Abstract
Purpose
Breast cancer (BC) is increasing in black South African women, but few studies have investigated its risk factors.
Methods
We conducted an analysis of reproductive factors and BC risk in the South African Breast Cancer (SABC) study—a population-based case–control study of black South African women from Soweto that included 399 cases and 399 matched controls. Information on lifestyle and reproductive history was obtained by interviews. Conditional logistic regression was used to determine the association of reproductive factors with BC, adjusting for potential confounding factors.
Results
Seventy-five percent of all BC cases were ER+, 66% PR+, 30% HER2+, and 16% TN. None of the reproductive variables were associated with BC overall or by subtype in the overall population, nor in pre- (n = 135 cases) or in post-menopausal women separately. In HIV-negative pre-menopausal women (n = 97 cases), later age at first pregnancy and longer time between menarche and first full-time pregnancy were inversely related to BC risk (OR 0.89 (95% CI 0.82–0.97; and 0.93 95% CI 0.86–1.01, respectively).
Conclusion
In this population of black South African women, reproductive factors were not associated with BC risk.
Keywords: Breast cancer, Black South African women, Reproductive factors
Introduction
Breast cancer is the most common incident cancer in South African women, outnumbering cancer of the cervix uterus, with an age-standardized rate of 49 per 100,000 women and a mortality rate of 16.3 per 100.000 in 2018, corresponding to 14,097 new cases (15.4% of all cancer) and 4690 deaths. This burden is projected to double by 2030 [1].
The South African population is currently undergoing significant transitions in terms of reproductive and lifestyle factors, especially in expanding urban areas [2]. Secular trends in breast cancer risk factors are evident, including decreasing age at menarche and lower number of children [3]
It has been suggested that breast cancer in African women has a different epidemiology and etiology compared to Caucasian women, being characterized by excessive numbers of young cases (beyond that expected from a younger age distribution), and a higher proportion of triple-negative receptor tumours in both US-born women of African ancestry and African-born women [4]. Whether histological differences are real is still under debate; doubts have been raised over the quality of tumor samples and testing in some studies, related to suboptimal tissue preparation and different laboratory processing practices [5]. An in-depth knowledge of molecular and pathological characteristics of breast cancer in South African women is lacking, with major consequences for cancer treatment and survival.
Reproductive factors, including age at menarche, age at first birth, parity, and menopause have among the strongest and most consistent associations with breast cancer risk [6]. Higher parity is known to be protective for breast cancer at all ages. However, previous studies conducted in US-born women of African ancestry have shown differential results according to breast tumor characteristics. For example, it has been shown that higher parity is associated with lower risk of estrogen-receptor positive (ER+), but higher risk of estrogen-receptor negative (ER-) breast cancer, and that breastfeeding could reduce the risk of ER- disease associated with increased parity [7]. The effects of younger age at first birth and parity are less consistent in women diagnosed with breast cancer at younger ages (< 40 years). Also, a transient increase in the risk of breast cancer has been observed just after giving birth in some studies [8, 9].
To obtain insights into the role of reproductive factors in breast cancer etiology among South African women, we conducted an analysis within the South African Breast Cancer Study (SABC)—a population-based case–control study on breast cancer in black South African women living in Soweto.
Methods
The SABC study [10, 11] is a population-based breast cancer case–control study conducted in black South African women in Soweto, Johannesburg, home to a high-density black urban population. Women with breast cancer were recruited at the Breast Unit of the Chris Hani Baragwanath Hospital (CHBH, led by co-PI Dr Cubasch) between 2014 and 2017. The protocol was approved by the CHBH and the University of the Witwatersrand institutional review boards and by the International Agency for Research on Cancer (IARC) ethics committee.
Eligible cases were the following: (1) black South African women of any age and ethnicity; (2) with histologically confirmed (biopsy-positive) incident cases of invasive primary breast cancer, diagnosed at the CHBH Breast Clinic, with TNM clinical staging; (3) able to participate and provide bio-specimens prior to the start of any treatment; and (4) able to decide whether to provide signed informed consent. Cases were invited to participate at referral for diagnostic biopsy, and failing that, as soon as possible after diagnosis. Reasons for refusal were recorded. Cases were recruited before the start of any therapies.
Controls were recruited using a multistep sampling procedure from the areas of residency of the cases and matched on age (± 5 years) and place of residence.
