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Triple Negative Breast Cancer—Review of Current and Emerging Therapeutic Strategies Further understanding of the biology of TNBC has come from the discovery that some sporadic tumors share similar characteristics with those tumors that have a germline mutation in the DNA repair gene BRCA1, which plays a role in DNA double-strand break repair by homologous recombination. This has led to the term ‘BRCAness,’ referring to genotypes of TNBC that are BRCA proficient but exhibit a clinical and biologic phenotype similar to those with BRCA deficiencies. There are likely alternative mechanisms leading to defects in homologous recombination in TNBCs without germline BRCA1/2 mutations, including promotor methylation, somatic BRCA mutations, and altered expression of other genes, such as TP53, PALB2, ATM, and HORMAD1. This phenotype has important implications, as TNBCs that harbor defects in homologous recombination have therapeutic sensitivities similar to those with BRCA mutations. 13 Current management of early stage disease Given the lack of approved targeted agents, the mainstay of treatment for TNBC is not unique and continues to be cytotoxic chemotherapy. All eligible patients with tumors over 0.5 cm in size should receive treatment with chemotherapy in either the neoadjuvant or adjuvant setting. There is no evidence favoring the use of neoadjuvant over adjuvant therapy in terms of outcome, but the neoadjuvant setting offers the advantage of having measurable disease to assess response to therapy, providing prognostic information. In addition, neoadjuvant therapy is the preferred approach for those patients who are not operable at diagnosis or who are not candidates for breast conserving therapy due to tumor size or location. Pathologic complete response TNBC has a higher response rate to neoadjuvant chemotherapy compared to breast cancers that are ER positive and a similar response rate to those that are HER2 positive. Those with TNBC who achieve a pathologic complete response (pCR) have improved outcomes compared to those who have residual disease. 14,15 In a pooled analysis by Cortazar et al., there was an improvement in event free survival (EFS) (HR 0.24) and OS (HR 0.16) in patients with TNBC who achieved a pCR. However, pCR could not be validated as a surrogate endpoint for survival on a trial level analysis. 15 In the neoadjuvant CALGB 40603 study, a pCR in the breast and axilla was associated with a 70% decrease in the risk of recurrence and an 80% decrease in the risk of death at three years. 16 However, despite significantly more patients with TNBC achieving a pCR than those with luminal breast cancers, those with TNBC have a higher risk of recurrence. This paradox is likely due to the poorer prognosis of patients with residual disease. Residual disease in patients with TNBC confers a worse prognosis than residual disease in those with non-TNBC, with a significantly shorter recurrence free survival, decreased overall survival, and increased likelihood of developing visceral metastases. 17,18 Choice of regimen Similar to treatment of hormone positive or HER2 positive breast cancer, the preferred chemotherapy regimens in either the neoadjuvant or adjuvant setting contain an anthracycline and/or a taxane. The optimal regimen is not well defined and the choice of therapy ultimately depends on patient characteristics and preferences. There has been question of whether anthracyclines could be withheld in patients with HER2 negative breast cancer in the curative setting in order to avoid additional toxicity. A large pooled analysis by Gennari et al. in 2008 showed no added benefit in terms of disease-free or overall survival for the addition of an anthracycline to adjuvant chemotherapy. 19 In addition, in a phase III trial by Jones et al. in 2006 comparing adjuvant doxorubicin plus cyclophosphamide (AC) to docetaxel plus cyclophosphamide (TC) in all E U ROPEAN ON COL OGY & HAEMATO LOG Y Figure 1: Venn diagram depicting the relationship between the triple negative immunophenotype and the basal-like molecular subtype Basal-like • Express basal cytokeratins • 20–40% are not triple negative Triple negative and basal-like Triple negative • ER/PR negative, HER2 negative • 20–30% are not basal-like ER = estrogen receptor; HER2 = human epidermal growth factor 2; PR = progesterone receptor. types of breast cancer, disease-free survival (DFS) favored the TC arm and established this as an effective non-anthracycline choice. 20 However, results recently presented at the 2016 American Society of Clinical Oncology (ASCO) annual meeting of the pooled ‘ABC trials’ (USOR 06-090, NSABP B-46I/USOR 07132, and NSABP B-49) settled this question. The trials sought to evaluate whether TC was non-inferior to AC with a taxane. Results of the pooled analysis found that TC was not as effective as the regimens containing both an anthracycline and a taxane with a HR of 1.23 (p=0.04), or a 23% reduction in recurrence, favoring anthracyclines. The benefit was greatest in the HER2 negative, ER negative patients, with a HR of 1.42. 21 While increased risk of heart failure and secondary leukemia should be discussed with patients, anthracyclines should not be withheld unless clinically necessary, and TC should not be considered an equivalent regimen in patients with TNBC. Role of additional agents Improving upon the anthracycline and taxane backbone has proven to be difficult. Despite initial promise for antiangiogenic therapy in breast cancer, phase III trials of the addition of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab to adjuvant chemotherapy in TNBC failed to show improvement in disease-free or overall survival. 22 In addition, the role of the addition of the antimetabolites capecitabine and gemcitabine remains unclear, with mixed results. Recently reported long-term outcomes from the FinXX trial of adjuvant capecitabine added to docetaxel, epirubicin, and cyclophosphamide showed no significant improvements in recurrence-free survival (RFS) or OS. While the subgroup analysis did how improvement for TNBC (RFS HR 0.54, OS HR 0.55), these results should be interpreted with caution given the small sample size. The US Oncology group trial 01062 also failed to show a DFS benefit when capecitabine was added to an anthracycline and taxane backbone. 23 Furthermore, the addition of gemcitabine also did not improve outcomes in the NSABP B-38 study when added to adjuvant chemotherapy. 24 In the Japanese CREATE-X trial, adjuvant capecitabine alone did improve DFS and OS in patients with HER2 negative disease who did not achieve a pCR after neoadjuvant anthracycline and taxane therapy, with the most impressive benefit being for patients with TNBC. 25 The results are hypothesis-generating, and while capecitabine may be beneficial for a highly selective patient population, its role in early TNBC requires further study before routine clinical use. Role of platinum agents Similar to TNBCs arising in patients with germline BRCA mutations, many sporadic TNBCs also harbor defects in aspects of DNA repair, such as homologous recombination. 26 Preclinical work has shown 113