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Triple negative (TN) breast cancer is defined as a subtype that is negative for estrogen receptor (ER), progesterone receptor (PgR) and human growth factor receptor2 (HER2). This cancer was diagnosed at a slightly advanced stage and with more cases positive for lymph node metastasis than other subtypes.
A large proportion of basal breast cancer was found to be negative for estrogen receptor (ER) progesterone receptor (PR) and to lack over expression/amplification of HER2. Breast cancers lacking these markers were subsequently dubbed triple negative tumors, although it should be pointed out that not all basal breast cancers are Triple Negative tumors and conversely not all Triple Negative tumors are basal type. Triple Negative tumors are not a homogenous group but differ in their gene expression, response to chemotherapeutic and biological therapies as well as prognosis.
Triple negative breast cancer represents an important clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents. The metastatic potential in triple negative breast cancer is similar to that of other breast cancer subtypes, but these tumors are associated with a short median time to relapse and death.
Patients with triple negative breast cancers have relatively poor prognosis, with significantly shorter survival and a poorer response to standard treatment strategies.
Triple Negative breast cancer accounts for approximately 15% of all breast cancer cases world-wide. The most powerful risk factors for this poor prognosis subtype of breast cancer are age less than 40 years, being non-Hispanic, black and, to a lesser extent, being Hispanic.
Studies have shown that breast cancers in women with germ-line BRACA1 mutations are more likely to be triple-negative and high-grade.
Histologically, TN tumors have broad pushing tumor borders, and are often characterized by large areas of central or geographic necrosis and fibrosis, and are often associated with a ribbon-like tumor architecture, and show a prominent lymphocytic infiltrate. Less commonly, TN breast carcinomas show metaplastic changes, with squamous and spindled tumor cells, chondroid or osseous metaplasia, or features of carcinosarcoma .
The different faces of Triple Negative Breast Cancer include Medullary carcinoma, Metaplastic carcinoma, Adenoid cystic carcinoma.
In addition to having a short disease-free survival, triple-negative breast tumors are aggressive in the metastatic setting, significantly contributing to the shortened overall survival.
Even in early-stage TNBC, early relapse is common. There is a predilection for visceral metastasis, including lung, liver and, notably, brain metastasis. Current estimates are that approximately 15% of TNBC patients develop brain metastasis. The risk for developing brain metastasis is higher for patients with TNBC than with other types of breast cancer. Studies have shown that even in patients with cerebral metastasis, TNBC patients have a poor prognosis, as metastasis to the brain occurred earlier.TNBC is often categorized as the basal subtype. In actuality only 85% of TNBC are basal-like with the remaining composed of a heterogeneous groups.
Gene expression profiling studies have noted TNBC to be heterogeneous being composed of further subgroups including the basal-like, claudin-low, HER2-enriched and the interferon-rich subgroups each with distinct prognostic outcomes.
Diagnosis of breast cancer is carried out by triple assessment which includes clinical evaluation, breast imaging, and tissue diagnosis (cytological or histological assessment).
TN cancers are a distinct entity. In imaging, some radiological characteristics that are predictive of this cancer subtype have been described and radiologists should be aware of these: the appearance of a mass on mammography, sonography and MRI; clear or even marked hypoechogenicity, posterior enhancement; rim-enhancement on MRI, visible enlarged axillary lymph nodes. Some TN tumors that may be interpreted as being benign based on conventional radiological investigations may show suspicious features on MRI.
TNBC patients do not have the option of endocrine or anti-HER2 therapy as they lack the targets for these agents. In the absence of targeted treatment, the current option is chemotherapy. Patients with chemo sensitive disease lack a standardized approach. Patients with cytotoxic resistant disease are in urgent need of new therapies.
TNBC is treated with a combination of surgery, radiation and chemotherapy. Because it tests negative for the three receptors mentioned above, it isn’t treated with hormone or targeted therapy. Chemotherapy works well in TNBC. It may work even better for TNBC than for other types of breast cancer.
As data continue to emerge regarding optimal therapeutic regimens for patients with TNBC, the current mainstay of treatment is systemic cytotoxic chemotherapy.
Despite consensus regarding increased chemo sensitivity in TNBC, there is no agreement regarding optimal choice or schedule of cytotoxics. Most evidence derives from retrospective, subgroup analyses with small patient numbers and inadequate power. Whilst most clinicians would currently employ an intensive approach, including an anthracycline and a taxane, and the notion of DNA damaging platinums is gaining popularity, there is currently limited prospective evidence to support these approaches in TNBC populations.
The search for new therapeutic targets in triple negative breast cancer has been intense over the past several years. Recent studies targeting specific molecular defects characteristic of this disease, specifically DNA repair defects, have identified potential targets for the treatment of patients with triple-negative breast cancer. The challenge at present is to narrow the gap between the current standard in the clinic with that in the laboratory. Efforts to identify and validate predictive biomarkers of response are critical to rationally accelerate the clinical development of these novel treatment strategies in the adjuvant setting. Targeted & recent treatment options include: PARP inhibitors, Antiangiogenic therapy, EGFR antagonists, Src Inhibitors as Dasatinib.
TNBC seems to be more aggressive than other breast carcinoma subtypes. Therefore, it is necessary to analyze if a more aggressive surgical treatment should be offered to this subgroup of patients. Many studies have been conducted to analyze medical treatments in patients with triple negative breast cancer, but only a few are addressed to surgical treatment.
Triple-negative breast cancer remains a major challenge to physicians and patients, and a source of great interest to laboratory investigators. Although triple-negative breast cancer accounts for a relatively small minority of breast cancer cases, it is responsible for a disproportionate number of breast cancer deaths. Moreover, there have been fewer advances in the treatment of triple-negative breast cancer than have been seen with other subtypes.
The recent focus on this subgroup of tumors has arisen for two major reasons. First, unlike tumors that are estrogen receptor and/or HER2 positive, triple-negative tumors lack an established therapeutic target. As a result, conventional chemotherapy is the only effective systemic treatment for these patients and there is an urgent need for new treatment approaches. Second, recent developments in gene expression arrays have categorized breast cancer into distinct subgroups.