|Ahead of print
Association of hormonal and reproductive risk factors with breast cancer in Indian women: A systematic review of case–control studies
Ajeet P Maurya, Swagata Brahmachari
Department of General Surgery, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
|Date of Submission||07-Mar-2021|
|Date of Decision||11-Mar-2021|
|Date of Acceptance||24-Aug-2021|
|Date of Web Publication||12-Oct-2022|
Ajeet P Maurya,
Department of General Surgery, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
The incidence of breast cancer in India has seen a rapid increase in recent years. Hormonal and reproductive risk factors for breast cancer have been affected by socioeconomic development. Studies on breast cancer risk factors in India are limited by the small sample size and specific geographical area. The current systematic review was carried out to assess the association of hormonal and reproductive risk factors with breast cancer in Indian women. A systematic review of MEDLINE, Embase, Scopus, and Cochrane database of systematic reviews were done. Relevant case–control studies published in peer-reviewed indexed journals were analyzed for hormonal risk factors such as age at menarche, menopause, and first childbirth; breastfeeding; abortion; and oral contraceptive pills use. Younger age (<13 years) at menarche was associated with high risk (odds ratio 1.23–3.72). Other hormonal risk factors with strong association were age at first childbirth and menopause, parity, and duration of breastfeeding. Abortion and the use of contraceptive pills did not have a clear association with breast cancer. Hormonal risk factors have a higher association in premenopausal disease and estrogen receptor–positive tumors. There is a strong association between hormonal and reproductive risk factors and breast cancer in Indian women. The protective effect of breastfeeding is related to the cumulative duration of breastfeeding.
Keywords: Breast cancer, breast cancer in India, epidemiology, risk factor
|How to cite this URL:|
Maurya AP, Brahmachari S. Association of hormonal and reproductive risk factors with breast cancer in Indian women: A systematic review of case–control studies. Indian J Cancer [Epub ahead of print] [cited 2022 Dec 2]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=358396
| » Introduction|| |
Breast cancer is the most common form of cancer in Indian women. The incidence of breast cancer has increased in recent years; annual percentage change has increased about 5.8 times, from 0.91% to 5.31% over a period of 1988 to 2012 in Delhi. The change in the incidence is in parallel to the socioeconomic development. The rise in breast cancer incidence has been attributed to the change in living standards, behavioral pattern, and social development indicators of women. Age at menarche, marriage, first childbirth and menopause; total duration of breastfeeding; obesity; age and family history are often described as risk factors. Known risk factors account for only 47% of breast cancer cases. Although risk factors for breast cancer are the same, differences in their distribution and temporal change may explain the variation in the incidence of the disease. The study of the migratory population has shown the effect of local sociocultural practices overweighing the genetic effects. The growth and development of breast tissues are influenced by estrogen and progesterone. Estrogen increases the mammary cell proliferation with an increased risk of replication error.
Indian women are affected early in life by breast cancer in comparison with Western women. Studies evaluating risk factors for breast cancer in Indian women are limited by a lesser number of patients and specific geographical area. Indian population is heterogeneous in economic development and sociocultural practices. The current systematic review was undertaken with the aim of assessing the association of hormonal and reproductive risk factors with breast cancer in Indian women.
| » Materials and Methods|| |
The methodology described in the Cochrane Handbook for Systematic Reviews of Interventions and preferred reporting items for systematic reviews and meta-analysis (PRISMA) were followed. A predefined protocol was developed. Databases such as MEDLINE, Embase, Scopus, and Cochrane database of systematic reviews were searched using specific keywords. The reference list of published studies was also searched. Keywords used were (breast cancer or breast neoplasm or breast health) and (in India, risk factors, epidemiology, causative factors, risk assessment). Data available till 2019 were included. The inclusion criteria for studies were case–control and cohort studies assessing hormonal and reproductive risk factors in the Indian population. Studies published only in peer-reviewed indexed journals were included. Review articles, interventional and observational studies were excluded. Studies assessing risk factors other than hormonal and reproductive factors were also excluded. Only English literature was examined.
The initial search using keywords resulted in 2,156 articles. They were further evaluated based on the abstract and 79 articles about risk factors for breast cancer in Indian women were found. Full-text articles were retrieved and filtered according to the inclusion criteria. There were 39 case–control studies about the hormonal and reproductive risk factors. Two duplicated studies were also excluded. Seventeen articles published in peer-reviewed indexed journals were included for analysis [Figure 1]. A primary search of the literature was done by the first author and was rechecked by the second author.
