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Deng Hong, Department of Oncology, Guangdong Provincial Hospital of Traditional Chinese Medicine
Triple negative breast cancer (TNBC) is a special type of breast cancer that is negative for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2). TNBC lacks endocrine and anti-HER2 therapeutic targets, and there is no standard treatment protocol for TNBC.
Treatment recommendations for TNBC in major clinical guidelines
Currently, the treatment of breast cancer follows the St. Gallen consensus, the National Comprehensive Cancer Network (NCCN) guidelines, the American Society of Clinical Oncology (ASCO) guidelines and the European Society of Medical Oncology (ESMO) guidelines. For the treatment of TNBC, the St. Gallen consensus only briefly mentions that chemotherapy should be the mainstay, and the ASCO guidelines do not specifically mention the treatment of TNBC. The ESMO guidelines and the NCCN guidelines, on the other hand, have separate chapters discussing the treatment of TNBC (Tables 1 and 2).
Current status of treatment for TNBC
The medical treatment of TNBC is still dominated by chemotherapy. TNBC is more sensitive to DNA double-strand breakers, such as platinum and topoisomerase I and II inhibitors. Clinical studies of neoadjuvant chemotherapy have shown that cisplatin alone can achieve high rates of complete pathological remission.
However, the US Food and Drug Administration (FDA) has not approved any drugs specifically for TNBC. Treatment options for advanced TNBC are limited. Most patients have long been treated with anthracyclines, paclitaxel, and cyclophosphamide, and once relapsed and metastasized, there are few options available and the prognosis for patients is extremely poor.
Research directions of TNBC treatment
In the past 5 years, the focus of research on TNBC treatment has gradually focused on molecularly targeted drugs, including epidermal growth factor receptor (EGFR) antibodies, small-molecule single- and multi-target tyrosine kinase inhibitors (TKI), anti-angiogenic [vascular endothelial growth factor (VEGF) antibodies] and key enzymes that act on cell proliferation and DNA repair [e.g., poly(adenosine diphosphate ribose) polymerase 1 (PARP1)], etc. (Table 3). These advances in drug research are expected to provide more therapeutic options for TNBC patients to increase the cure rate and improve the prognosis.
PARP1 inhibitor-related studies
PARP1 is a key enzyme in the process of cell proliferation and DNA repair. Studies have shown that BRCA1 gene-deficient TNBC cells are sensitive to PARP1 inhibitors.
ASCO 2009 Annual Meeting reported the results of a multicenter, randomized, open phase II clinical study using gemcitabine/carboplatin (G/C) in combination with PARP1 inhibitor BSI-201 for the treatment of TNBC.
Patients were randomized to either the G/C group or the G/C + BSI-201 group for treatment. The results showed that patients in the G/C + BSI-201 group had significantly higher objective remission rates (48% vs. 16%) and clinical benefit rates (62% vs. 21%) compared to the G/C group; median progression-free survival (6.9 months vs. 3.3 months) and median overall survival (9.2 months vs. 5.7 months) were also significantly longer. It was also observed that BSI-201 was safe as well as well-tolerated by patients when combined with G/C.
However, the results of recently reported phase III clinical trials applying PARP1 inhibitors have been disappointing.
EGFR antibody-related studies
In terms of antibody therapy, there is also a first glimpse of the role of cetuximab in advanced TNBC.
The Translational Breast Cancer Research Consortium (TBCRC) 001 phase II multicenter clinical study showed that first-line treatment with cetuximab in combination with carboplatin in patients with advanced TNBC significantly improved objective efficiency (18% vs. 6%) compared to the sequential carboplatin group after progression on cetuximab alone.
In a phase II clinical study by the US Oncology Group, patients with metastatic breast cancer were randomized to either the irinotecan+carboplatin or irinotecan+carboplatin+cetuximab treatment groups. In the TNBC subgroup analysis, the objective effective rates were 30% and 49% in the two groups, respectively.
In addition, three randomized, open phase II clinical studies of cetuximab in combination with carboplatin or cisplatin for metastatic TNBC (NCT04203-29, NCT00492375 and NCT 00463788) were initiated from December 2006 to June 2007, and we look forward to the release of relevant survival data.
Other Related Studies
Multi-targeted TKI in TNBC treatment is increasingly studied. Preclinical trials have demonstrated that TNBC may be sensitive to dasatinib treatment. Phase II clinical trials evaluating the efficacy of dasatinib as a second-line agent for the treatment of TNBC that is relapsed, locally advanced, or has distant metastases are ongoing.
For anti-angiogenic therapy, phase III clinical studies of chemotherapy in combination with bevacizumab are ongoing in patients with early postoperative adjuvant therapy and in patients with advanced TNBC (BEATRICE trial and NCT00472693, respectively).
Phase II clinical studies evaluating the efficacy of the mTOR inhibitor everolimus in combination with neoadjuvant chemotherapy in TNBC are also underway.
Clinical studies are also underway with new agents such as EndoTAG-1 (a cationic liposomal paclitaxel) alone or in combination with other chemotherapeutic agents for the treatment of advanced TNBC.
Because of the many studies underway, no survival data have been published yet. Let’s wait and see, hoping to find targeted drugs for TNBC patients, which will help to develop a standard protocol for TNBC treatment.
(Author: Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences)