Why is Triple Negative Breast Cancer hard to detect & treat?
By Dr. Aarti Darra, Bioinformatician, Karkinos Healthcare
October is Breast Cancer Awareness Month, and Karkinos Healthcare is investing significant efforts to raise awareness of specific types of breast cancer. This article will delve into the risk factors, symptoms, genetic screening, and treatment modalities of Triple-Negative Breast Cancer.
In India, one woman is diagnosed with breast cancer every 4 minutes, and one woman dies from the disease every 8 minutes. Breast cancer is the most prevalent cancer among women, making up around 25% of all female cancer diagnoses.
Breasts are paired structures of fat, connective tissue, and glandular lobes. These structures are developed more prominently in women than in men. The cancer associated with breasts is the second most common cancer in Asia, affecting men and women both. The tumour displays a mild to aggressive form based on the representation of tissue features.
Understanding tissue features is essential for classifying and is inevitable for treatment decision-making. Features include exhibiting a biological molecule that can reveal a cancer’s properties.
There are three features for differentiating breast cancer types: Estrogen receptor, Progesterone Receptor, and Human epidermal growth factor receptor 2 (Abbreviated as ER, PR and HER2).
When breast cancer cells display estrogen receptor features, they are called ER-positive. In other words, these cells use estrogen to grow in number. Hence, administering anti-estrogen hormones as a treatment will block their growth. Similarly, when cells exhibit Progesterone Receptors, they are called PR-positive, and anti-progesterone hormone is the choice of therapy.
A tumour can display both these features, meaning it can be ER and PR positive (ER+/PR+). Breast cells can also exhibit Human Epidermal Growth Factor Receptor 2 on its surface. This factor is called HER2 positive (HER2+).
HER2 is a growth protein that helps cancer grow. It is also known as EGFR2 or ERBB2. This tumour type is not hormone-dependent, and treatment options, including surgery, drugs, or antibodies to HER2, may be chosen depending on the size and extent of the tumour’s spread.
In fact, breast cancer may not display any of these features, meaning it will be ER/PR/HER2 negative. This type is known as Triple-Negative Breast Cancer (TNBC). Hence, it is called triple-negative because the cancer cells lack three receptors: estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2).
These receptors are typically targeted in other types of breast cancer, but TNBC does not have these receptors, making it harder to treat.
It is the most aggressive form of breast cancer, meaning that it spreads fast beyond the breasts and is often detected at an advanced stage. It significantly reduces an individual’s lifespan, and the probability of recurrence of this type is very high.
To delineate the type of breast cancer or to arrive at a confirmed diagnosis, three laboratory-based biopsy tests for ER, PR, and HER2 (features) are performed. If all three tests are negative, the cancer is considered TNBC type.
Risk Factors
In India, the incidence of TNBC is higher among young women and makes up about 25% of breast cancer cases compared to 15% seen in Western countries (1). This means that as many as one in four women with breast cancer may be carrying a tumour of the TNBC type.
Looking at the statistics and understanding the risk factors would help us curb and devise prevention strategies. For example, individuals with a family history of breast cancer and those harboring alterations (or mutations) in BRCA genes are at a higher risk. BRCA stands for BReast CAncer genes, and changes in these genes increase the chance of developing breast cancer.
The genomics of breast cancer suggests that the mutations in BRCA1 and BRCA2 genes increase the risk of Breast Cancer. Around 13% of the Indian women with TNBC had BRCA alterations, implying the role of a genetic mutation (2) that proposes the need for genetic screening.
Besides genetics, menstrual and reproductive factors are also significant risk factors. Women who had their first period after the age of 15 are more likely to go for breast cancer screening.
Women who underwent breast cancer screening often had irregular periods, a higher body weight, used oral contraceptives, or had delayed age at childbirth. Women who had more children and breastfed for a long time were reported to have a lower risk of cancer (3).
Therefore, addressing both genetic and lifestyle factors is crucial in developing effective breast cancer prevention strategies in India.
Symptoms
In addition to providing knowledge on risk factors, maintaining vigilance and educating women on the symptoms and signs of breast cancer is equally important and is the first step in early diagnosis. There is a good chance of a full recovery if breast cancer is discovered early, and screening using self-examination and mammography is essential to this goal.
