Triple-Negative Breast Cancer

Overview

Breast cancer is the world’s most frequent cancer amongst women. One of the subtypes, known as triple-Negative Breast Cancer (TNBC), is characterised by an aggressive nature, poor prognosis, limited response to treatments, and high risk of recurrence.  

TNBC is defined by lack of expression of estrogen, progesterone, and human epidermal growth factor receptors, and by a high heterogeneity from both a clinical and molecular perspective. Both these features make TNBC very challenging to target with previously approved cancer drugs, such as the monoclonal antibody drug trastuzumab (Herceptin).

TNBC represents up to 26% of total breast cancers and is characterized by high recurrence and metastatic expansion. The life expectancy for patients depends on many factors, including the size and stage of progression of cancer, as well as the patient’s general health. However, according to the American Cancer Society, in more than 75% of the cases, patients’ life span is reduced to 5 years maximum, thus making early detection and intervention a critical aspect in the management of TNBC patients.

Standard diagnostic procedures for breast cancer, such as mammography or ultrasound, are often not sufficient to identify early-stage TNBC due to the elevated similarity in clinical presentation with benign tumour masses. Therefore, the high resolution of magnetic resonance imaging is used to highlight unique features of this aggressive cancer type, including the necrotic core and expanding borders, that represents clinical markers to evaluate the nature and stage of progression of TNBC.

Signs and Symptoms

Initial signs and symptoms of TNBC can easily be confounded with other less aggressive breast cancer types. These include the presence of a lump or swelling in the breast or armpit, breast pain and redness, nipple discharge, and anomalies in the shape or position of the nipples. Findings of a lump during breast self-examination are the most common way to identify the presence of breast cancer; however, tissue masses can often represent benign cysts and fibroadenomas, which can be removed through surgical intervention following a doctor’s examination and consultation.

Causes and Risk Factors

The causes underlying breast cancer are still mostly unknown. However, a series of risk factors have been identified that might contribute to the development, progression, and prognosis of these cancers, including TNBC. Indeed, although it has been observed that TNBC can develop in women of any age and ethnicity, black women under 40 years old are reported to have a higher predisposition compared to the general population. Moreover, genetic mutations in BRCA1 and BRCA2 genes running within the family have been associated with an increased risk of developing this subtype. This could be explained by looking at the role played by genes in the BRCA family within the cell. Extensive studies have shown that BRCA genes are involved in DNA damage repair, cell cycle checkpoint control, regulated cell death and gene expression. Therefore, alteration in their sequence and function may cause uncontrolled cellular proliferation and defective repairing mechanisms, ultimately leading to tumour formation, expansion and spreading.

Diagnosis

At the initial examination, TNBC presents as a tissue mass that can be detected by self-examination. Mammography and ultrasound imaging techniques usually represent the first tier for medical imaging in cases of suspected breast cancer. However, with their level of resolution, tumours appear like non-calcified hyperdense mass, without any information on the unique morphological features of TNBC lesions, thus making the diagnosis inconclusive or, even more dangerously, incorrect.

In contrast, unique clinical markers can be observed following high-resolution magnetic resonance that would highlight features of the tumour such as rim enhancement, areas of high intratumoral T2 signal intensity, lobulated shape, and smooth margins.

Following medical imaging, tissue biopsy is recommended to collect a sample of the breast tumour that will be observed under the microscope. The diagnosis of TNBC is also achieved by laboratory testing looking at the expression of receptors for estrogen, progesterone and human epidermal growth factor on the surface of the of the tumour cells.

Volumetric rendering of a full human body captured using a combination of Positron Emission Tomography (PET) and Computed Tomography (CT) techniques to obtain information on both anatomy and metabolic functions. The breast tissue appears as a dense radiolucent (dark) region. Image obtained using 3Dicom Viewer.

Treatment

Despite the effort in developing novel molecular therapies, the heterogeneity and lack of hormonal receptors on TNBC tissue masses make the tumour often unresponsive to the currently available treatment options. Therefore, surgical intervention is generally recommended to remove the tissue mass and avoid expansion and risk of spreading to other organs through the circulatory system. Depending on the size, positioning and stage of the tumour, the medical practitioner may recommend a breast-conserving surgical approach, also known as lumpectomy. This procedure leads to the removal of the cancerous (or non-cancerous) mass by also excising a rim of healthy tissue surrounding the lump (surgical margin) to minimise the risks of relapse. In most complex cases, when more than one tumour is identified in the breast, or malignant calcium deposits are observed throughout the breasts, the removal of the whole breast through a procedure known as mastectomy.

In the presence of large tumour masses, surgical procedures can be combined with radiotherapy, which uses radiation of beams with high energy towards the region of interest to induce DNA damage and cellular death, and ultimately improving local control of the tumour mass.

From a pharmacological perspective, neoadjuvant chemotherapeutic agents can be administered in combination with other therapies or surgical interventions, aiming to reduce the tumour size and destroy circulating cancer cells. For instance, multiple DNA-damaging agents such as platinum or inhibitors of cellular duplication have been tested in BRCA-associated cases of TNBC, offering some hope for the improvement of patients’ outcomes. Nevertheless, although considerable research has been devoted to the identification of an effective therapeutic strategy for TNBC, up to date the optimal combination of treatments against this aggressive form of breast cancer has not been identified yet.

The content shared on the Health Literacy Hub website is provided for informational purposes only and it is not intended to replace advice, diagnosis, or treatment offered by qualified medical professionals in your State or Country. Readers are encouraged to confirm the information provided with other sources and to seek the advice of a qualified medical practitioner with any question they may have regarding their health. The Health Literacy Hub is not liable for any direct or indirect consequence arising from the application of the material provided.

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