Triple-negative breast cancer is a subtype of breast cancer that is clinically negative for expression of estrogen and progesterone receptors (ER/PR) and HER2 protein. It is characterized by its unique molecular profile, aggressive behavior, distinct patterns of metastasis, and lack of targeted therapies. Although not synonymous, the majority of triple-negative breast cancers carry the “basal-like” molecular profile on gene expression arrays. The majority of BRCA1-associated breast cancers are triple-negative and basal-like; the extent to which the BRCA1 pathway contributes to the behavior of sporadic basal-like breast cancers is an area of active research. Epidemiologic studies illustrate a high prevalence of triple-negative breast cancers among younger women and those of African descent. Increasing evidence suggests that the risk factor profile differs between this subtype and the more common luminal subtypes. Although sensitive to chemotherapy, early relapse is common and a predilection for visceral metastasis, including brain metastasis, is seen. Targeted agents, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and poly (ADP-ribose) polymerase (PARP) inhibitors, are currently in clinical trials and hold promise in the treatment of this aggressive disease.
More recently, scientific efforts aimed at dissecting the biology of triple-negative breast cancer have revealed several promising targeted strategies including EGFR-targeted agents, antiangiogenic agents, and PARP inhibitors.
• EGFR Inhibitors—As mentioned previously, EGFR expression is seen in approximately 60% of triple-negative breast tumors, thus providing a rational, targeted treatment approach. Cetuximab (Erbitux) a chimeric monoclonal antibody targeting EGFR, elicits little response to single-agent therapy in the setting of advanced triple-negative breast cancer. However, a phase II trial evaluating the combination of cetuximab and carboplatin (area under the concentration-time curve [AUC]2, weekly for 3 of 4 weeks) reported a response rate of 18% and overall clinical benefit rate of 27% among 102 patients with advanced pretreated triple-negative breast cancer. Time to progression was 2 months, and overall survival was 12 months, which reflects the aggressive nature of this disease.
A second study evaluating the combination of irinotecan and carboplatin with or without cetuximab reported response rates of 49% and 30%, respectively, among 72 patients with pretreated triple-negative breast cancer. The incidence of toxicity, including grade 3/4 fatigue, diarrhea, vomiting, neutropenia, and thrombocytopenia, was higher among patients who received cetuximab.
• PARP Inhibitors—PARP1, a gene that encodes a chromatin-associated enzyme that modifies various nuclear proteins, is involved in the molecular events leading to cell recovery from DNA damage. When PARP1 is inhibited, double-strand DNA breaks accumulate that under normal conditions would be repaired via homologous recombination. Both BRCA1 and BRCA2 are required for the homologous recombination pathway to function properly. Therefore, cells deficient in either BRCA1 or BRCA2 are exquisitely sensitive to PARP1 inhibition, resulting in cell death/apoptosis.[56,57] Inhibition of the PARP pathway has become an attractive research question for patients with BRCA-associated malignancies. Several PARP1 inhibitors (ie, AZD2281, BSI-201) are currently in clinical development and hold promise in this unique setting.[1,58,59]
• Antiangiogenic Agents—The antiangiogenic agent bevacizumab (Avastin), a monoclonal antibody targeting all forms of vascular endothelial growth factor (VEGF)-A, is active in a variety of solid tumors including breast cancer. The landmark study E2100 illustrated improvement in progression-free survival (11.8 vs 5.9 months, HR = 0.60, P < .001) when adding bevacizumab to paclitaxel chemotherapy compared with single-agent paclitaxel alone in first-line treatment of metastatic disease. Subset analyses indicated that the treatment effect persisted among ER/PR–negative patients (HR = 0.53, 95% confidence interval = 0.40–0.70) in this largely (> 90%) HER2-negative patient population. Additionally, small-molecule inhibitors of the VEGF pathway appear to have activity in the subset of pretreated triple-negative breast cancer; definitive studies are underway.[61,62]
Several contemporary studies are examining antiangiogenic strategies alone or in tandem with other investigational approaches in triple-negative breast cancer. CALGB 40603, for example, is a neoadjuvant study examining the benefit of carboplatin added to paclitaxel and the benefit of bevacizumab added to primary chemotherapy. Echoing the oft-noted need for better tissue correlates in targeted therapy trials, this is a clinical trial with correlative science studies embedded; pretherapy research biopsies are mandatory. This trial, which is expected to open to accrual in the fall of 2008, will not only help answer two specific clinical questions in triple-negative breast cancer—the role of platinum agents and the role of antiangiogenics—but in addition, it will provide crucial data regarding response and resistance patterns within this subtype.
In summary, triple-negative breast cancer largely represents a subtype of breast tumors with unique molecular and clinical characteristics, distinctive risk factors and patterns of recurrence, association with BRCA1 mutation status, inferior prognosis, and expanding therapeutic options. Multiple excellent approaches to improved care of triple-negative breast cancer, including DNA-damaging agents such as platinums, targeted agents against EGFR and VEGF, and PARP inhibitors are under investigation. Current research strategies are aimed at better understanding both the risk factors and the biology underlying triple-negative breast cancer, with the goal of developing preventive measures and improving treatment strategies for this challenging subtype of breast cancer.
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