Here are the indicators to watch out for:
- Lumps in the breast – Lumps are usually thickened, painless areas, irregular in shape, and may feel hard and different than the rest of the breast
- Pain or discomfort in the breast that does not go away
- Change in the skin or redness in the area – Any visible change in the skin mimicking the orange peel appearance or marked with redness/soreness or rash along
- Thickening or puckering of the skin – Swelling of the breast or the feeling of dimpling or skin pulling inside
- Abnormal nipple discharge, like blood or nipple turning inwards
These are the signs, and they do not mean cancer. It requires individuals with breasts to consult a doctor for ultrasound and mammograms as screening tools to take appropriate steps.
Genetic screening
With advancements in DNA technology, screening for cancer has become accessible. Our DNA contains information that could reveal the changes that make us susceptible to cancer. For example, Changes (mutations) in two genes, BRCA1 and BRCA2, increase a person’s chance of getting breast cancer by 50-80%.
These mutations are found in about 16-18% of people with breast cancer. According to guidelines from the National Comprehensive Cancer Network (NCCN), people, even those without a family history of breast cancer, can have these changes. This is why the NCCN recommends that genetic testing for BRCA1 and BRCA2 should be done for everyone, not just those with a family history, to help catch and prevent breast cancer early.
Treatment options
Hormone therapy is not an option for treating this type of cancer because the tumour lacks the surface genes that can be targeted are not present. Depending on the size and spread of the cancer, following clinical guidelines are followed.
- For the initial stage of cancer, surgery with or without radiotherapy is followed by chemotherapy; where this approach is called Adjuvant therapy.
- For advanced cases, chemotherapy (with pembrolizumab after checking for toxicity) is given before surgery to shrink the tumour and for surgery to be less invasive, and this approach is known as neoadjuvant therapy.
A new set of molecular therapy, PARP inhibitors, is an approved therapy for individuals with a positive status of BRCA1/2 mutation. These PARP inhibitors perform better than chemotherapy during and after the treatment (5). A cancer signature called HRD (Homologous Recombination Therapy) is also an indication for the above therapy. It is showing promise in research and will be an advancement that would enable tailored treatment (6) in individuals with no mutations in BRCA genes.
Conclusion
Thus, early screening, along with surveillance of family history and understanding of the genetic cause, will be a stepping stone in reducing the burden and improving the survival rate of TNBC.
References:
- Sarkar S, Akhtar M (2022) Triple Negative Breast Cancer Prevalence in Indian Patients over a Decade: A Systematic Review. Int J Clin Biostat Biom 8:045. doi.org/10.23937/2469-5831/1510045
- Rajagopal, T., Seshachalam, A., Jothi, A. et al. Analysis of pathogenic variants in BRCA1 and BRCA2 genes using next-generation sequencing in women with triple negative breast cancer from South India. Mol Biol Rep 49, 3025–3032 (2022). https://doi.org/10.1007/s11033-022-07129-2
- Das, U., Soren, S. & Kar, N. Menstrual and reproductive factors associated with risk of breast cancer among Indian women: a cross sectional study from National Family Health Survey, 2019-21. Arch Public Health 82, 55 (2024). https://doi.org/10.1186/s13690-024-01266-9
- Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up☆Loibl, S. et al.Annals of Oncology, Volume 35, Issue 2, 159 – 182
- Barchiesi, G.; Roberto, M.; Verrico, M.; Vici, P.; Tomao, S.; Tomao, F. Emerging Role of PARP Inhibitors in Metastatic Triple Negative Breast Cancer. Current Scenario and Future Perspectives. Front. Oncol. 2021, 11, 769280
- Daly, G.R., Naidoo, S., Alabdulrahman, M. et al. Screening and Testing for Homologous Recombination Repair Deficiency (HRD) in Breast Cancer: an Overview of the Current Global Landscape. Curr Oncol Rep 26, 890–903 (2024). https://doi.org/10.1007/s11912-024-01560-3.
Dr. Aarti Darra is currently working as a Bioinformatician at Karkinos Healthcare. With a profound interest in cancer genomics and microbiome research, she brings extensive expertise to her role, underpinned by her research experience and commitment to integrating genomics into clinical practice.