Quadruple-Negative Breast Cancer: Novel Implications for a New Disease

Shristi Bhattarai; Geetanjali Saini; Keerthi Gogineni; Ritu Aneja


Breast Cancer Res. 2020;22(115) 

In This Article

Abstract and Introduction


Based on the androgen receptor (AR) expression, triple-negative breast cancer (TNBC) can be subdivided into AR-positive TNBC and AR-negative TNBC, also known as quadruple-negative breast cancer (QNBC). QNBC characterization and treatment is fraught with many challenges. In QNBC, there is a greater paucity of prognostic biomarkers and therapeutic targets than AR-positive TNBC. Although the prognostic role of AR in TNBC remains controversial, many studies revealed that a lack of AR expression confers a more aggressive disease course. Literature characterizing QNBC tumor biology and uncovering novel biomarkers for improved management of the disease remains scarce. In this comprehensive review, we summarize the current QNBC landscape and propose avenues for future research, suggesting potential biomarkers and therapeutic strategies that warrant investigation.


Triple-negative breast cancer (TNBC) is defined by the lack of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression.[1] Compared to other breast cancer (BC) subtypes, patients with TNBC have a more aggressive clinical course and poorer prognosis, with higher rates of local recurrence and distant metastasis within 5 years of diagnosis.[2] The disease disproportionately affects women of African ancestry and pre-menopausal women.[2–5] Mounting evidence suggests that non-biological and epidemiological factors play a substantial role in the etiology of TNBC. Factors associated with increased risk of TNBC include African ancestry, younger age, obesity, BMI, shorter breastfeeding duration, higher parity, oral contraceptive usage for ≥ 1 year, low socioeconomic status, a diet high in animal fat, and low physical activity. Some of these, including obesity, breastfeeding, and physical inactivity, have been linked to androgen secretion dysregulation.

The stark inter-patient and intra-tumoral heterogeneity render TNBC challenging to cure.[6,7] Based on gene expression profiling, TNBCs have been sub-classified, raising the potential for more precise therapeutic intervention.

An updated version by Lehmann and colleagues classifies TNBC into four distinct molecular subtypes including two basal-like subtypes, i.e., (BL1 and BL2), mesenchymal (M), and luminal androgen receptor (LAR).[8] Retrospective analysis of these TNBC subtypes demonstrated significant differences in response to neoadjuvant chemotherapy between subtypes, with LAR displaying worse response and BL1 responding more favourably.[9] Additionally, Burstein et al. categorize TNBC into luminal androgen receptor (LAR), mesenchymal (MES), basal-like immunosuppressed (BLIS), and basal-like immune activated (BLIA).[10]

Although TNBCs exhibit greater chemosensitivity compared to non-TNBCs, many TNBC patients diagnosed with advanced-stage disease relapse following treatment with conventional anthracycline/taxane-based chemotherapy.[3–5] Hence, the identification of robust prognostic biomarkers and novel therapeutic targets is of high clinical importance.

Androgen receptor (AR) is expressed in approximately 10–43% of TNBCs depending on the AR positivity cutoff used; therefore, it has emerged as a promising therapeutic target for TNBC patients.[11] AR antagonists, such as enzalutamide and bicalutamide, currently in clinical trials, are showing promising results in AR-positive TNBC patients.[12–16] However, the remaining 67%–90% of TNBCs that lack AR expression, also referred to as quadruple-negative breast cancers (QNBCs), do not benefit from AR antagonists, and some studies have reported a worse prognosis for QNBC patients[17–22] compared to those with AR-positive TNBC. Recent evidence suggests that QNBC differs from TNBC in its molecular and genetic make-up. This calls for extensive identification and annotation of key AR-dependent proteins and a delineation of the mechanistic action of AR. Herein, we summarize the current landscape of QNBC, implications of AR absence or presence, and rationally designed therapeutic strategies for QNBCs, as well as suggest avenues for future research in disease management.