Cases and controls were given an information sheet, available in English, Sotho, Xhosa, and Zulu, describing the study and what participation entailed (interview, providing blood and urine samples) before being asked to provide written informed consent. Participants were provided with 150 Rands per visit as required by the Medicine Regulatory Authority of South Africa, the Medicines Control Council, to cover transport, refreshment, and lost hours of work taken off for the study.
Data collection
Face-to-face interviews and sample collection were conducted at the research study office within CHBH by trained health staff using standardized procedures. Trained nurses administered lifestyle and quantified food frequency questionnaires (QFFQ), conducted anthropometric measurements (weight, waist circumference (WC), hip circumference (HC), and sitting height, dual energy X-ray absorptiometry—DEXA), according to standardized procedures, and collected biological samples (blood and spot urine samples).
The lifestyle questionnaires included information on socio-economic status (SES) during infancy and early childhood (based on parental education and occupation, place of residency and type of housing during childhood), health and reproductive history, history of benign breast disease (BBD), smoking habits, alcohol intake, body mass index (BMI) at age 18 years, body silhouette at different ages, physical activity (household and recreational), and sedentary hours (e.g., TV watching), ethnicity, and family history of cancer. The QFFQ and physical activity questionnaire were based on a modification of previously used methods implemented in the Transition and Health during Urbanisation of South Africa (THUSA), a cross-sectional study of lifestyle and diet in 1,850 adults [3, 12]
Reproductive history and determination of menopausal status
Information on age at menarche, cycle irregularity, pregnancy, number of births, age at each birth, breastfeeding, age at menopause, and hormone use (e.g., oral contraceptive (OC) use and hormone replacement therapy (HRT) use) were collected. Women were considered pre-menopausal if they answer “no” to the following question “Have you stopped having your period/menstrual cycle for more than 12 months in the last 2 years” and were considered post-menopausal otherwise. Additional questions were asked about the natural or surgical causes of menopause. If the information about menopausal status was missing (n = 24), we defined women’s menopausal status by using a conservative mean age 52 years. Overall, 20 women were defined as missing menopausal status.
Pathology review and immunohistochemical analyses
Formalin-fixed paraffin-embedded sections including breast core biopsies, or sections from tumor resection specimens before any treatment were selected in cases that underwent primary surgery. Immunohistochemical stains were performed for estrogen receptors (SP1, Roche Diagnostic Ventana, USA), progesterone receptors (IE2, Roche Diagnostic Ventana, USA), HER2 (4B5, Roche Diagnostic Ventana, USA), and Ki67 (30–9, Roche Diagnostic Ventana, USA) according to standardized and optimized protocols. All analyses were conducted at the National Health Laboratory Service, CHBH. Positivity for estrogen and progesterone receptor immunostaining was classified according to Allred scores [13]. HER2 membrane immunostaining 3+ was considered positive or a positive FISH result in cases with 2+ (equivocal) on immunohistochemistry. HER2 0–1+ was regarded as negative.
Statistical analyses
Descriptive statistics (mean/standard deviations (SD) and proportions) were calculated overall and stratified by menopausal status, and tumor subtypes considering ER+, ER−, and triple-negative (TN) tumor classification. Conditional logistic regression was used to calculate odds ratio and 95% CI for the association of reproductive factors including age at menarche (continuous), pregnancy ever (yes, no), age at first full-term pregnancy (continuous), time between menarche and first full-term pregnancy (continuous), parity (ordinal), breastfeeding ever (yes, no), and duration of breastfeeding (continuous, months).
Matching variables included: age (± 5 years), and place of residence. Stratified analyses were conducted by HIV- status at recruitment (positive/negative), menopausal status, ER+ and ER, and triple-negative tumors and compared to controls groups. Age at recruitment, HIV-status, ethnicity (Zulu/Pedi/Swazi, Xhosa, Sotho, Tshwane, Venda, Tsonga and Ndebele), individual income (R1–R3000, R3001–R6000 and R6001+), level of education (none/primary school, high school and college/post-graduate/diploma), smoking (ever smokers vs never smokers), waist circumference (continuous), BMI (continuous), and habitual physical activity/day (active = “Intense physical activity at least once a week one year ago” or less active), were tested as potential confounding factors. Our final multivariate models included all factors that changed our risk estimate by more than 10% (age at recruitment, menopausal status, HIV-status, education, ethnicity, BMI, physical activity and smoking). All analyses were also conducted separately in HIV-negative women, excluding HIV + women at recruitment (66 cases and 90 controls), using unconditional logistic regression analyses, adjusted by age, place of residence, and menopausal status. Final multivariate models included age at recruitment, menopausal status, place of residence, education, income, ethnicity, BMI, physical activity and smoking). All statistical analyses were performed using 9.4 version of SAS software.
