidence. Hence majority of patients here are still treated at locally advanced and metastatic stages. A multidisciplinary approach to breast cancer including awareness programs, preventive measure, screening programs for early detection and availability of treatment facilities are vital for reducing both incidence and mortality of breast cancer in Indian women. The cancer projection data shows that the number of cases will become almost double by The projections of cancer incidence shows an urgent need for strengthening and augmenting the existing diagnostic/treatment facilities, which is inadequate and unable to handle the current load of cancer in India. REFERENCES 1 Ferlay J, Soerjomataram I, Dikshit R et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN Int J Cancer 2015; 136: E Gupta A, Shridhar K, Dhillon PK. A review of breast cancer awareness among women in India: cancer literate or awareness deficit? Eur J Cancer 2015; 51: Porter PL. Global trends in breast cancer incidence and mortality. Salud Pública de México 2009; 51: s141 s46. Asia-Pac J Clin Oncol 2017; 13:

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