Healthy Life Style

Factors such as age at menopause and breast-feeding practices may influence the risk for the development of certain types of breast cancer, according to the results of a study reported in the August 25 Online Publication issue of Cancer.

“Molecular profiling studies have identified subtypes of breast cancer that can be approximately classified by estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu (HER-2) [human epidermal growth factor receptor 2] expression,” write Amanda I. Phipps, MPH, from Fred Hutchinson Cancer Research Center in Seattle, Washington, and colleagues. “These molecular subtypes are prognostically significant, but to the authors’ knowledge, differences in their etiologic profiles have not been established. Reproductive factors may plausibly be differentially correlated with the risk of different breast cancer subtypes because these factors are presumed to impact exposure to endogenous sex hormones.”

Pooled data from 2 population-based, case-control studies of breast cancer in women ages 55 to 79 years included 1476 control subjects and 1023 cases of patients with luminal breast cancer, 39 cases of patients with HER-2–overexpressing breast cancer, and 78 cases of patients with triple-negative breast cancer. To compare each case group with control subjects, the investigators used polytomous logistic regression.

The associations varied based on molecular subtype. Early age at menarche was associated only with the risk for HER-2–overexpressing disease (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.4 - 5.5). In contrast, breast-feeding for 6 months was protective only for luminal breast cancer (OR, 0.8; 95% CI, 0.6 - 1.0) and triple-negative disease (OR, 0.5; 95% CI, 0.3 - 0.9).

Predictive factors of the risk for luminal disease were older age at menopause (OR, 1.6; 95% CI, 1.1 - 2.2) and use of estrogen plus progestin hormonal therapy (OR, 1.7; 95% CI, 1.3 - 2.1). There were no differences by subtype in risks associated with parity or age at first live birth.

“Certain reproductive factors may have a greater impact on the risk of certain molecular subtypes of disease compared with others,” the study authors write. “Future studies that further define the etiology of breast cancer subtypes will add to the biologic understanding of this disease.”

Limitations of this study include statistical power limited by the inclusion of only 78 triple-negative and 39 HER-2–overexpressing cases; exclusion of 84 (7%) potentially eligible cases lacking sufficient tumor marker data to be classified into a subtype; inability to distinguish between basal-like and unclassified cases; and possible misclassification of case subtypes resulting from the use of estrogen receptor, progesterone receptor, and HER-2 data taken from multiple laboratories.

“Although definitive conclusions regarding which risk factors are more strongly related to certain molecularly defined subtypes of breast cancer cannot be made based on the current study, our data do support the premise that risk factor profiles vary by breast cancer subtype and that hormonal risk factors have a greater impact on luminal-type breast cancers than HER-2–overexpressing or triple-negative tumors,” the study authors conclude. “The observation that breastfeeding has now been shown to reduce the risk of triple-negative disease in 2 studies is intriguing, but the biologic basis for this association is unclear and this finding requires further replication. Given the well-defined clinical differences between breast tumor subtypes, the relatively poor prognoses of HER-2–overexpressing and triple-negative disease, and the paucity of existing epidemiologic data, further research is needed to clarify the epidemiology of these tumors because at the current time no consistent risk factors for either of these 2 subtypes have been identified.”

Clinical Context

Molecular profiling studies have identified subtypes of breast cancer that can be approximately classified by estrogen receptor, progesterone receptor, and HER-2 expression. These molecular subtypes are prognostically significant, and differences in their etiologic profiles have not been well defined. Known breast cancer risk factors include age at menarche and menopause, parity, age at first live birth, and breast-feeding. These factors influence risk primarily through endogenous hormonal mechanisms. Such reproductive factors may plausibly be differentially correlated with the risk for different subtypes of breast cancer.

The aim of this study was to correlate between reproductive characteristics and the risks for luminal breast cancer, HER-2–overexpressing breast cancer, and triple-negative breast cancer.
Study Highlights

* In this study, 2 population-based, case-control studies of breast cancer were pooled in women ages 55 to 79 years for an analysis. This resulted in 1476 control subjects and 1023 cases of patients with luminal breast cancer, 39 cases of patients with HER-2–overexpressing breast cancer, and 78 cases of patients with triple-negative breast cancer.
* Study questionnaires were administered regarding several risk factors including lifestyle factors, reproductive history, use of hormonal therapy, and family history of cancer.
* Polytomous logistic regression was used to compare each case group with control subjects.
* Nonreproductive breast cancer risk factors were evaluated as potential confounders, including educational level (? high school degree/some college/college graduate), smoking status (yes/no), alcohol consumption (nondrinker, ? 7 drinks per week, or > 7 drinks per week), and family history of breast cancer in first-degree relatives (yes/no).
* Results demonstrated that associations varied by molecular subtype.
* Demographic factors demonstrated that patients with luminal disease were more likely to have a first-degree family history of breast cancer and to be diagnosed at an earlier stage.
* In addition, patients with HER-2–overexpressing disease were less likely to be non-Hispanic whites and to be college graduates, and patients with triple-negative disease were more likely to be younger.
* Regarding reproductive characteristics, early age at menarche was only found to be associated with the risk for HER-2–overexpressing disease (OR, 2.7; 95% CI, 1.4 - 5.5), whereas breast-feeding for 6 months or longer was only found to be protective for luminal disease (OR, 0.8; 95% CI, 0.6 - 1.0) and triple-negative disease (OR, 0.5; 95% CI, 0.3 - 0.9).
* The risk for luminal breast cancer was lower in women who had a surgical menopause vs women who experienced a natural menopause (OR, 0.7; 95% CI, 0.6 - 0.9).
* Both late age at menopause and the use of estrogen plus progestin hormonal therapy were only found to be associated with the risk for luminal disease (OR, 1.6; 95% CI, 1.1 - 2.2, and OR, 1.7; 95% CI, 1.3 - 2.1, respectively).
* No differences in the risks associated with parity or age at first live birth were observed by subtype.
* Limitations of this study included the lack of statistical power of the analyses because of the inclusion of only 78 patients with triple-negative disease and 39 patients with HER-2–overexpressing disease, the inability to distinguish between basal-like and unclassified cases, and the possible misclassification of case subtypes.

Pearls for Practice

* Age at menarche, age at menopause, parity, age at first live birth, and breast-feeding are all established factors that influence the risk for breast cancer through hormonal mechanisms.
* This study demonstrated that certain reproductive factors may have a greater effect on the risk for certain molecular subtypes of breast cancer vs other subtypes of the disease.