In a population-based epidemiologic study of African-American and white women, we observed differing magnitudes of association for several breast cancer risk factors when we subdivided cases according to the “intrinsic” subtypes (luminal A, luminal B, basal-like, HER2+/ER−and unclassified). Exploratory case-case comparisons were most striking for luminal A versus basal-like breast cancer, and analyses comparing cases and controls yielded several potential risk factors for basal-like cancer that differed in magnitude and direction in comparison with luminal A. Parity combined with lack of breastfeeding, early-onset menarche, younger AFFTP, use of lactation suppressants, elevated WHR and gain in adiposity since childhood were positively associated with basal-like breast cancer. Notably, each of these risk factors was more prevalent among younger African-American women, as represented by controls in the CBCS. The results suggest that a large part of the racial difference in the distribution of the “intrinsic” breast cancer subtypes may be attributable to differing distributions of specific risk factors related to reproductive history, breastfeeding, adiposity and weight gain.
In a recent article, Anderson et al. [32
] examined incidence rates for breast tumors with poor prognostic features (ER and PR negative, tumor size greater than 2.0 cm, lymph node positive, high grade) compared to tumors with a more favorable prognosis (hormone receptor positive, size 2.0 cm or less, lymph node negative, low grade). Incidence rates were higher for poor prognosis tumors until ages 30–44, followed by a plateau at age 50 and a subsequent reduction, whereas incidence rates for more favorable prognosis tumors were higher in women aged 50 years and continued to rise as women grew older. The authors hypothesized that high- and low-risk breast tumors represent distinct subtypes of breast cancer with separate risk factor profiles and/or cell types of origin. In a similar vein, Bernards and Weinberg [33
] cited biologic data to support a theory that breast cancer prognosis is “preordained by the spectrum of mutations that progenitor cells acquire relatively early in tumorigenesis; that is, some cancers start out on the wrong foot” [33: page 823]. Therefore, incidence rates and genetic data together support the idea that poor prognosis breast tumors in younger women have a different underlying etiology than more favorable breast cancers in older women. This hypothesis is especially relevant for younger African-American women, for whom breast cancer incidence remains high compared to white women [34
] and mortality from hormone receptor negative, high grade breast cancer is a major public health problem [35
Increased parity and younger AFFTP have been associated with increased risk of breast cancer among younger African-American women in several studies [38
] including the CBCS [41
], but not in others [42
] (for review, see Swanson et al. [35
]). We observed a statistically significant increase in risk of basal-like breast cancer with increasing number of children, a relationship that was not observed for luminal A breast cancer. The relationship between parity and basal-like breast cancer was not confined to younger women, and basal-like cases were no more likely to be diagnosed following a pregnancy than luminal A cases. Thus, the positive association between parity and basal-like breast cancer was not restricted to the well-documented short-term increase in risk of breast cancer following live birth [41
]. Nor did the increase in risk appear to be attributable to younger age at menarche or younger AFFTP which have also been associated with increased risk of breast cancer in younger African-American women [35
]. Rather, the increased risk for basal-like breast cancer with increasing parity appeared to be largely confined to women who did not breastfeed (). Furthermore, the effects of increased parity and lower breastfeeding, and the contrast between basal-like and luminal A breast cancer, were observed across all four age-race groups. In the case-only analysis comparing basal-like versus luminal A breast cancer, the OR for parity ≥3 and no breastfeeding (adjusted for age and race) was 1.9 (95% CI 1.1–3.4) for all women. In the four patient groups, ORs (adjusted for age) were 2.2 (95% CI 0.7–6.6) for pre-menopausal African-American women, 1.9 (95% CI 0.6–5.9) for postmenopausal African-American women, 1.8 (95% CI 0.5–7.0) for premenopausal white women, and 1.7 (95% CI 0.5–5.6) in postmenopausal white women.
