Pathological definition of triple negative breast cancer

Abstract

We are witnessing tremendous advances in the understanding of the biological and clinical implications of heterogeneity of breast carcinomas. Indeed, taking advantage of the many peculiar clinical, histopathological and biological features of the different tumour types, we have learnt how to evaluate more reliably the risk of disease progression, to better tailor systemic interventions and to target specific molecular pathways with new therapeutic agents. Together with the current strategies for early detection of breast carcinoma and the refinements of the local treatments by surgery and radiation therapy, the improved quality of systemic therapies have resulted in the reduction of the mortality rate for a disease whose prevalence is continuously increasing worldwide [1,2]. Basic, translational and clinical researchers have started coordinating their efforts to unveil new biological features of breast cancer that might become either targets for novel specific drugs or new predictive parameters to better tailor existing therapies. New clinical questions are being addressed, with the aim of improving the selection of the candidate patients to tailored interventions and eventually identifying those who will actually respond to these therapies. A new generation of randomised clinical trials for pre-defined subpopulations of breast cancer patients selected according to the biological characteristics of their tumours are being conducted and newly launched to prove the efficacy of tailored treatments. The design and the conduct of these new clinical trials require an unprecedented coordination of the activity of clinical investigators, pathologists and translational researchers worldwide. The patients who are less likely to have benefited from the advances in the systemic treatments of breast carcinoma are those with the so-called triple negative (TN) tumours (i.e. immunohistochemicallly negative for oestrogen receptor (ER) and progesterone receptor (PgR) and lacking over-expression and amplification of the HER2 gene). They account for some 10−20% of all breast cancer patients, but they also account for the most lost lives due to breast cancer [3]. The increasing clinical interest for these tumours of the breast stems from their alleged poor prognosis despite high response rates to conventional chemotherapeutic regimens in the neoadjuvant setting [4], and from the lack of any targeted therapies. Indeed, patients with TN tumours are not offered either hormonal or antiHER2 interventions, being candidates for non-tailored cytotoxic chemotherapy. The lack of any positive immunophenotypical marker has long prevented these tumours from being investigated more thoroughly. Only the advent of more sophisticated assays, enabling the exploration of the whole universe of gene expression of the tumour cells, has shed some light into the black box of TN breast cancer [5]. The pioneering studies of gene expression profiling have documented that the majority of TN tumours belong to the molecular class of the basal-like breast cancers, although these two tumour types do not overlap completely. Far from being limited to a new taxonomic approach to breast cancer, the molecular investigations have provided new insights into the biological pathways driving the neoplastic transformation and tumour progression of TN carcinomas. Some positive markers for these tumours have eventually been identified (EFGR, cKit) which may represent possible targets for new therapeutic approaches.