Risk of bias in included studies
Case–controls studies are retrospective in nature and prone to bias. Date for most of the life events was based on memory and may be affected by recall bias. Most of the studies (14/17) have included hospital-based controls leading to referral bias. Most of the studies have not studied socioeconomic status as a risk factor and also have not specified whether cases and controls were matched with respect to it. Other risk factors such as obesity, nutrition, lifestyle, and genetic factors were not matched leading to confounding bias. Sample size for various risk factors was different, so studies may be underpowered for some of the risk factors. Possible bias in individual studies is listed in [Table 1].
| » Results|| |
A total of 8,405 cases and 9,042 controls were included in the review. The time period of the studies was from 1972 to 2018. Fifteen studies had a case–control ratio of 1:1. Patients of age 20 to 80 years were included. Residential distribution of patients was provided in six studies, and the rural population contributed about 38% to 60%. The mean age of the cases was 45 to 50.8 years. All patients were diagnosed with breast cancer based on cytology or histopathology. The characteristics of included studies are described in [Table 1], and the major findings are shown in [Table 2] and [Table 3].
Age at menarche
Fourteen studies with 7,131 cases and 7,873 controls have studied the effect of age at menarche. There was heterogeneity in data analysis with regard to age at reference. Most of the studies (11 out of 14) reported a higher odds ratio (OR) at a younger age compared with older age at menarche. The odds of developing malignancy in patients achieving menarche at less than 13 years of age varied from 1.23 to 3.72. Two studies with a sample size of 354 found a protective effect of younger age at menarche,, whereas there was no significant difference in one study. Subgroup analysis revealed a protective effect of younger age at menarche in postmenopausal and estrogen receptor–negative women.,
Age at marriage
The effect of age at marriage on breast cancer was measured in 10 studies. Younger age at marriage was protective in all except one study. Women married at the age of 20 to 21 years or more had an OR of 2.52 to 3.8.,, The association of breast cancer and higher age at marriage was stronger in postmenopausal women and estrogen receptor–negative subtype.,
The effect of marital status were was noted in eight studies. The odds of developing breast cancer in unmarried women were 2.0 to 5.6 times. One study reported a higher risk (OR 1.10) in married women.
Age at first childbirth
Fifteen studies measured the effect of age at first childbirth. There was great heterogeneity among studies for age at reference. The odds of developing malignancy increased with increasing age at first childbirth. Women with first childbirth at age 20 to 21 years had an OR of 1.4–2.0 compared with women with first childbirth before age of 20 years. The OR for patients with age at first childbirth more than 25 years was 1.23 to 2.8 compared with women of age less than 25 years, and at age 30 years it ranged 4.18 to 10.5.
Number of pregnancies
All studies commented on the effect of parity. Nulliparous women had a higher risk of malignancy compared with parous women (OR 1.4–6.1); the association was stronger in premenopausal women than in postmenopausal women (OR 4.3 versus 1.5). The protective effect of parity increases with the number of children. OR for women with five children is 0.31 compared with 0.55 for those with three children (women with one child taken as reference).
Eight studies evaluated the effect of abortion on breast cancer. Three studies found a higher risk (OR 2.08–6.2), whereas the other five had a lower risk (OR 0.75–0.85) of malignancy in women with a history of abortion.
Duration of breastfeeding
The total duration of breastfeeding was protective in all relevant studies (13 out of 17). The level of protection was higher with a longer duration of breastfeeding. The protective effect was higher in women with premenopausal disease and estrogen-positive histology. The odds of developing breast cancer were 2.88 times higher in women with a total duration of breastfeeding less than 2 years.
Oral contraceptive pills use
Seven studies reported the effect of oral contraceptive pill (OCP). Four studies found higher odds of malignancy in OCP users (OR 1.97–9.5), whereas three studies demonstrated a protective effect (OR 0.36–0.53) of OCP.
