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.[ 1 ] 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 .[ 2 ] Known risk factors account for only 47% of breast cancer cases.[ 3 ] 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.[ 4 ] The study of the migratory population has shown the effect of local sociocultural practices overweighing the genetic effects.[ 5 ] 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.[ 6 ]
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.
Figure 1: Flow diagram showing selection of studies
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 .
Table 1: Characteristics of studies
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 Tables 2 and 3 .
Table 2: Hormonal risk factors
Table 3: Reproductive risk factors
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,[ 12 , 17 ] whereas there was no significant difference in one study.[ 18 ] Subgroup analysis revealed a protective effect of younger age at menarche in postmenopausal and estrogen receptor–negative women.[ 11 , 22 ]
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.[ 19 ] Women married at the age of 20 to 21 years or more had an OR of 2.52 to 3.8.[ 8 , 9 , 11 ] The association of breast cancer and higher age at marriage was stronger in postmenopausal women and estrogen receptor–negative subtype.[ 11 , 22 ]
Marital status
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.[ 12 ]
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).
Abortion
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%.[ 25 ] Besides age at menarche, age at onset of regular menses is also important in deciding the risk of malignancy.[ 26 ] Earlier onset of ovulatory cycle has been seen in women achieving menarche at a younger age.[ 27 ] 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 .[ 28 , 29 ] 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.[ 30 ] 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.[ 31 ] 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 .[ 32 ]
One full-term pregnancy decreases the risk of breast cancer by 25% compared with nulliparous women.[ 33 ] The protective effect of parity increases with the number of children; each birth decreases the risk of breast cancer by about 7%.[ 34 ] 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.[ 35 ] 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.[ 36 ]
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.[ 37 ] Another study reported 2.4 times increased risk of breast cancer following spontaneous or induced abortion before FFTP.[ 38 ] Vessey et al .[ 39 ] 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.[ 40 ] 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.[ 41 ] 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.[ 30 ]
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 .[ 42 ] Full-term pregnancies have a long-term protective effect, whereas in short term, within 3 years, they may increase the risk of breast cancer .[ 43 ] 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.[ 42 ] 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.[ 34 ] 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.[ 44 ] The magnitude of the protective effect depends on the duration of breastfeeding; some studies have found no association,[ 45 ] whereas others with longer duration of breastfeeding showed a protective effect.[ 46 ] 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.
Limitations
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
Nil.
Conflicts of interest
There are no conflicts of interest.
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