How many diseases is triple negative breast cancer: the protagonism of the immune microenvironment

Abstract

Triple negative breast cancer (TNBC) is a type of breast cancer (BC) that does not express the oestrogen and the progesterone receptors and the human epidermal growth factor receptor type 2 (HER2). Since there are no positive markers to reliably classify TNBC, these tumours are not yet treated with targeted therapies. Perhaps for this reason they are the most aggressive form of breast carcinomas. However, the clinical observation that these patients do not carry a uniformly dismal prognosis, coupled with data coming from pathology and epidemiology, suggests that this negative definition is not capturing a single clinical entity, but several. We critically evaluate this evidence in this paper, reviewing clinical and epidemiological data and new studies that aim to subclassify TNBC. Moreover, evidence on the role of tumour infiltrating lymphocytes (TILs) on TNBC progression, response to chemotherapy and patient outcome have been published. The heterogeneity, observed even at TILs level, highlights the idea that TNBC is much more than a single disease with a unique treatment. The exploration of the immune environment present at the tumour site could indeed help in answering the question 'How many diseases is TNBC' and will help to define prognosis and eventually develop new therapies, by stimulating the immune effector cells or by inhibiting immunological repressor molecules. In this review, we focus on the prospect of the patient's diverse immune signatures within the tumour as potential biomarkers and how they could be modulated to fight the disease.

Keywords: Triple negative breast cancer; gene expression profile; heterogeneity; tumour infiltrating lymphocytes.

Figure 1

An inflammatory triple negative breast cancer of an African woman before (A) and after (B) treatment. Patients that descend from African ethnicity have a higher probability of developing more aggressive forms of breast cancer with lower curability rates. In fact, this patient, although the breast mass decreased (B), did not respond to the treatment and developed very aggressive meningeal carcinomatosis (C) 6 months after diagnosis while still finishing neoadjuvant chemotherapy with an opening pressure in the lumber tap of 40 mm Hg (normal 15–20 mm Hg) and died within 2 weeks of this diagnosis despite intrathecal treatment.

Figure 2

Heterogeneity in the natural history of triple negative breast cancer. Metastasis develop preferentially in the viscera in patients that relapse more rapidly, leading to a bad prognosis. On the other hand, patients with later relapse present TNBC with a tendency to develop bone metastasis, leading to a better prognosis.

Figure 3

Histological and molecular heterogeneity of triple negative breast cancer (TNBC). (A) Most TNBCs are infiltrating ductal carcinoma (IDC), leading to bad prognosis. The other types of TNBCs have better prognosis, with the exception of metaplastic and inflammatory. (B) There is a high overlap between TNBC and basal-like breast cancer, however, not all TNBCs are basal-like and vice versa. (C) Some patients with TNBC have a BRCA1 germline mutation, which leads to an improved patient prognosis.