Breast cancer is one of the most common malignant tumors in women and the leading cause of death among middle-aged women (1). Breast cancer may be classified into several subtypes according to its different etiology, clinicopathological presentation, molecular characteristics and response to therapy. Molecular biological methods are considered to be the gold standard for their accuracy in diagnosis due to the nature of the specific biological characteristic of the different breast cancer subtypes (2). In general, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are used as markers for invasive breast cancer classification in order to predict the outcome and select the optimal therapeutic strategies for the management of breast cancer (3).

With the development of molecular biology technology in recent years, an increasing number of molecular markers may be selected to classify the subtypes of invasive breast cancer. Due to the complexity, cost and lack of uniform standards of gene chip technology, it is difficult to apply in clinical practice. In clinical practice, immunohistochemistry for determining the ER, PR and HER2 status has been used to classify breast cancer into four subtypes, namely luminal A, luminal B, HER2-overexpressing and triple-negative breast cancer (TNBC) (4).

TNBC is a subtype of breast cancer, in which the expression of all three molecular markers is negative, and accounts for 10–20% of all breast cancers. TNBC has a higher mortality and risk of metastasis compared with other subtypes of breast cancer (5,6). In addition, it is highly invasive and is associated with a high local recurrence risk, and poor cancer-specific and disease-free survival (7–9).

The reasons for the low survival rate of TNBC are mainly as follows: First, compared with other subtypes of breast cancer, TNBC is associated with a higher rate of chromosomal mutations, high mitotic count, mutation of the p53 and BRCA1 genes, and lymphatic dissemination (10,11). Second, TNBC cannot be accurately diagnosed using conventional imaging examinations and is often only detected at an advanced stage (12). Third, therapies such as hormone therapy, targeted therapy and chemotherapy have not been shown to be effective (12).

Previous studies have demonstrated that there is a strong association between TNBC and race. TNBC accounts for 12–17% of all breast cancers in Western populations (13), whereas its incidence is higher (≤50%) in African-American women. The incidence in Asian women is similar to that in Caucasian women, and BRCA1 mutations are more common in these patients (11,14). Previous findings have also demonstrated that obese women are at a greater risk of developing TNBC compared with non-obese women (15). The use of oral contraceptives (OCs) has been identified as an important factor in the development of breast cancer (16), but there are currently no studies clearly indicating an association between OCs and TNBC. Moreover, the established risk factors for breast cancer as a whole may not apply to this unique subgroup of patients.

The aim of the present systematic review and meta-analysis was to focus on case-control studies and elucidate the strength of the association between OCs and TNBC, enabling a better understanding of TNBC, helping clinicians integrate biological and epidemiological characteristics, providing a theoretical basis and more information for epidemiology researchers focusing on the etiology, prevention and treatment of TNBC.

Previous studies indicated that the use of OCs may increase the risk of TNBC; however, the conclusions of these studies were conflicting. Indeed, Dolle et al (20), Beaber et al (18) and Kwan et al (23) reported that OC use increases the risk of TNBC; however, Marchbanks et al (29), Kawai et al (25) and Kabat et al (22) did not confirm this association.

The onset of TNBC is affected by multiple factors. The results of this analysis demonstrated that OC use increases the risk of TNBC. This result suggested that i) the pathological mechanism underlying OC use increasing the risk of TNBC requires further investigation; and ii) women who use OCs should be more closely followed regarding TNBC screening and prevention. It was previously demonstrated that TNBC was associated with family history (30,31), race (32,33), obesity (15,34) and menopausal status (35). These conclusions indicated that TNBC exhibits a certain association with hormone status. OCs are likely to exert a certain effect on hormone levels; thus, it is reasonable to infer that OC use is a likely risk factor for TNBC, with several hypotheses explaining this phenomenon. One of the mechanisms through which OC use affects breast cancer in younger women is the combination of estrogen and ER positivity in the mammary gland developing cancer, which promotes tumor growth and angiogenesis. The second mechanism is that estrogen increases the density of vascular distribution and recruitment of stromal cells systematically, which promotes tumor growth in ER⁻ as well as ER⁺ cases (36). The second mechanism may play a leading role in breast carcinogenesis.

The present meta-analysis analyzed the strength of association between OC use and TNBC, compared with non-TNBC cases or the healthy population. The non-TNBC control group demonstrated that OC use may cause an increase in the risk of TNBC, and the healthy population further confirmed this conclusion.

The present systematic review and meta-analysis had several limitations. First, the number of TNBC cases was relatively small and the history of OC use was dichotomous. This classification is relatively crude, and cannot explain the association between exposure dose of OCs and TNBC. Second, the use of hormone replacement therapy was not controlled in this analysis. Therefore, the population under investigation may have obvious endocrinology heterogeneity. In order to obtain a more accurate strength of association between TNBC and OC use, this analysis requires more studies to appropriately control the abovementioned potential confounding factors. In addition, the study classified the use of OCs into never or ever users, whereas more detailed information such as types or dose of OCs was not taken into consideration. Because of the relatively limited number of studies and heterogeneous information obtained by different analyses, information on confounding factor control and heterogeneity are difficult to obtain.

Even with these limitations, the present study provides a new perspective on the association between TNBC and physiological and pathological conditions. In order to ensure the accuracy of the analysis, a funnel plot was used to analyze the publication bias of the included studies, with the results showing that publication bias was not significant.

The identification of risk factors for TNBC may provide a reference for the screening and prevention of the target population. Overall, the results of this meta-analysis indicate that women who use OCs are more likely to develop TNBC compared with women who do not. Women who use OCs, particularly combined with other risk factors of TNBC, should be followed more closely. In addition, the mechanism underlying the increased risk of breast cancer, such as TNBC, also requires further investigation.

The results of the present study should draw more attention to the disease screening and follow-up of TNBC patients and the use of OCs, particularly as risk factors of TNBC.