ALDH1: A potential therapeutic target for cancer stem cells in solid tumors
What To Know About Triple-positive Breast Cancer
Triple-positive breast cancer is a type of breast cancer that tests positive for estrogen receptors, progesterone receptors, and high levels of HER2 protein.
Some types of breast cancer cells use estrogen and progesterone as well as a protein called HER2, which refers to human epidermal growth factor, to grow.
Knowing whether cancer cells have estrogen or progesterone receptors and the level of HER2 protein can help determine the best course of treatment.
This article looks at the diagnosis and treatment for triple-positive breast cancer and the outlook for people with a diagnosis of this cancer type.
These features mean that treating triple-positive breast cancer can involve using hormone therapy and drugs to target hormone receptors and HER2.
Around 10% of all breast cancers are hormone receptor-positive and HER2-positive.
Estrogen and progesterone receptors
Estrogen and progesterone receptors are proteins in cells that attach to the hormones estrogen and progesterone to allow the cells to grow. Typical breast cells have these receptors.
Some breast cancer cells also have estrogen and progesterone receptors. This means the cancer cells can attach to the hormones to grow.
If breast cancer cells have estrogen receptors, they are ER-positive. If they have progesterone receptors, they are PR-positive.
One or both of these receptors means the breast cancer is hormone receptor-positive. Hormone therapy drugs can help prevent estrogen and progesterone from attaching to the receptors to stop cancer growth. These medications include tamoxifen and differ from hormone replacement therapy drugs, which a person may take after menopause.
HER2 protein
HER2 is a protein that allows breast cancer cells to grow quickly. If breast cancer has a higher amount of HER2 than usual, the breast cancer is HER2-positive.
To diagnose triple-positive breast cancer, doctors will test a biopsy sample for hormone receptors and HER2 levels.
A doctor may use an immunohistochemistry (IHC) test to check cancer cells for estrogen and progesterone receptors.
An IHC test uses antibodies to see if they attach to certain substances in cancer cells. It can also determine whether cancer cells have hormone receptors or high levels of HER2.
A doctor may also use a fluorescence in situ hybridization (FISH) test to check HER2 levels in cancer cells.
A FISH test uses specialized fluorescent dye and DNA to show changes in chromosomes and can also show levels of the HER2 gene.
Treating triple-positive breast cancer may include using a combination of treatment methods, which may vary for each case.
Most people with breast cancer will have surgery to remove as much of the known cancer as possible. This may include partial or total breast removal.
People may have additional treatments to shrink a tumor before surgery or destroy any remaining cancer cells after surgery. This may include:
According to a 2018 article, treating triple-positive breast cancer may include using hormone therapy to target hormone receptors, either on its own or alongside drugs to target HER2.
The type of hormone therapy may depend on whether people have gone through menopause. In those who are premenopausal, treatments may include:
Tamoxifen attaches to the hormone receptors in the breast cancer cells, stopping them from accessing the hormones they need to multiply.
In people who are postmenopausal, treatments may include:
Treatments to target HER2 may include:
CDK4/6 inhibitors are a more recent treatment option to prevent cancer cell growth and include the drugs palbociclib, ribociclib, and abemaciclib. People may have CDK4/6 inhibitors in combination with hormone therapy to treat triple-positive breast cancer.
Individuals may also want to speak with a healthcare professional about participating in clinical trials currently exploring new breast cancer treatments.
The outlook for someone with triple-positive breast cancer may depend on many different factors, including:
HER2-positive breast cancer may be more likely to grow and spread more quickly than HER2-negative breast cancers. However, HER2-positive breast cancers are far more likely to respond to treatments that target the HER2 protein.
According to a 2021 article, treatment with trastuzumab and pertuzumab may improve the outcome for HER2-positive breast cancers. Advances in anti-HER2 treatments have resulted in significant outlook improvements for people with HER2-positive breast cancer.
The research also suggests 5 to 10 years of hormone therapy treatment for hormone receptor-positive breast cancer may significantly improve survival rates.
Hormone receptor-positive breast cancer may grow more slowly than hormone receptor-negative breast cancers. People with hormone receptor-positive breast cancer may have a more positive short-term outlook, although the cancer may return after treatment.
Triple-positive breast cancer means the breast cancer cells test positive for estrogen receptors and progesterone receptors and have higher than usual levels of HER2 protein.
This means that hormone therapy and drugs targeting HER2 may help treat triple-positive breast cancer. Other treatments may include surgery, chemotherapy, and radiation therapy.
