Triple-Negative Breast Cancer (TNBC): Understanding Diagnosis and Treatment

Triple Negative Breast Cancer (TNBC) is one of the most aggresive types of breast cancer. It’s the kind of breast cancer that doesn’t have estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2. The lack of these receptors in the breast cancer cells affects both the prognosis and treatment options for patients. And the lack of these common receptors makes traditional breast cancer treatments ineffective. The molecular profile is what sets TNBC apart from other types of breast cancer so the treatments available for hormone receptor positive or HER2 positive breast cancer can’t be used.

TNBC makes up about 10-20% of all invasive breast cancers, so it’s relatively common. ^[3] Its aggressive nature and unique characteristics have made it a hot topic of research and clinical interest in recent years. The lack of the three receptors not only defines TNBC but also affects its behavior, treatment options and prognosis in general.

Table of Contents

• Epidemiology and Risk Factors
• Symptoms and Diagnosis
• Clinical Characteristics and Prognosis
• Molecular Subtypes
• Treatment Strategies
• TNBC Living
• Follow-up and Recurrence Risk
• Challenges and Future Directions
• Closing Thoughts
• References

Epidemiology and Risk Factors

There is an epidemiological profile for TNBC, which is more frequently diagnosed among specific types among different ethnicities, with higher frequencies seen in African American women, perimenopausal women, BRCA1 carrier women. It presents at similar mean ages as breast cancer but usually advanced. Potential risk factors reported for TNBCs include:

Risk factors for TNBC

Race and ethnicity: TNBC is more common in African American and Hispanic women than other ethnicities and races. ^[5]

Age: TNBC is more common in women under 40.

Genetic predisposition: People with mutations in the breast cancer gene, specifically BRCA1 and BRCA2 have a higher risk of TNBC. These gene mutations can cause uncontrolled tumor growth so there’s a strong link between BRCA mutations and TNBC risk in women.

Obesity: Some studies show a link between obesity and TNBC, especially in premenopausal women.

Finding high risk individuals and giving them targeted prevention is key to these risk factors.

Symptoms and Diagnosis

Triple negative breast cancer (TNBC) is hard to diagnose because it doesn’t have the typical symptoms of other breast cancers. However, here are some signs and symptoms that may indicate TNBC:

• A new lump or thickening in the breast
• Changes in the size or shape of the breast
• Dimpling or puckering of the breast skin
• Redness or scaliness of the skin
• Nipple discharge or tenderness
• Changes in the size or shape of the nipple

Diagnosing TNBC involves a combination of clinical tests. These may include mammography, ultrasound and MRI to visualize the breast tissue. But the most definitive test is a biopsy where a sample of the breast tissue is examined under the microscope. ^[1] If the biopsy shows the cancer cells are ER negative, PR negative and HER2 negative, the diagnosis of TNBC is confirmed. This exact identification is important because it guides the treatment and differentiates TNBC from other breast cancers.

Clinical Characteristics and Prognosis

TNBC has a clinical behavior that changes patient outcome. Here are the major clinical characteristics:

Fast growing: The tumor grows aggressively in most patients and seems to grow faster than other breast cancers.

High grade tumors: Most cases are high grade tumors; very few are low grade and those are more conservative than TNBC.

Early recurrence: The risk of recurrence in TNBC peaks within the first 3 years after diagnosis, unlike other breast cancer subtypes where the risk of recurrence can persist for many years.

Metastatic patterns: TNBC is more likely to metastasize to visceral organs, particularly the lungs and brain, rather than bones. Affected lymph nodes can indicate TNBC spread and guide treatment decisions especially on surgery, chemotherapy and radiation protocols.

So patients with TNBC have poorer prognosis compared to other breast cancer subtypes. In fact TNBC has poorer 5 year mortality rate from diagnosis. Overall survival rates are worse in the TNBC population vs non-TNBC across all stages. This only emphasizes the need to come up with more and better treatment against this aggressive recurring variant.

Molecular Subtypes

Recent genomic studies have shown that TNBC is not a single disease but has several molecular subtypes. ^[7] The 4 main subtypes are:

Basal-like 1 (BL1): Cell cycle and DNA damage response pathways

Basal-like 2 (BL2): Growth factor signaling pathways

Mesenchymal (M): Epithelial-mesenchymal transition and stem cell features

Luminal Androgen Receptor (LAR): Androgen receptor signaling

This molecular heterogeneity is the reason for the clinical variability of TNBC and emphasizes the need for personalized approach. Understanding these subtypes is very important for targeted therapy and treatment prediction. ^[6]

Treatment Strategies

Treatment for TNBC is challenging because there are no traditional drug targets in cancer treatment. However, there are several approaches that show promise:

Chemotherapy: It is still the mainstay of treatment for TNBC. ^[4] TNBC is generally chemosensitive and anthracyclines and taxanes have shown activity against the disease. Neoadjuvant chemotherapy before surgery to downstage the tumor is common, and outcomes are better for those with pathological complete response. The evolving landscape of TNBC treatment includes new therapies being studied and developed.

Breast Conserving Surgery: In TNBC treatment, breast conserving surgery with radiation is often done. This targets the remaining breast tissue after surgery, hence its importance in comprehensive cancer treatment.

Immunotherapy: Some patients with TNBC have benefited from PD-L1 inhibitors. ^[8]

PARP inhibitors: These drugs take advantage of the defects in the DNA repair pathway and have shown to be effective in BRCA mutated TNBC.

Antibody-Drug Conjugates: These targeted therapies are emerging as new options for TNBC treatment.

Androgen Receptor Targeted Agents: May be effective in LAR subtype of TNBC.

Clinical Trials: Clinical trials are important in researching new treatments for TNBC. They offer patients to join studies that may give access to new treatments, potentially better than standard treatment.

TNBC Living

Living with triple negative breast cancer can be emotionally and physically challenging. But there are ways to cope with the diagnosis and treatment:

• Get support: Reach out to family, friends and support groups for emotional and practical help.
• Practice stress-reducing techniques: Meditation, yoga, deep breathing exercises can help manage stress.
• Stay active: Regular exercise can reduce fatigue, improve mood and overall well-being.
• Consider therapy: Professional help can address emotional issues and provide coping mechanisms.
• Connect with others: Online forums and support groups can give you a sense of community and shared experience with other TNBC women.

Remember, each TNBC is different. What works for one may not work for another. By getting support and staying informed, TNBC women can better navigate the diagnosis and treatment.

Follow-up and Recurrence Risk

After finishing treatment for triple negative breast cancer, follow-up care is important to watch out for any recurrence. American Cancer Society recommends the following follow-up schedule:

• Every 3-6 months for the first 3 years
• Every 6 months for the 4th and 5th year after treatment
• Annually after 5 years

During these follow-up visits, your doctor will do physical examination to check for any signs of recurrence, review your medical history and discuss any new symptoms or concerns you may have.

Also, be aware of the recurrence risk of TNBC. According to National Cancer Institute, the risk of recurrence for TNBC is higher than other breast cancer types, especially within the first few years after diagnosis. But with regular follow-up and monitoring, recurrence can often be detected early and treated promptly.

By following the recommended follow-up schedule and being proactive with your health, you can manage the risks and live well after TNBC treatment.

Challenges and Future Directions

Despite the progress, treatment for triple negative breast cancers (TNBC) still has many challenges due to its aggressive nature and need for better treatment options: ^[2]

Biological heterogeneity: The molecular landscape of TNBC is complex. Most breast cancers are classified based on the presence of specific hormone receptors such as estrogen and progesterone which are important in determining treatment plan and tumor behavior. TNBC does not have these common receptors.

Drug resistance: Many patients develop resistance to initial treatment and relapse.

Limited targeted therapies: Precision medicines where common targetable mutations are few and far between, hence many targeted therapies are limited.

Future directions to TNBC will be further subtype classification, new targets, combination regimens, and the capstone would be tailoring treatment to personalized mechanisms of action to hopefully better outcomes of TNBC.

Closing Thoughts

Triple negative breast cancer is one of the toughest to treat in breast cancer due to its aggressiveness and molecular heterogeneity with very few targeted therapy options. Research on its biology and potential drug targets gives hope for better outcomes in the future. The more we understand TNBC the more we can have better and personalized therapies.

References

^{[1] Wu, S. Y., Wang, H., Shao, Z. M., & Jiang, Y. Z. (2021). Triple-negative breast cancer: new treatment strategies in the era of precision medicine. Science China. Life sciences, 64(3), 372–388. https://doi.org/10.1007/s11427-020-1714-8}

^{[2] Zagami, P., & Carey, L. A. (2022). Triple negative breast cancer: Pitfalls and progress. NPJ breast cancer, 8(1), 95. https://doi.org/10.1038/s41523-022-00468-0}

^{[3] Kumar, P., & Aggarwal, R. (2016). An overview of triple-negative breast cancer. Archives of gynecology and obstetrics, 293(2), 247–269. https://doi.org/10.1007/s00404-015-3859-y}

^{[4] Won, K. A., & Spruck, C. (2020). Triple‑negative breast cancer therapy: Current and future perspectives (Review). International journal of oncology, 57(6), 1245–1261. https://doi.org/10.3892/ijo.2020.5135}

^{[5] Boyle P. (2012). Triple-negative breast cancer: epidemiological considerations and recommendations. Annals of oncology : official journal of the European Society for Medical Oncology, 23 Suppl 6, vi7–vi12. https://doi.org/10.1093/annonc/mds187}

^{[6] Nunnery, S. E., Mayer, I. A., & Balko, J. M. (2021). Triple-Negative Breast Cancer: Breast Tumors With an Identity Crisis. Cancer journal (Sudbury, Mass.), 27(1), 2–7. https://doi.org/10.1097/PPO.0000000000000494
Bou Zerdan, M., Ghorayeb, T., Saliba, F., Allam, S., Bou Zerdan, M., Yaghi, M., Bilani, N., Jaafar, R., & Nahleh, Z. (2022). Triple Negative Breast Cancer: Updates on Classification and Treatment in 2021. Cancers, 14(5), 1253. https://doi.org/10.3390/cancers14051253}

^{[7] Medina, M. A., Oza, G., Sharma, A., Arriaga, L. G., Hernández Hernández, J. M., Rotello, V. M., & Ramirez, J. T. (2020). Triple-Negative Breast Cancer: A Review of Conventional and Advanced Therapeutic Strategies. International journal of environmental research and public health, 17(6), 2078. https://doi.org/10.3390/ijerph17062078}

^{[8] Pareja, F., Geyer, F. C., Marchiò, C., Burke, K. A., Weigelt, B., & Reis-Filho, J. S. (2016). Triple-negative breast cancer: the importance of molecular and histologic subtyping, and recognition of low-grade variants. NPJ breast cancer, 2, 16036. https://doi.org/10.1038/npjbcancer.2016.36}