Albergaria et al. BMC Cancer 2011, 11:299 http://www.biomedcentral.com/1471-2407/11/299 the ER-positive branch, comprising the luminal A and B subtypes, and three ER-negative branch, which com- prises at least, two reproducible subtypes: the HER2- overexpressing group and the basal-like group [6,8,9,13-15]. An additional group of tumours displaying molecular features of normal breast tissue, and therefore named as “normal-like”, has been also included in this ER-negative branch. However, it has been suggested that this group represents an artefact with high contamina- tion from normal breast tissue rather than a distinct molecular subtype [14]. Among the molecular subtypes of breast cancer identified through gene expression pro- filing studies, none has generated as much interest or controversy as the basal-like breast cancer group (BBC) [1]. Recently, a review published by a large group of renown breast pathologists and clinicians, advocated that there is still no internationally accepted definition for BBC and discussed how best to define these tumours [1]. Nevertheless, it is commonly accepted that the term “basal-like” reflects the similarity of the protein expres- sion profile of these tumours with the one of basal epithelial cells of the normal mammary gland [16-19], including high-molecular-weight cytokeratins (CK) 5/6, 14 and CK17, vimentin, P-cadherin, caveolins-1 and 2, aB-crystalin and fascin [8,20-29]. BBC, the only group consistently defined by gene expression arrays [30], account for up to 15% of all breast cancers [1,11]. These tumours frequently lack or show low levels of ER and PR, lack HER2 overexpression and amplification [21,31,32] and in approximately 85% of the cases display p53 expression by immunohistochemistry or TP53 mutations [8,33]. Additionally, BBCs show exceedingly high levels of proliferation-related genes [6,8,9,13] and express EGFR in a significant number of cases [21,34]. Defined by microarray-based expression profiling or by panels of immunohistochemical markers as surrogates, BBCs are known by their clinically aggressive behaviour [8,10,21,32]. Specimens that display BBC features (hormone recep- tors and HER-2 lack of expression), are called, in rou- tine practice, as “triple-negative” breast cancer (TNBC). Controversial and provocative data has been recently published questioning whether TNBC and BBC are synonymous. Because a majority of BBCs are also TNBCs and approximately 80% of TNBCs are also BBCs [21,35], it has been claimed that the TNBC and BBC are effectively synonymous [36,37]. However, clinical, micro- array and immunohistochemical data have shown that equating TNBC with BBC is misleading [15,33]. TNBC patients lack the benefit of routinely available target therapy, which explains the undeniable growing attention of both pathologists and oncologists as an easily recognisable group of breast cancer with aggres- sive behaviour and poor therapeutic options [2,38]. The Page 2 of 10 prognosis of women with TNBC is significantly poor, compared to women with other subtypes of breast can- cer. The higher recurrence and mortality rates of TNBC patients may be in part explained by different routes of metastatic spread [39]. There are conflicting results on the prevalence of lymph node metastasis at the time of diagnosis in TNBC patients [11]. Some studies described a higher prevalence of lymph node metastasis in TNBC [40], while others have found no statistical differences [3] or even an inverse association between TNBC and lymph node metastasis [41]. The currently accepted the- ory is that TNBCs seems to disseminate to axillary nodes and bones less frequently than the non-triple- negative cancers, presenting a preferential haematogen- ous route [32,42-44] with a proclivity to develop meta- static deposits in the brain and lungs [11]. The Nottingham Prognostic Index (NPI) combines nodal status, tumour size and histological grade [45], reflecting metastatic behaviour, growth rate and genetic instability of breast cancers [46,47]. Most importantly, as a continuous variable, NPI offers a responsive and sensi- tive means of modelling a continuum of clinical aggres- siveness [46], indexing the outcome likelihood of invasive breast cancer patients [48]. NPI can define 3 subsets of patients with different probabilities of dying from breast cancer; good (≤3.4), moderate (3.41 - 5.4), and poor (> 5.4) prognosis groups [48]. Three factors, found to be independently associated with survival on multivariate analysis, were combined to give the NPI algorithm. One of these factors is the lymph node stage, which has tradi- tionally been regarded as the most powerful prognostic factor in breast cancer. The greater the number of nodes involved, the worse the prognosis [45]. As above mentioned, TNBCs are believed to infre- quently disseminate to axillary lymph nodes in favour of distant and visceral metastatic spread [32,39,42], an assumption that theoretically jeopardize the reliability of using NPI as a tool for TNBCs prognostication, since lymph nodal status is a major component for NPI calculation. Herein, we investigated a large series of breast tumours and also a second cohort only composed by TNBC phe- notype. These cohorts were used to test the clinical utility of NPI in predicting breast cancer patient outcome. Comparative analyses were performed within the TNBC subgroup of patients in order to evaluate the contribution of each Nottingham Prognostic components to the risk of worse survival and prognosis in TNBCs. Methods Patient Selection A series of 467 primary invasive breast carcinomas diag- nosed between 1978 and 1992 were retrieved from the Pathology Department, Hospital Xeral-Cíes, Vigo, Spain.