The outlook for people with triple-positive breast cancer may depend on various factors, including the stage of cancer, how the cancer responds to treatment, and a person's age and overall health.
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 FactorsThere 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 TNBCRace 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 DiagnosisTriple 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:
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 PrognosisTNBC 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 SubtypesRecent 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 StrategiesTreatment 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 LivingLiving with triple negative breast cancer can be emotionally and physically challenging. But there are ways to cope with the diagnosis and treatment:
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 RiskAfter 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:
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 DirectionsDespite 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 ThoughtsTriple 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.0000000000000494Bou 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
Progesterone Receptor Positive (PR+) Breast Cancer: Characteristics, Treatment And Prognosis
Progesterone Receptor Positive (PR+) breast cancer is a distinct biological subtype of hormone receptor positive breast cancer. This type of cancer grows in response to progesterone, a hormone that is key in the menstrual cycle and pregnancy. Breast cancer cells with hormone receptors, such as estrogen and progesterone sensitive ones, drive cancer growth and are key to treatment decisions.
Like Estrogen Receptor Positive (ER+) breast cancer, PR+ tumors are treated with hormone therapy so they are a key part of the bigger picture of breast cancer. [1] Knowing the molecular underpinnings, treatment and prognosis of PR+ breast cancer is crucial to get the best outcome for patients.
Table of Contents
Epidemiology and Clinical RelevanceBreast cancer is the most common cancer in women worldwide with many subtypes and characteristics including hormone receptor positive subtypes (ER+/PR+) which account for about 70% of cases. PR is found in a large proportion of ER+ tumors and is associated with better outcomes as endocrine therapies are more effective. [3] But challenges remain including resistance mechanisms and the impact of menopausal hormone therapy on cancer risk.
Pathophysiology: Molecular Mechanisms and Risk FactorsHormonal Regulation and Hormone Receptor Status: The progesterone receptor (PR) is an estrogen receptor (ER) dependent gene product meaning its expression is driven by ER activation. [5] Hormones estrogen and progesterone are key in breast cancer as cancer cells use hormone receptors to fuel their growth. This close relationship between the receptors is biological interdependence in breast cancer.
Modulation of Estrogen Receptor-α (ERα): PR acts as a modulator of ERα, how estrogen receptor pathways drive tumor growth. This is key to understanding the different responses to hormone therapies. [2]
Risk FactorsThe presence of hormone receptors on cancer cells determines treatment and tumor growth, so both diagnostic and therapeutic implications of different types of breast cancer.
Staging SystemsHormone therapy is the mainstay for PR+ breast cancer. Options include:
PR+ breast cancer is a clinically relevant subtype that responds well to hormone therapy. PR+ tumors have better PFS and OS than PR- tumors so PR is a prognostic biomarker. But hormone therapy risks and resistance need to be addressed. Research targeting PR specific pathways and resistance mechanisms will help improve patient care.
References[1] Zhang, M., Yan, M., Lv, H., Niu, L., & Zeng, H. (2021). Clinical study of first-line endocrine therapy for type ER+/PR+ and ER+/PR- advanced breast cancer. Annals of palliative medicine, 10(1), 238–243. Https://doi.Org/10.21037/apm-20-2180
[2] Dembinski, R., Prasath, V., Bohnak, C., Siotos, C., Sebai, M. E., Psoter, K., Gani, F., Canner, J., Camp, M. S., Azizi, A., Jacobs, L., & Habibi, M. (2020). Estrogen Receptor Positive and Progesterone Receptor Negative Breast Cancer: the Role of Hormone Therapy. Hormones & cancer, 11(3-4), 148–154. Https://doi.Org/10.1007/s12672-020-00387-1.
[3] Wei S. (2023). Hormone receptors in breast cancer: An update on the uncommon subtypes. Pathology, research and practice, 250, 154791. Https://doi.Org/10.1016/j.Prp.2023.154791
[4] Salagame, U., Banks, E., O'Connell, D. L., Egger, S., & Canfell, K. (2018). Menopausal Hormone Therapy use and breast cancer risk by receptor subtypes: Results from the New South Wales Cancer Lifestyle and EvaluAtion of Risk (CLEAR) study. PloS one, 13(11), e0205034. Https://doi.Org/10.1371/journal.Pone.0205034
[5] Li, Z., Wei, H., Li, S., Wu, P., & Mao, X. (2022). The Role of Progesterone Receptors in Breast Cancer. Drug design, development and therapy, 16, 305–314. Https://doi.Org/10.2147/DDDT.S336643
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