The Collaborative Group on Hormonal Risk Factors in Breast Cancer [44
] determined that breastfeeding exerts a protective effect on overall breast cancer risk beyond that of parity alone. Potential mechanisms include induction of terminal differentiation and/or removal of initiated breast epithelial cells, removal of estrogens via breast fluid, excretion of carcinogenic agents, delay in ovulation, and changes in breast pH [45
]. Use of lactation suppressants has also been associated with increased breast cancer risk, although results were not consistent across studies [45
]. Several lines of evidence suggest a link between basal-like breast cancer and lack of breastfeeding. Symmans et al. [46
] found that overexpression of the basal-like marker, GABApi, was associated with younger age at diagnosis and shorter duration of breastfeeding among Hispanic breast cancer patients. BRCA1
, but not BRCA2
, mutation carriers show a high prevalence of basal-like breast cancer (for review, see Tischowitz and Foulkes [47
]). In one study, BRCA1
carriers who breastfed for 1 year or longer were less likely to develop breast cancer than mutation carriers who did not breastfeed; no effect of breastfeeding was seen for BRCA2
]. As suggested by Tischowitz and Foulkes [47
], full-term pregnancy followed by failure to breastfeed or reduced duration of breastfeeding could result in retention of initiated progenitor cells that ultimately die or differentiate during lactation, and these retained cells could presumably develop into basal-like breast tumors. Pregnancy confers specific gene expression signatures on breast tissue and may effect the distribution and differentiation of potential breast cancer stem cells [49
], but the effects of lactation on gene expression and the differentiation status of mammary epithelial cells are not well understood.
The other strong risk factor for basal-like breast cancer identified in the CBCS was WHR. Elevated WHR was associated with a strong increase in risk of basal-like breast cancer among pre- and postmenopausal women, and a more modest increase for luminal A among postmenopausal women. When the two components of WHR were examined separately, elevated waist circumference showed a strong positive association with basal-like breast cancer among pre- and postmenopausal women, while ORs for hip circumference were slightly inverse (data not shown). Waist circumference and WHR serve as surrogates for abdominal adiposity: waist circumference is correlated with the amount of visceral and subcutaneous fat, while WHR is used as an index of the relative accumulation of abdominal versus gluteal fat [28
]. Previous epidemiologic studies have shown a consistent association between elevated central adiposity and increased breast cancer risk in postmenopausal women [50
], while results for premenopausal women have been less consistent [28
]. Abdominal adiposity is correlated with hyperinsulinemia and insulin resistance among African-American and white women [51
], and insulin resistance has been hypothesized to increase breast cancer risk in premenopausal women through increased mitotic activity and enhanced cell proliferation in breast epithelial tissue [28
]. There are currently no biologic data linking insulin resistance with basal-like breast cancer, and our data do not support an association between prior history of diabetes mellitus and increased risk of basal-like disease. However, overexpression of the leptin receptor is found in breast tumors with high grade [53
], a feature associated with basal-like breast cancer.
Our results combining recalled weight in fifth grade with measured WHR at the time of interview suggest that weight gain and/or gain in abdominal adiposity over a woman’s lifetime may contribute to increased risk of basal-like breast cancer. Previous studies reported a stronger association between weight gain and risk of postmenopausal compared with premenopausal breast cancer [54
]. Slattery et al. [56
] found that weight gain since age 15 and elevated WHR were both associated with increased risk of ER–negative breast cancer. The latter results were presented combining pre- and postmenopausal women, and HER2 status was not included in tumor subtyping.
In addition to Slattery et al. [56
], the work of other researchers suggests that risk factors for breast cancer differ depending upon hormone receptor status of the tumor [22
]. Although differences were slight, the results suggest that traditional risk factors based upon reproductive history are associated with increased risk of hormone-receptor positive disease [63
], which is consistent with our findings for the luminal A breast cancer subtype. Other studies stratified cases based upon HER2 positivity; but strong differences were not noted (for review, see Huang et al. [65
Previous studies reported a higher frequency of hormone-receptor negative breast cancer and later stage at diagnosis among African-American and other minority women compared with white women in the United States [37
]. Recently, researchers at the California Cancer Registry found that breast cancer patients with the “triple negative” (ER−, PR−, HER2−) phenotype were more likely to be under age 40, African-American, or Hispanic [66
]. “Triple negative” breast cancer was more frequent among women of lower socioeconomic status. The authors used the “triple negative” phenotype as a partial surrogate for basal-like breast cancer, since IHC data were limited to ER, PR and HER2 status. Individual-level data were not available on breast cancer risk factors, and socioeconomic status was assigned at the census block level using address at the time of diagnosis. In the CBCS, lower socioeconomic status (based upon income and education) was not associated with increased frequency of basal-like breast cancer. However, lower socioeconomic status was strongly associated with several risk factors for basal-like cancer, including lower breastfeeding (P
< 0.0001) and elevated WHR (P
< 0.0001). Future studies are needed to determine whether the increased prevalence of triple negative breast cancer found among Hispanic women in California may be attributable to reproductive history, breastfeeding, central adiposity and other basal-like risk factors.
