Triple negative breast cancer: looking for the missing link between biology and treatments

// Giuseppe Palma 1,* , Giuseppe Frasci 2 , Andrea Chirico 3,6 , Emanuela Esposito 2 , Claudio Siani 2 , Carmela Saturnino 4 , Claudio Arra 1 , Gennaro Ciliberto 5 , Antonio Giordano 3,7 and Massimiliano D’Aiuto 2,* 1 S.S.D. “Sperimentazione Animale”, National Cancer Institute, IRCCS, “Fondazione Pascale”, Naples, Italy 2 Division of Breast Surgery, Department of Breast Disease, National Cancer Institute, IRCCS, “Fondazione Pascale”, Naples, Italy 3 Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA, USA 4 Department of Pharmacy and Biomedical Science, University of Salerno, Fisciano, Italy 5 National Cancer Institute, IRCCS, “Fondazione Pascale”, Naples, Italy 6 Department of Psychology of Developmental and Socialisation Processes, “La Sapienza” University of Rome, Rome, Italy 7 Department of Medicine, Surgery and Neuroscience, “University of Siena”, Siena, Italy * These authors contributed equally to this manuscript Correspondence to: Massimiliano D’Aiuto, email: // Antonio Giordano, email: // Keywords : breast cancer, triple negative, oncology, treatments, biology Received : August 12, 2015 Accepted : August 24, 2015 Published : August 30, 2015 Abstract The so called “Triple Negative Breast Cancer” (TNBC) represents approximately 15-20% of breast cancers. This acronym simply means that the tumour does not express oestrogen receptor (ER) and progesterone receptor (PR) and does not exhibit amplification of the human epidermal growth factor receptor 2 (HER2) gene. Despite this unambiguous definition, TNBCs are an heterogeneous group of tumours with just one common clinical feature: a distinctly aggressive nature with higher rates of relapse and shorter overall survival in the metastatic setting compared with other subtypes of breast cancer. Because of the absence of well-defined molecular targets, cytotoxic chemotherapy is currently the only treatment option for TNBC. In the last decades, the use of more aggressive chemotherapy has produced a clear improvement of the prognosis in women with TNBC, but this approach results in an unacceptable deterioration in the quality of life, also if some support therapies try to relieve patients from distress. In addition, there is the general belief that it is impossible to further improve the prognosis of TNBC patients with chemotherapy alone. In view of that, there is a feverish search for new “clever drugs” able both to rescue chemo-resistant, and to reduce the burden of chemotherapy in chemo-responsive TNBC patients. A major obstacle to identifying actionable targets in TNBC is the vast disease heterogeneity both inter-tumour and intra-tumour and years of study have failed to demonstrate a single unifying alteration that is targetable in TNBC. TNBC is considered the subtype that best benefits from the neoadjuvant model, since the strong correlation between pathological Complete Response and long-term Disease-Free-Survival in these patients. In this review, we discuss the recent discoveries that have furthered our understanding of TNBC, with a focus on the subtyping of TNBC. We also explore the implications of these discoveries for future treatments and highlight the need for a completely different type of clinical trials.