Understanding the heterogeneity of triple-negative breast cancer to develop targeted therapies

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Aishwarya Subramanian

Breast cancer has shown to be a really aggressive condition. About 12% of the women in the US are known to develop invasive breast cancer, where the disease spreads into surrounding healthy tissues ^[a]. Now it is well established that breast cancer is a very heterogeneous disease. Genome studies show that breast cancer can be categorized into four major subtypes: ER/PR positive (expressing hormone-related genes), basal-like (BL), and HER-2 positive ^[b]. 

Triple-negative breast cancer (TNBC) approximately represents 15% of all types of breast cancer^[b] and lacks both HER2 and hormone receptor (Estrogen/Progesterone) related genes expression- hence the term triple-negative. It is also known to be the most aggressive type of breast cancer- associated with poor prognosis and shorter survival rates. 

Profiling assays help to understand expression levels of different genes involved in cancer and to make an informed decision for suitable therapies to get a better prognosis. Using these approaches, TNBC can be classified under the category of basal-like type, but not all TNBC can be classified as BL^[b]. This further emphasizes the vast heterogeneity of this disease. The heterogeneous nature of TNBC has vastly limited the scope of developing targeted therapies to treat triple-negative breast cancer, as there is no unique molecular target that can be used to develop a therapy against this disease subtype. Chemotherapy is used as the standard therapy for treatment.

To develop better therapies for better outcomes of this disease it is very important to understand the nature of this subtype of breast cancer. Before molecular profiling (analysis of cancer tissue to determine the different proteins, DNA, and RNA involved in cancer formation- to help make informed treatment decisions) established the significant heterogeneity of this disease, patient outcomes and clinical data have shown that no patient has the same outcome. Some patients show a pathologic complete response (absence of residual tumor) after surgery and chemotherapy whereas some show immediate recurrence aka relapse after treatment. These data show how crucial it is to understand the disease better.

Therefore, using tools that help to understand the molecular and genetic basis of TNBC is really important. Employing these various tools to identify the different genetic changes (aka mutations) that occur in all kinds of primary breast cancer, one out of every ten tumors were identified to show mutations in the same three genes (one of them is TP53– a tumor suppressor protein). In the case of TNBC, these three genes along with BRCA mutation (may cause hereditary breast or ovarian cancer in individuals) and have either high or low numbers of cancer-resistant cells depending on the patient cases and cancer therapy which adds to the heterogeneity.

Research has shown that TNBC can be further categorized into six different subtypes based on gene expression profiling^[c], providing a better understanding and analysis of the molecular drivers of TNBC. The knowledge can further help in the development of targeted therapies. These analyses were performed on 587 different TNBC cases and have given more insights into the potential sensitivity of these subtypes towards different therapeutic drugs^[c]. 

To date, standard chemotherapy has been the go-to treatment strategy for TNBC. I hope that the use of profiling assays to understand the heterogeneity and gene expression will further help develop targeted therapies in the future. The end goal will be to improve patient outcomes and clinical response.

Works Discussed

1. Triple-negative breast cancer: treatment challenges and solutions- Joëlle Collignon, Laurence Lousberg,  Hélène Schroeder and Guy Jerusalem doi: 10.2147/BCTT.S69488
2. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies- Brian D. Lehmann,1Joshua A. Bauer,1 Xi Chen,2 Melinda E. Sanders,3 A. Bapsi Chakravarthy,4 Yu Shyr,2 and Jennifer A. Pietenpol1 https://doi.org/10.1172/JCI45014
3. Immunotherapy for triple-negative breast cancer: Existing challenges and exciting prospects- Jia H1, Truica CI2, Wang B3, Wang Y4, Ren X5, Harvey HA2, Song J6, Yang JM7. doi: 10.1016/j.drup.2017.07.002

Image Credits

Needle Biopsy, Source: National Cancer Institute, Author: Linda Bartlett (photographer)