Only one previous population-based study examined risk factors for breast cancer based upon the joint distribution of ER, PR, HER2, HER1, and CK5/6, the five IHC markers used to identify the “intrinsic” subtypes in the CBCS. Using data collected from a case–control study in Poland, Yang et al. [67
] calculated ORs for each of the five breast cancer subtypes versus controls. Results were similar to the CBCS, in that luminal A and basal tumors showed distinct risk factor profiles, with luminal A showing associations typically described for breast cancer as a whole. The authors reported positive associations for younger age at menarche and parity with basal-like cancer, but breastfeeding was not addressed. An inverse association between elevated BMI and luminal A breast cancer was observed among premenopausal women, but no association was seen for basal-like breast cancer, similar to our results. The authors did not examine WHR. Age at menarche and parity were associated with luminal A but not HER2+/ER− breast cancer. In the CBCS, case–control ORs for HER2+/ER− were almost identical to luminal A, with the exception of a slight inverse association for elevated WHR among postmenopausal women. Yang et al. [67
] reported a stronger association with family history for basal-like breast cancer compared to the other subtypes. In our study, associations with family history were nearly identical across the five subtypes, with age and race-adjusted case–control ORs equal to 1.5 (95% CI 1.2–1.9) for luminal A and 1.7 (95% CI 1.1–2.5) for basal-like breast cancer. The only other epidemiologic study to examine risk factors for the “intrinsic” breast cancer subtypes was a population-based case series from Sweden [8
] in which the authors subdivided cases based upon gene expression profiling. Current users of HRT were over-represented in the “normal-like” or “unclassified” breast tumor subtype. In the CBCS, the case–control OR for postmenopausal HRT and the unclassified subtype was 1.0 (95% CI 0.6–1.7).
A primary focus of the present analysis was to identify modifiable risk factors that could be targeted to reduce the risk of basal-like breast cancer, particularly among younger African-American women who have the highest incidence of this breast cancer subtype. Mortality rates are higher among younger African-American breast cancer patients, and the disparity in breast cancer outcomes has worsened over time [34
]. Since basal-like breast cancer confers a poor prognosis [6
], understanding the etiology of this breast cancer subtype is an important public health problem. We estimated that approximately two-thirds (68%) of basal-like breast cancer in younger African-American women (and over half of the disease in the general population) could be prevented by interventions that increase breastfeeding and decrease abdominal adiposity.
There are a number of limitations to PAF estimates, since they are based upon very strong assumptions. First, PAFs estimate the proportion of disease that would be eliminated if the entire population was moved from the exposed to the unexposed level for each of the relevant risk factors, assuming that the exposures in question are causal. One or more of the associations observed in this article could have resulted from recall bias, confounding, or other sources of systematic error. However, it is unlikely that exposure misclassification would be differential by breast cancer subtype, and extensive analyses were conducted to address the possibility of confounding. Analyses of participants with and without IHC marker data, and previous analyses comparing participants and non-participants in the CBCS [68
], suggest that selection bias is also unlikely. Data from subsequent population-based studies that utilize “intrinsic” subtypes will provide important information as to whether the associations observed in this article are causal. Second, the afore-mentioned PAF estimates assume that all women in the population are able to breastfeed children and reduce their WHR below 0.77. Clearly, not all women will have children, and there may be significant barriers to both breastfeeding and reducing abdominal adiposity. Third, the calculations assume independence of breastfeeding and WHR from other risk factors, such that the remaining risk factors for basal-like breast cancer are not changed by modifying the two exposures in question. Finally, PAFs should not be interpreted as the proportion of disease that can be “explained” by any specified group of risk factors. Since PAFs do not necessarily add up to 100%, it is possible that many additional exposures could contribute to the risk of basal-like disease. Despite these limitations, PAF calculations perform an important function for public health in that they provide a framework for greater understanding of disease etiology in populations, and stimulate the public health community to evaluate the feasibility of primary prevention strategies [69