Age at menopause
Nine studies reported the effect of age at menopause. In women achieving menopause at age 50 or above, the risk of breast cancer was higher (OR 1.7–2.68) in seven studies, whereas two studies reported lower risk (OR 0.47 and 0.16). According to menopausal status, the risk of cancer was higher (OR 2.50 and 2.27) in postmenopausal women in two studies, whereas another two studies reported a higher risk (OR 1.2 and 1.6) in premenopausal women.
| » Discussion|| |
Age at menarche is a risk factor for both premenopausal and postmenopausal breast cancer. Delay in menarche by 2 years decreases the risk of breast cancer by 10%. Besides age at menarche, age at onset of regular menses is also important in deciding the risk of malignancy. Earlier onset of ovulatory cycle has been seen in women achieving menarche at a younger age. In the current review, women with menarche at or less than 13 years had a 1.2 to 3 times higher risk of malignancy compared with women achieving menarche at more than 13 years of age. The effect of age at menarche is stronger in premenopausal and hormone receptor–positive breast cancer., Findings in this review were consistent with other reports. In a meta-analysis including 118,964 women with breast cancer, menarche at younger age increased the risk of breast cancer by a factor of 1.050 (95% confidence interval [CI] 1.044–1.057; P < 0·0001) for each year younger at menarche. Earlier menarche increases the risk of breast cancer by increasing the total number of menstrual cycle and the higher level of estradiol in postmenopausal women. The interval between menarche and first childbirth will be longer in women with menarche at younger age leading to a higher risk of breast cancer.
One full-term pregnancy decreases the risk of breast cancer by 25% compared with nulliparous women. The protective effect of parity increases with the number of children; each birth decreases the risk of breast cancer by about 7%. The present review shows that the risk of breast cancer is 1.2 to 2.4 times higher in women with their first full-term pregnancy (FFTP) after the age of 21 years compared with women with their FFTP at or before 21 years. In our study compared with nulliparous women, the odds of developing malignancy were 0.55 and 0.31 for women with three and five children respectively. Early FFTP induces differentiation of lobular epithelium making them less prone to malignancy; studies have also shown changes in specific genomic signatures in lobular epithelial cells of parous women. An analysis of case–control studies has shown odds of 1.07 (95% CI: 1.01–1.13) for breast cancer with each 5-year increase at FFTP.
The effect of abortions, both spontaneous and induced, on the risk of breast cancer is not clear. A meta-analysis showed an increased risk (OR 1.3) following induced abortion. Another study reported 2.4 times increased risk of breast cancer following spontaneous or induced abortion before FFTP. Vessey et al. found no association between breast cancer risk and abortion before FFTP. In the present review, three studies showed higher risk (OR 2.08–6.2), whereas five studies demonstrated a protective effect of abortion (OR 0.75–0.85).
Earlier menopause had a protective effect; a 5-year delay in menopause increases the risk of breast cancer by 17%. Early menopause, whether natural or artificial, has the same protective effect. One study has reported an age-dependent protective effect of artificial menopause and castration before age of 40 years decreased the risk of breast cancer by 75%, and such a protective effect was not seen if artificial menopause happened after age 40 years. In the present review, women achieving menopause at or above 50 years had a higher risk (OR 1.4–2.6) compared with women with menopause before 50 years. A meta-analysis of epidemiological studies has shown an increased risk of breast cancer by a factor of 1.029 (95% CI: 1.025–1.032; P < 0·0001) for each year of delayed menopause.
Age at FFTP is protective of breast cancer, whereas first pregnancy at higher age (>35 years) is associated with a higher risk of breast cancer. Full-term pregnancies have a long-term protective effect, whereas in short term, within 3 years, they may increase the risk of breast cancer. Women with their first childbirth at less than 20 years of age have 50% of breast cancer risk compared with women with their first childbirth at or above 30 years of age. The findings of the current review are consistent with other reports.
The effect of OCP on the risk of breast cancer has been debated. OCPs transiently increase the breast cancer risk in current users (relative risk 1.24 [1.15–1.33]), but there is no residual risk of breast cancer 10 years after cessation of OCP. The present review has mixed results with a higher risk in four studies, whereas a protective effect was seen in the other three studies.
Breastfeeding is a modifiable risk factor. Lactational amenorrhea decreases the number of ovulatory menstrual cycles. One year of lactation results in 8.1 months of anovulation. The magnitude of the protective effect depends on the duration of breastfeeding; some studies have found no association, whereas others with longer duration of breastfeeding showed a protective effect. In the current review, breastfeeding had a protective role, and the protection was higher with a longer duration of breastfeeding.
| » Conclusions|| |
Hormonal and reproductive risk factors have a strong association with breast cancer in Indian women. A consistent association was present for risk factors such as age at menarche, age at first childbirth, and age at menopause. The protective effect of breastfeeding was higher in women with a longer duration of breastfeeding. Abortion and the use of OCPs did not have consistent association with the risk for breast cancer. The effects of hormonal and reproductive risk factors were stronger in women with the premenopausal disease.