Results
The median age at recruitment was 54 years for the cases (10–90% 39–73) and 54 years (10–90% 39–74) for the controls (Table 1). Thirty-four percent of the cases and 34% of the controls were pre-menopausal women at recruitment. Sixteen percent of the cases and 23% of the controls were HIV-positive, and these proportions were higher in pre-menopausal than in post-menopausal women. The distribution of breast cancer characteristics is presented in Table 1. Seventy-five percent (n = 300) of all cases were ER+, 65% (n = 263) were progesterone receptor positive (PR+), 30% (n = 114) were HER2+ (irrespective of ER/PR status), and 16% (n = 65) were triple-negative. Pre-menopausal women were more likely to have PR+ tumors than post-menopausal women (p = 0.007 for PR+). No significant difference was observed between pre- and post-menopausal women for ER+, HER2+ and TN (p = 0.17, p = 0.15 and p = 0.24, respectively) (Table 1).
Table 1.
Characteristics of the study population, overall and by menopausal status
| All¥ | Pre-menopausal women¥ | Post-menopausal women¥ | ||||
|---|---|---|---|---|---|---|
| Cases (n = 399) | Controls (n = 399) | Cases (n = 135) | Controls (n = 136) | Cases (n = 249) | Controls (n = 258) | |
| Age at recruitment (years) | 54 (39–73) | 54 (39–74) | 42 (34–46) | 42 (33–47) | 62 (49–76) | 61 (51–76) |
| HIV positivity | 16.5% | 22.6% | 28.2% | 38.2% | 9.6% | 14.0% |
| Tumor characteristicsa | ||||||
| ER+ | 300 (75%) | – | 108 (80%) | – | 183 (73%) | – |
| PR+ | 263 (66%) | – | 102 (76%) | – | 153 (61%) | – |
| HER2 + | 114 (30%) | – | 45 (35%) | – | 66 (27%) | – |
| Triple-negative | 65 (16%) | – | 17 (13%) | – | 44 (18%) | – |
| Reproductive variables | ||||||
| Age at menarche (years) | 15 (12–18) | 15 (13–18) | 14 (12–18) | 14 (12–18) | 15 (13–18) | 15 (13–18) |
| Pregnancy (n; %) | 380 (95.2) | 385 (96.5) | 127 (94.1) | 128 (94.1) | 240 (96.4) | 252 (97.7) |
| Age at 1rst FTP#b (years) | 20 (17–27) | 20 (17–27) | 21 (17–29) | 22 (18–29) | 20 (17–25) | 20 (17–25) |
| Parityb(n) | 3 (1–5) | 3 (1–5) | 3 (1–4) | 3 (1–4) | 3 (2–6) | 3 (2–6) |
| Nulliparous | 4.8% | 3.5% | 5.9% | 5.9% | 3.6% | 2.3% |
| 1–2 children | 31.8% | 36.9% | 40.7% | 46.3% | 26.9% | 31.4% |
| 3 children | 30.1% | 25.8% | 33.3% | 29.4% | 29.3% | 24.0% |
| More than 3 children | 33.3% | 33.8% | 20.1% | 18.4% | 40.2% | 42.3% |
| Time between menarche and 1st FTP#b (years) | 5 (1–12) | 5 (1–13) | 6 (1–14) | 7 (2–15) | 5 (1–11) | 5 (1–10) |
| Breastfeeding ever | 90% | 91% | 86% | 87% | 92% | 94% |
| Total months breastfeedingc | 36 (6–96) | 41 (9–96) | 31 (5–80) | 30 (7–72) | 36 (8–99) | 42 (9–107) |
| Family history of breast cancer | 6.5% | 4.3% | 6.7% | 5.9% | 6.8% | 3.5% |
| History of benign breast disease | 0.3% | 0.5% | 0% | 1.5% | 0.4% | 0% |
| Level of education | ||||||
| None/primary | 24% | 18% | 7% | 2% | 34% | 26% |
| High school | 65% | 71% | 71% | 79% | 61% | 66% |
| College/post-graduate/diploma | 11% | 11% | 22% | 19% | 5% | 8% |
| Income | ||||||
| R1-R3000 | 87% | 85% | 76% | 81% | 93% | 87% |
| R3001-R6000 | 8% | 8% | 17% | 10% | 4% | 8% |
| R6001+ | 5% | 7% | 7% | 9% | 3% | 5% |
| Ethnicity | ||||||
| Zulu, Pedi, Swazi | 6.5% | 6.3% | 4.4% | 5.9% | 6.8% | 6.2% |
| Xhosa | 5.5% | 5.7% | 6.7% | 6.6% | 5.2% | 5.0% |
