Recent progress in medical science has led to a sophisticated classification of breast carcinomas, based on variations in gene expression patterns derived from cDNA microarrays. This classification, distinguishing breast cancers into basal type (triple negative), luminal, and HER2/neu, has been correlated with clinical outcome and response to therapy [1
]. However, currently available immunohistochemical markers can be used to closely reproduce the more complex gene expression patterns [28
]. When this study was started, cDNA microarrays were not used yet as a standard of classification for clinical practice and design of therapeutic strategy. We utilized the immunohistochemical classification scheme, adopting the terminology of triple negative to characterize patients with ER−, PGR−, HER2−, at high risk for recurrence [29
]. Here, we present the 81 months follow-up of a study, of patients with TNBC, treated homogeneously by a multi-modality therapeutic protocol that included induction therapy with taxanes and anthracyclines, surgery, simultaneous CMF and XRT, and two courses of high-dose CBDCA, VP-16, ifosfamide, supported by hematological growth factors. Several reports focusing on the treatment of TNBC have confirmed the worse prognosis of this cancer type, compared with others. Hence, despite the initial sensitivity and high response rate to chemotherapy, patients with TNBCs show a paradoxical feature with poor long-term outcome [9
]. The largest described series from MD Anderson Hospital [30
] included a cohort of 1118 patients who had received neoadjuvant chemotherapy. Of these patients, 255 (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates but lower 3-year PFS and OS rates.
Other strategies have been adopted to improve the clinical outcome of patients with TNBC. In recent years several studies have emphasized the role of vascular endothelial growth factor (VEGF) as a key mediator of angiogenesis. Bevacizumab (Avastin), the best-known anti-angiogenic agent, is a humanized monoclonal antibody that binds to VEGF and prevents it from interacting with vascular endothelial cells [31
]. Bevacizumab has been shown to improve response rate and PFS when combined with chemotherapy in patients with TNBC. However, a 2011 meta-analysis highlighted the dangers of the drug: Compared with chemotherapy alone, the addition of bevacizumab was associated with an increased risk of fatal adverse events, the most common being hemorrhage (23.5%), neutropenia (12.2%), and gastrointestinal tract perforation (7.1%), especially when bevacizumab was associated with taxanes or platinum drugs [33
]. TNBC have intrinsic defects in mechanisms of DNA repair, making this cancer a rational target for therapy based on PARP inhibition. In a phase II study, a total of 123 patients were randomly assigned to receive gemcitabine and carboplatin with or without the PARP inhibitor, Iniparib. The addition of Iniparib to chemotherapy improved the clinical benefit and survival of patients with metastatic TNBC without significantly increased toxicity [8
We and others have previously shown that two courses of CBDCA, CTX, and VP16 as consolidation therapy provide significant survival benefits to patients with basal-like TNBC [22
]. Gluz et al. [35
], in a randomized trial, evaluated a cohort of patients with high-risk breast cancer, with >9 involved lymph nodes, who received different chemotherapy dose-intensification strategies. The most pronounced benefit of dose-intensified chemotherapy was observed in triple-negative tumors: In this subgroup, median PFS was not reached in the high-dose arm, whereas it was only 32.3 months in the dose-dense arm. This translated into an estimated 5-year PFS of 71% in the triple-negative cohort treated by high-dose compared with only 26% in the dose-dense arm.
Collectively, it is common opinion that mastectomy renders radiation therapy unnecessary unless the tumor is 5 cm or larger, its margins are irregular with signs of invasion through basal membranes of adjacent normal mammary tissue, or if there is nodal metastasis. Tseng et al., however, suggested that adjuvant radiation in all patients with metaplastic breast cancer may lead to improved OS [36
]. Due to the high locoregional recurrence rate that TNBC shows, we selected to administer concurrent radiation therapy with CMF-based chemotherapy, a strategy whose rationale is supported by recent studies demonstrating that the magnitude of benefit of CMF chemotherapy is largest in patients with triple-negative, node-negative breast cancer [37
In conclusion, in our cohort of patients with TNBC our multipronged approach involving induction chemotherapy, followed by chemoradiation therapy and by HDCT provides a prolonged disease-free period and a significant increase in OS, with an acceptable toxicity profile. We anticipate that our results will prompt the application of our treatment strategy in the clinical management of TNBC.