There may be selection bias due to the strict inclusion criteria, and also gray literature has not been searched. The current review is also limited by the heterogeneity of data and the use of different age groups as a reference in various studies. The effect of postmenopausal hormonal therapy was not studied in any of the included studies. Individual studies may have a confounding bias as other risk factors were not matched between the cases and controls.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Armstrong K, Eisen A, Weber B. Assessing the risk of breast cancer. N Engl J Med 2000;342:564-71.
Madigan MP, Ziegler RG, Benichou J, Byrne C, Hoover RN. Proportion of breast cancer cases in the United States explained by well-established risk factors. J Natl Cancer Inst 1995;87:1681-5.
Bernstein L, Teal CR, Joslyn S, Wilson J. Ethnicity-related variation in breast cancer risk factors. Cancer 2003;97(1 Suppl):222-9.
Ziegler RG, Hoover RN, Pike MC, Hildesheim A, Nomura AM, West DW, et al
. Migration patterns and breast cancer risk in Asian-American women. J Natl Cancer Inst 1993;85:1819-27.
Yager JD, Davidson NE. Mechanisms of disease: Estrogen carcinogenesis in breast cancer. N Engl J Med 2006;354:270-82.
Antony MP, Surakutty B, Vasu TA, Chisthi M. Risk factors for breast cancer among Indian women: A case-control study. Niger J Clin Pract 2018;21:436-42.
] [Full text]
Babita, Kumar N, Singh M, Malik JS, Kalhan M. Breastfeeding reduces breast cancer risk: A case-control study in North India. Int J Prev Med 2014;5:791-5.
Babita R, Kumar N, Karwasra RK. Reproductive risk factors associated with breast carcinoma in a tertiary care hospital of North India: A case-control study. Indian J Cancer 2014;51:251-5.
] [Full text]
Balasubramaniam SM, Rotti SB, Vivekanandam S. Risk factors of female breast carcinoma: A case control study at Puducherry. Indian J Cancer 2013;50:65-70.
] [Full text]
Bhadoria AS, Kapil U, Sareen N, Singh P. Reproductive factors and breast cancer: A case-control study in tertiary care hospital of North India. Indian J Cancer 2013;50:316-21.
] [Full text]
Gajalakshmi V, Mathew A, Brennan P, Rajan B, Kanimozhi VC, Mathews A, et al
. Breastfeeding and breast cancer risk in India: A multicenter case-control study. Int J Cancer 2009;125:662-5.
Gajalakshmi CK, Shanta V. Risk factors for female breast cancer. A hospital-based case-control study in Madras, India. Acta Oncol 1991;30:569-74.
Jayalekshmi P, Varughese SC, Kalavathi, Nair MK, Jayaprakash V, Gangadharan P, et al
. A nested case-control study of female breast cancer in Karunagappally cohort in Kerala, India. Asian Pac J Cancer Prev 2009;10:241-6.
Lodha R, Joshi A, Paul D, Lodha KM, Nahar N, Shrivastava A, et al
. Association between reproductive factors and breast cancer in an urban set up at central India: A case-control study. Indian J Cancer 2011;48:303-7.
] [Full text]
Singh M, Agrawal A, HR N. Assessment of risk factors of breast cancer among women attending tertiary care hospital of Chattisgarh: A case control study. Indian J Surg 2020. https://doi.org/10.1007/s12262-019-02034-8
Pakseresht S, Ingle GK, Bahadur AK, Ramteke VK, Singh MM, Garg S, et al
. Risk factors with breast cancer among women in Delhi. Indian J Cancer 2009;46:132-8.
] [Full text]
Paymaster JC, Gangadharan P. Some observations on the epidemiology of cancer of the breast in women of Western India. Int J Cancer 1972;10:443-50.
Kamath R, Mahajan KS, Ashok L, Sanal TS. A study on risk factors of breast cancer among patients attending the tertiary care hospital, in Udupi district. Indian J Community Med 2013;38:95-9.
] [Full text]
Aich RK, Mondal NK, Chhatui B, Sepai HM, Aich R, Acharyya A, et al
. Relevance of risk factors of breast cancer in women: An Eastern Indian scenario. J Cancer Res Ther 2016;12:302-8.
Rao D, Ganesh B, Desai P. Role of reproductive factors in breast cancer in a low-risk area: A case-control study. Br J Cancer 1994;70:129-32.
Das S, Sen S, Mukherjee A, Chakraborty D, Mondal PK. Risk factors of breast cancer among women in eastern India: A tertiary hospital based case control study. Asian Pac J Cancer Prev 2012;13:4979-81.
