Triple-negative breast cancer
Triple-negative breast cancer (TNBC) is any
Triple-negative breast cancer comprises 15–20% of all breast cancer cases[3] and affects more young women or women with a mutation in the BRCA1 gene than other breast cancers.[4] Triple-negative breast cancers comprise a very heterogeneous group of cancers. TNBC is the most challenging breast cancer type to treat.[5] Hormone therapy that is used for other breast cancers does not work for TNBC.[6] In its early stages, the cancer is typically treated through surgery, radiation and chemotherapy. In later stages where surgery is not possible or the cancer has spread from the initial localised area, treatment is limited to chemotherapy and in some cases further targeted therapy.[6]
Triple-negative breast cancers have a relapse pattern that is very different from hormone-positive breast cancers where the risk of relapse is much higher for the first 3–5 years, but drops sharply and substantially below that of hormone-positive breast cancers afterwards.[2][7]
Risk factors
The overall proportion of TNBC is very similar in all age groups. Younger women have a higher rate of basal or BRCA related TNBC, while older women have a higher proportion of apocrine, normal-like and rare subtypes including neuroendocrine TNBC.[2]
A study in the US has shown that, among younger women, African American and Hispanic women have a higher risk of TNBC,[8] with African Americans facing worse prognosis when diagnosed later than other ethnic groups.[9]
One known risk factor for triple-negative breast cancer is germline mutations. These are alterations within the heritable lineage that is being passed down to the offspring. Due to their high disposition for cancers of the breast, ovaries, pancreas, and prostate, the BRCA1 and BRCA2 genes were identified as high risk for triple-negative.[10] Changes or mutations in 19p13.1 and MDM4 loci have also been associated with triple-negative breast cancer, but not other forms of breast cancer. Thus, triple-negative tumors may be distinguished from other breast cancer subtypes by a unique pattern of common and rare germline alterations.[11]
In 2009, a
Classification
Breast cancer classification is used to assess the tumor to decide on treatment and prognosis. Classification can be performed using molecular, immunohistochemical, and clinical characteristics.[13] One of the important classification types is receptor status, because it identifies those cancers that have specific targeted treatments available. Breast cancer tumors have traditionally been classed using immunohistochemistry as one of four types:[13]
- estrogen receptor positive
- progesterone receptor positive
- HER2 overexpression positive
- triple-negative
There are targeted therapies for estrogen and progesterone receptor cancers and more recently HER2 receptor cancers but there are no targeted therapies for TNBC as a whole.[13]
The threshold level for hormone receptor positivity was changed in 2010 and now requires more than 1% positive tumor nuclei are found in the tumor sample.[14]
Newer techniques for categorising breast cancer are based on gene expression in the tumor which classifies breast cancer into:[15][16]
- luminal A (HR+/HER2-) 68%
- luminal B (HR+/HER2+) 10%
- HER2 overexpressing (HR-/HER2+) 4%
- basal-like (HR-/HER2-) 10%
with 7% of unknown subtype. HR indicates hormone receptor and +/- indicates status whether positive or negative.