There are several additional limitations to the present analysis. BRCA1
carrier status was determined for only a small sample of women in the CBCS [70
]. It is possible that some basal-like cases were BRCA1
mutation carriers, but this number is likely to be very small given the low frequency of BRCA1
carriers in the CBCS [70
] and other population-based studies [71
]. Another caveat is that IHC surrogates were used to subtype CBCS cases since fresh tumor samples were unavailable to perform gene expression profiling. The IHC surrogates have been validated in another study population, showing excellent agreement with gene expression profiling [10
], and they have been utilized in other studies to detect the presence of the five “intrinsic” breast cancer subtypes [67
]. Although tumor blocks tended to be available from cases with larger tumors, the case-only subtype comparisons did not differ when we adjusted for stage at diagnosis. Sample size was small for many of the subsets of interest, and our results need to be replicated in other population-based studies. Our study was limited largely to African-American and white women, and studies of the epidemiology of basal-like breast cancer among Hispanic women and other minority groups is an important area for future investigation.
Interventions to reduce the risk of basal-like breast cancer have strong prior justification. In a summary of existing data on breast cancer among younger African-American women, Bernstein et al. [43
] targeted increasing breastfeeding, losing weight, and increasing physical activity as the most effective ways of reducing disease risk. Our study adds further support for these recommendations. The benefits of breastfeeding for mother and child are well-documented [75
]. The Centers for Disease Control and Prevention Goals for Healthy People 2010 lists a target of 75% of mothers breastfeeding in the immediate postpartum period, with at least 50% continuing to breastfeed for 6 months [76
]. As observed in the CBCS, the prevalence of breastfeeding is reported to be lower among younger African-American women compared to white women [42
]. Lack of information about benefits, restrictions surrounding employment, and social pressures limit breastfeeding [75
], and maternal obesity decreases initiation as well as continuation of lactation [77
]. Teenage mothers may experience particular barriers to breastfeeding. In the CBCS, the proportion of controls who reported having a child before the age of 20 was higher among African-American (45%) compared with white women (23%, P
< 0.0001). Thus, the reasons for lower prevalence of breastfeeding among younger African American women are complex, and interventions to encourage breastfeeding must operate at the level of the community, the workplace, and society at large [78
Public health interventions aimed at avoiding over-nutrition, promoting a healthy diet, and encouraging physical activity [79
] could impact the incidence of basal-like breast cancer, especially programs that target excessive weight gain. Reduction in abdominal adiposity would provide additional benefits, including reduced risk of diabetes mellitus and heart disease [28
]. The prevalence of obesity is increasing among pregnant women [80
], leading to increased risk of hypertension and perinatal mortality [81
]. A variety of barriers at the school and neighborhood level [82
] may need to be overcome to promote physical activity among young girls.
Interventions to reduce risk of basal-like breast cancer would take years to have an impact, especially if early stages of carcinogenesis were targeted. Measures to improve survival for patients with basal-like breast cancer will have a more immediate impact. Increased adiposity at the time of diagnosis can confer a worse prognosis for younger breast cancer patients [83
], and this poor prognosis may be especially relevant for women with basal-like disease. Timely and effective treatment is vitally important for patients with basal-like breast cancer, and a variety of new drugs are being evaluated in clinical trials [84
]. However, African-American women historically suffer from reduced access to quality health care, delays in diagnosis and treatment, and low enrollment in clinical trials, and these disparities need to be addressed more effectively in the future [85
]. Health care providers need to be aware of the possibility of a breast cancer subtype with distinct etiology and worse prognosis. Unfortunately, clinicians may overlook breast cancer among younger women when patients do not present with a “classic” set of risk factors [35
]. Determination of the sensitivity and specificity of screening mammography for basal-like breast cancer would have important implications for detection and diagnosis of breast cancer, particularly in younger women. Finally, risk assessment models for breast cancer may need to be modified to identify women at high-risk for the basal-like subtype.