Kour A, Sharma S, Sambyal V. Risk factor analysis for breast cancer in premenopausal and postmenopausal women of Punjab, India. Asian Pac J Cancer Prev 2019;20:3299-304.
Dey S, Boffetta P, Mathews A. Risk factors according to estrogen receptor status of breast cancer patients in Trivandrum, South India. Int J Cancer 2009;125:1663-70.
Hsieh CC, Trichopoulos D, Katsouyanni K, Yuasa S. Age at menarche, age at menopause, height and obesity as risk factors for breast cancer: Associations and interactions in an international case-control study. Int J Cancer 1990;46:796-800.
Henderson BE, Pike MC, Casagrande JT. Breast cancer and the oestrogen window hypothesis. Lancet 1981;2:363-4.
Apter D, Vihko R. Early menarche, a risk factor for breast cancer, indicates early onset of ovulatory cycles. J Clin Endocrinol Metab 1983;57:82-6.
Kelsey JL, Gammon MD, John EM. Reproductive factors and breast cancer. Epidemiol Rev 1993;15:36-47.
Ma H, Bernstein L, Pike MC, Ursin G. Reproductive factors and breast cancer risk according to joint estrogen and progesterone receptor status: A meta-analysis of epidemiological studies. Breast Cancer Res 2006;8:R43.
Collaborative Group on Hormonal Factors in Breast Cancer. Menarche, menopause, and breast cancer risk: Individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol 2012;13:1141-51.
Endogenous Hormones and Breast Cancer Collaborative Group. Circulating sex hormones and breast cancer risk factors in postmenopausal women: Reanalysis of 13 studies. Br J Cancer 2011;105:709-22.
Li CI, Malone KE, Daling JR, Potter JD, Bernstein L, Marchbanks PA, et al
. Timing of menarche and first full-term birth in relation to breast cancer risk. Am J Epidemiol 2008;167:230-9.
Layde PM, Webster LA, Baughman AL, Wingo PA, Rubin GL, Ory HW. The independent associations of parity, age at first full term pregnancy, and duration of breast feeding with the risk of breast cancer. J Clin Epidemiol 1989;42:963-73.
Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and breastfeeding: Collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 2002;360:187-95.
Russo J, Moral R, Balogh GA, Mailo D, Russo IH. The protective role of pregnancy in breast cancer. Breast Cancer Res 2005;7:131-42.
Chie WC, Hsieh C, Newcomb PA, Longnecker MP, Mittendorf R, Greenberg ER, et al
. Age at any full-term pregnancy and breast cancer risk. Am J Epidemiol 2000;151:715-22.
Brind J, Chinchilli VM, Severs WB, Summy-Long J. Induced abortion as an independent risk factor for breast cancer: A comprehensive review and meta-analysis. J Epidemiol Community Health 1996;50:481-96.
Pike MC, Henderson BE, Casagrande JT, Rosario I, Gray GE. Oral contraceptive use and early abortion as risk factors for breast cancer in young women. Br J Cancer 1981;43:72-6.
Vessey MP, McPherson K, Yeates D, Doll R. Oral contraceptive use and abortion before first term pregnancy in relation to breast cancer risk. Br J Cancer 1982;45:327-31.
Key TJ, Verkasalo PK, Banks E. Epidemiology of breast cancer. Lancet Oncol 2001;2:133-40.
Feinleib M. Breast cancer and artificial menopause: A cohort study. J Natl Cancer Inst 1968;41:315-29.
MacMahon B, Cole P, Lin TM, Lowe CR, Mirra AP, Ravnihar B, et al
. Age at first birth and cancer or the breast. A summary of an international study. Bull WHO 1970;43:209-21.
Bruzzi P, Negri E, La Vecchia C, Decarli A, Palli D, Parazzini F, et al
. Short term increase in risk of breast cancer after full term pregnancy. Br Med J 1988;297:1096-8.
Yuan JM, Yu MC, Ross RK, Gao YT, Henderson BE. Risk factors for breast cancer in Chinese women in Shanghai. Cancer Res 1988;48:1949-53.
London SJ, Colditz GA, Stampfer MJ. Lactation and risk of breast cancer in a cohort of US women. Am J Epidemiol 1990;132:17-26.
McTiernan A, Thomas DB. Evidence for a protective effect of lactation on risk of breast cancer in young women. Results from a case-control study. Am J Epidemiol 1986;124:353-8.
[Table 1], [Table 2], [Table 3]