| Sotho, missing | 28.1% | 36.6% | 28.2% | 33.1% | 28.9% | 38.4% |
| Tswana | 4.8% | 4.8% | 8.2% | 6.6% | 3.2% | 3.5% |
| Venda | 10% | 14% | 4.4% | 15.4% | 13.3% | 13.6% |
| Tsonga, Ndebele | 45.1% | 32.6% | 48.2% | 32.4% | 42.6% | 33.3% |
| Smoking | ||||||
| Ever smoker | 9.0% | 11.0% | 5.2% | 5.9% | 11.7% | 14.0% |
| Anthropometric measurements | ||||||
| Weight (kg) | 77 (55–101) | 77 (56–104) | 78 (55–103) | 78 (54–106) | 76 (55–100) | 77 (57–103) |
| Height (m) | 1.58 (1.50–1.66) | 1.57 (1.51–1.66) | 1.60 (1.53–1.67) | 1.60 (1.52–1.69) | 1.56 (1.48–1.64) | 1.57 (1.50–1.65) |
| BMI (kg/m2) | 31.1 (22.1–40.8) | 31.7 (23.2–41.1) | 30.9 (21.8–39.5) | 30.8 (21.0–39.8) | 31.6 (22.4–41.1) | 32.0 (24.0–41.8) |
| Waist (cm) | 94 (75–111) | 97 (77–114) | 90 (72–108) | 93 (74–111) | 96 (79–112) | 98 (80–116) |
| Physically activeŦ | 7.8% | 14.8% | 11.9% | 21.3% | 5.6% | 11.6% |
20 subjects with missing information on menopausal status: 15 cases and 5 controls
n; n(%); or median (p10-p90)
Tumor receptor status: ER+estrogen positive, PR+progesterone positive, HER2 + human epidermal growth factor receptor 2 positive (14 missing). Positivity defined by Allred scores [13]
Among parous women
Among breastfeeding women
FTP: full-term pregnancy
Intense physical activity at least once a week during one year
The distribution of reproductive variables including age at menarche, pregnancy, age at first full-term pregnancy (FFTP), time between menarche and FFTP, parity, breastfeeding, duration of breastfeeding, and ever use of oral contraceptives were similar among cases and controls (Table 1). Among pre-menopausal women, controls had a later age at first pregnancy and a longer time between menarche and FFTP than the cases. In post-menopausal women, median age at menopause (48 years),and time since menopause (15 years) were similar among cases and control (results not shown). None of the participants reported using hormone replacement therapy.
In conditional logistic regression analyses, none of the reproductive variables were statistically significantly associated with the risk of breast cancer among all women, nor in pre or in post-menopausal women separately (Fig. 1), nor by receptor status (ER+ and ER–, and TN, results not shown). However, when restricting the analyses to HIV-negative women only, later age at first pregnancy and longer time between menarche and FFTP were inversely associated with the risk of breast cancer (OR 0.89 (95% confidence interval, CI 0.82–0.97) and 0.93 (95% CI 0.86–1.01), respectively) in pre-menopausal women (results not shown). In this group, 87% of the cases (n = 84) were ER+, and 9% (n = 9) TN.
Fig. 1.
Association (Odds ratio and 95% confidence internal) between reproductive variables and breast cancer overall and by menopausal statusŦ
# FTP : full term pregnancy
•Conditional logistic regression minimally adjusted on age, menopausal status and HIV status
Discussion
To our knowledge, this is the largest population-based case–control study exploring the association between several reproductive factors and breast cancer risk overall, and by menopausal status, in black South African women. Overall, in this population, reproductive factors were not associated with breast cancer risk.
