Triple Negative Breast Cancer Types detection and diagnosis

What is Triple Negative Breast Cancer?
In our body, cell division is kept under very strict vigilance, both by the same cell, as well as by those of the Immunity system. Since the signal for a cell to divide (or stop dividing) begins from the DNA level, it is of no surprise that gene mutations play a large role in the development of cancer . In some cancers, the cells exhibit receptors on their surface which bind to external signals and turn on cell proliferation. If the receptors for these growth promoting signals are over-expressed due to genetic mutations, cells proliferate more. An advantage of such types of cancer is, one can target these overexpressed receptors and block them to prevent the increased signal from causing uncontrolled cell growth. This is the basis of several protocols that are used for treatment of cancer. However, some cancers may also develop without expressing such receptors. Needless to say, the treatment of such cancers is more challenging. One example of this type of cancers is triple negative breast cancer .

What does it mean when breast cancer is triple-negative?
The classification of cancer types is done by techniques such as microarray analysis and next genome sequencing. These techniques allow cancers to be distinguished based on the molecular markers (molecules present in/on surface of these cells that distinguish them from other cells) they carry. In this way, breast cancers can be either estrogen (ER) positive or estrogen negative, based on whether they have estrogen receptor, or not. Molecular markers also dictate the treatments that can be used for that particular type of cancer. Thus, Tamoxifen is a drug that is used as a part of hormone therapy for those cancers that exhibit hormone receptors. Another example is Herceptin for cancer cells that overexpress HER2. A similar type of breast cancer is Triple Negative Breast Cancer. It is one of the most aggressive types of breast cancer. Widely considered as an orphan disease, Triple Negative Breast Cancer is characterized by the absence of three receptors on the surface of the cancer cells. These receptors are estrogen receptors, progesterone receptors, and epidermal growth factor receptor 2 (HER-2/neu). Triple Negative Breast Cancer is a major cause for concern in India, as it has a prevalence of 43.5%. Since these cancers do not respond to hormones therapy, development of long-term therapeutic strategies is the need of the hour.

Book CA 15.3 Breast Cancer marker test

Who is most at risk for triple-negative breast cancer?
- Triple Negative Breast Cancer usually presents at a younger age (premenopausal women, lower than 50 years) as compared to non-Triple Negative Breast Cancers.
- These tumors are larger in size as compared to other tumors at the time of presentation and are also diagnosed at later stages (stage III). Triple Negative Breast Cancers are therefore more rapid growing and aggressive.
- Triple Negative Breast Cancers are associated with BRCA1 mutations, and are more common in some ethnicities than others. The highest percentage of Triple Negative Breast Cancer cases is reported to be in India.
- Many casesof Triple Negative Breast Cancer are also reported to show node involvement (spread of the cancer to lymph nodes).
- The recurrence of cancer after treatment of Triple Negative Breast Cancer is reported to occur earlier than recurrences of other cancers. However, the higher risk is present only for 2 to 3 years after treatment and starts to decline after 5 years'. Triple Negative Breast Cancers generally have poorer prognosis, and metastasis also occur earlier in Triple Negative Breast Cancers as compared to other cancers.
- Triple Negative Breast Cancers are reported to respond better to chemotherapeutic drugs, which is the main mode of treatment of Triple Negative Breast Cancer. Those most at risk of Triple Negative Breast Cancer are...
- People who have BRCA1 and BRCA2 mutations
- Younger women (under 50 years of age)
- Asians (including Indians), Hispanics and African Americans
- Those with previous history of breast cancer
- As per some studies, reproductive factors like higher number of children, reduced breast feeding, greater use of oral contraception, being premenopausal are also linked with Triple Negative Breast Cancer

What are the different types of triple negative breast cancer?
Gene expression studies have been carried out to understand the extent of heterogeneity of Triple Negative Breast Cancer. While most of cells found in Triple Negative Breast Cancer tumor (70%) are basal like cells, other subtypes of cells are also found in Triple Negative Breast Cancer. Classification by Lehman and colleagues has divided Triple Negative Breast Cancer into 7 different subtypes.

These subtypes are:
- Basal-like 2 (B12)
- Immunomodulatory (IM)
- Mesenchymal (M)
- Mesenchymal Stem-Like (MSL)
- Luminal Androgen Receptor (LAR)
- Unstable Subtype (UNS)
The division of Triple Negative Breast Cancer into these subtypes can also assist in therapy selection as they are based on gene expression profile. For instance, basal-like tumors are characterized by the increased activation of pathways of cell cycle and DNA damage response (ATR and BRCA). In these subtypes, targeting DNA damage pathways, therefore, is an effective therapeutic approach. Two agents that are used for this treatment protocol are platinum salt and PARP inhibitors. Platinum based therapeutic agents are also being tested for treatment of metastatic Triple Negative Breast Cancer.

How is triple negative breast cancer detected and diagnosed?
Currently no screening techniques are used specifically for Triple Negative Breast Cancer, routine self-examination of breast is ideally recommended to look out for suspicious masses for breast cancer in general. Genetic testing may sometimes be done but is not recommended for routine screening. Imaging techniques used for identifying Triple Negative Breast Cancer are the same as other types of breast cancers, but Triple Negative Breast Cancer present with different imaging features.
Mammography- Triple Negative Breast Cancer infrequently or rarely show the spiculated margins, irregular shape and calcifications that are exhibited by other breast cancers. Despite being larger in size, Triple Negative Breast Cancer tumors may remain hidden in the mammogram in some cases. Some Triple Negative Breast Cancer tumors may show circumscribed and microlobulated margins, focal asymmetry and a mass associated with calcifications (isolated calcifications are rare).
Ultrasound- highly sensitive for detection of Triple Negative Breast Cancer, the tumor presents as a discrete mass lacking suspicious sonographic features
MRI- also extremely sensitive for Triple Negative Breast Cancer, MRI scans show the morphological features of Triple Negative Breast Cancer more clearly. Triple Negative Breast Cancer mass is most commonly reported to be oval or round shaped with dominant margins. In addition, biopsy can be done for confirmation of Triple Negative Breast Cancer diagnosis.

Is there treatment for triple-negative breast cancer?
The absence of cell surface receptors in Triple Negative Breast Cancer means that this type of cancer does not respond to hormone therapy which are commonly used for treatment of breast cancer. These treatments target hormone and growth factor receptors which are overexpressed in most cancer cells. Hormonal therapies and HER2-targeted therapies inhibit the proliferative effect that estrogen, progesterone and HER2 have on breast cells. Inhibiting the proliferation of cancer cells helps to reduce the spreading of tumor.
- Current treatment for triple-negative breast cancer Treatment for Triple Negative Breast Cancers usually requires combination therapies and involves radiotherapy, chemotherapy, and surgery. Triple Negative Breast Cancers respond better to neoadjuvant therapy, in which chemotherapy drugs are administered before surgery to reduce tumor size. Surgery is done to remove the tumor, either by removing the whole breast (mastectomy) or removing the lump (lumpectomy). The surgery may be followed further by chemotherapy to eradicate any cancer cells that may have spread into other parts of the body. Radiation treatment can be done following lumpectomy. Immune therapy is also practisedfor treatment of some subtypes of Triple Negative Breast Cancer.

Preventive Health Checkup Packages

Future Aspects treatment for Triple Negative Breast Cancer
Some of the treatment strategies that are currently being investigated for Triple Negative Breast Cancer involve:
- Targeting the BRCAness of Triple Negative Breast Cancer- since Triple Negative Breast Cancers are associated with BRCA mutation, treatment with agents such as PARP inhibitor has shown promising results. BRCA is a gene involved in DNA damage repair. In the absence of BRCA, the cancer cell has to turn to PARP based pathway to repair its damaged DNA. This process can be inhibited by using PARP inhibitors, which prevents cancer cells from repairing damage to their DNA and succumbing to that damage.
- Inhibitors of PAM pathway- the PAM pathway controls the cell cycle from survival to cell death and is therefore important in the formation of tumor and its progression. Activation of the PAM pathway often results in development of chemoresistance in breast cancer.
- EGFR inhibitors. Epidermal Growth Factor Receptor 1 (HER1) is markedly overexpressed in Triple Negative Breast Cancer, which contributes to its poor prognosis. HER1 proteins could be targeted by monoclonal antibodies and/or tyrosine kinase

View Our Editorial Policy