In contrast to previous reports from African American women [14], we did not observe a high proportion of TN tumors in our population, and the proportion of TN tumors was lower among pre-menopausal women than among post-menopausal women. In contrast, the proportion of HER2+ positive tumors was slightly higher than previously reported [14, 15]. In a recent pooled analysis of 2,685 breast cancer and 2,448 controls aged 20–64 years who participated in population-based case–control studies, combining white and African American women only 8.5% of the breast cancer were HER2+ [16]
Some reproductive factors have been associated to breast cancer risk in African American women. In the Women’s Circle of Health study, including 786 African American breast cancer and 1,015 controls, parity was associated with a reduced risk of ER+ breast cancer but with an increased risk of ER– breast cancer, with increasing duration of breastfeeding reducing the risk of ER– disease [7].This result was later confirmed in the Amber consortium combining 2 cohort studies, and 2 population-based case–controls studies [17]. Parity was associated to a reduced risk for ER+, but to an increased risk for ER- and triple-negative tumors, while breastfeeding was related to a decreased risk of ER– but not ER+ breast cancers [17]. In addition, the risk of ER– breast cancer was reduced with older age at menarche. Longer time interval between menarche and first live birth was associated with an increased risk of ER+ breast cancer, suggesting that etiologic pathways involving adolescence and pregnancy may differ between ER– and ER+ breast cancer [14]. In a pooled analysis of case–control studies among African American women, duration of breastfeeding was related to a decreased risk of breast cancer in TN and luminal A cancers [16]. No additional reproductive factors were significantly associated with breast cancer.
In the Black Women Health Study cohort, Palmer et al. reported an increased risk of ER–/PR– breast cancer with increased parity, while a protective effect was observed among ER+/PR+ breast cancer [18]. Older age at first birth, never having breastfed, and abdominal adiposity were associated with increased risk of ER_ breast cancer in young women, but not with ER- cancer in older women, nor with ER+ cancers, regardless of age [19].
To our knowledge, only few studies have investigated the role of reproductive factors in women in South Africa: they were hospital-based studies, and showed little association between breastfeeding, age at menopause and breast cancer risk [20, 21], while an increase in risk was observed for contraceptive use [22]. As well, few studies have been conducted in African populations in Africa. In a hospital-based case–control study conducted in Bangui, later age at menarche and pregnancy were associated with a decreased risk of breast cancer. However, no stratification by menopausal status or breast cancer subtypes was conducted [23]. A recent study in Ghana [24] indicated that in women above 50 years, parity and extended breastfeeding were associated with decreased risk of breast cancer, which did not differ by ER status, while in women younger than 50 years, parity was associated with increased risk for ER-negative tumors only, which was offset by extended breastfeeding.
In our study, no significant association was observed between any of the reproductive factors and breast cancer risk in the overall population. Only in pre-menopausal, HIV- negative women, later age at first full-term pregnancy and longer time between menarche and first full-term pregnancy, were associated to a lower risk of breast cancer. Parity did not modify these associations. Although the association between HIV infection and breast cancer risk has not been fully explored, our results may suggest that breast cancer in HIV-positive women may have a different etiology than in HIV-negative women. Indeed, recent studies in the South African population, where the prevalence of this infection is relatively high, have shown that breast cancers develop at a much younger age in HIV-positive patients compared to the HIV-negative patients, with more aggressive appearing tumor biology [25]. Among post-menopausal women, none of the reproductive factors was associated with breast cancer. Analysis by subtypes of breast cancer did not identify any specific reproductive variables associated to risk.
Some limitations of our study should be noted. For example, due to a relatively modest number of breast cancer cases, we were limited in sample size for subgroup and cancer subtype analyses. In addition, our population was very homogenous with regard to reproductive variables, decreasing the probability to detect a significant effect. For example, the median age at first full-term pregnancy was 20 years both in cases and controls, 95% of cases and 97% of controls had children, and 90% of cases and 91% of control breastfed their children. Cumulative duration of breastfeeding was also similar in cases (36 months) and controls (41 months), and minimum duration was 5 months which has been shown to provide some protective effect on breast cancer in other populations [26]. Therefore, the results of our analyses must be interpreted with caution.
This study is the first conducted in black women from Soweto to identify risk factors for breast cancer incidence. While the studied reproductive factors were not associated with breast cancer, further analyses on lifestyle and environmental factors may provide further insight on determinants of breast cancer in this population.
Acknowledgments
The authors would like to thank the participants of the SABC study and the Directors of the Chris Hani Baragwanath Academic Hospital and Chris Hani Baragwanath Breast Unit. The authors would also like to thank the fieldworkers involved in this study: Phindile Mathe, Yvonne Chaka, Victor Shandukani, Siphesihle Sibiya, and Maria Sihlo and the SABC study project coordinators from the International Agency for Research on Cancer, Tracy Lignini and Robyn Smith.
Funding
This study was supported by a research grant secured from the World Cancer Research Fund International Grant Number 2012/591.
Footnotes
Publisher's Disclaimer: Disclaimer Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization.
Conflict of interest The authors declare that they have no conflict of interest.
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