The basal-like subtype has many overlapping features to TNBC and in addition to being receptor negative, has increased expression of basal cytokeratins.[15] 85% of basal-like tumors are TNBC.[13]
Subtypes are used to try to define better treatments or a more accurate prognosis. However, there is no standard classification for TNBC subtypes.[13] Although TNBC has a variety of different subtypes that may vary depending on how they are determined, to date the disease is still uniformly treated with chemotherapy although they may have additional targeted treatments.[13] One of the popular subtype classification for TNBC is:[13][14][17]
- basal-like 1 (BL1) 35%
- basal-like 2 (BL2) 22%
- mesenchymal (M) 25%
- luminal androgen receptor (LAR) 16%
Most of TNBC is invasive carcinoma of no special type. The following rarer breast tumors have a higher proportion of being TNBC:[18]
- adenoid cystic carcinoma 78.2% are TNBC
- metaplastic76.2% are TNBC
- medullary carcinoma 60.5% are TNBC
- apocrine adenocarcinoma56.7% are TNBC
- inflammatory 25.9% are TNBC
Prognosis
TNBC is more likely to recur within the first five years after treatment than other breast cancers. However, after five years the chance of recurrence is much less than for other breast cancers. [19] The risk of recurrence peaks at three years from diagnosis and reduces after that.[20]
Cancer survival is typically based on 5-year survival rates which is the survival rate compared to women without breast cancer and is based on the stage when the cancer is first diagnosed. These statistics do not apply if the cancer returns after treatment.[6]
stage | 5-year survival |
---|---|
Localised | 91% |
Regional | 65% |
Distant | 12% |
All stages | 77% |
Approximately 25% of those with localised disease will relapse with distant metastasis also known as stage IV.[20] Median survival from diagnosis of metastasis is around 12 months.[20] Metastasis in TNBC is different from other breast cancers with a tendency to spread to the brain and other organs such as lungs and liver and there is less of a tendency to spread to bones.[20]
Treatment
Early stage disease
Standard treatment is surgery with adjuvant chemotherapy and radiotherapy.
Surgery is primarily used for early stage disease and may be either a lumpectomy or a mastectomy. Studies have found that the overall survival for lumpectomy and radiotherapy was the same or higher than for a mastectomy for TNBC patients.[21]
Early stage TNBC is generally very susceptible to chemotherapy and can lead to a pathological complete response (pCR) i.e. no detectable cancer cells in the breast or lymph nodes.[22] Although this does not always translate into overall survival.
Chemotherapy used to treat early stage cancers are:[22]
- anthracyclines
- alkalating agents such as cisplatin and carboplatin. These are particularly effective with BRCA positive cases. These agents cause DNA damage which is unable to be repaired when there are BRCA defects leading to cell death.
- taxanes
Late stage disease
Late stage disease is known as metastatic TNBC (mTNBC).
Treatment depends on whether the tumour tests positive for the programmed death cell ligand 1 (PD-L1) protein or BRCA gene mutation. Also known as immunotherapy the presence of PD-L1 on cancer cells mates with an associate PD-1 receptor on the bodies own immune killer T cells which prevents the T cell from further attacking the cancer cell. By blocking these receptors the T-cells can attack both cancer cells and healthy cells.
The following treatment is recommended by the American Society of Clinical Oncology (ASCO) for metastatic TNBC:[23]
- mTNBC +PD-L1: 1st line: offered chemo + immune checkpoint inhibitor
- mTNBC -PD-L1: 1st line: single-agent chemo; 3rd line: sacituzumab govitecan
- mTNBC +BRCA: patients previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic disease should be offered PARP inhibitor rather than chemotherapy.
Sacituzumab govitecan (Trodelvy) is an anti-Trop-2 antibody linked to SN-38, developed by Immunomedics Inc. (now Gilead Sciences). It was approved by the FDA on 22 April 2020 for the treatment of metastatic TNBC.[24] Sacituzumab govitecan had previously received FDA priority review, breakthrough therapy, and fast track designations.[24]
Clinical trials
This section needs to be updated.(February 2016) |
Angiogenesis and EGFR (HER-1) inhibitors are frequently tested in experimental settings and have shown efficacy.[25] Treatment modalities are not sufficiently established for normal use, and it is unclear in which stage they are best used and which patients would profit.
By 2009 a number of new strategies for TNBC were being tested in clinical trials,
A novel antibody-drug conjugate known as glembatumumab vedotin (CDX-011), which targets the protein GPNMB, has also shown encouraging clinical trial results in 2009.[29]
PARP inhibitors had shown some promise in early trials[27] but failed in some later trials.[30]
An
Three early stage trials reported TNBC results in June 2016, for
In 2019, CytoDyn initiated a Phase 1b/2 trial with its humanized monoclonal antibody, leronlimab (
As of 2022[update] a combination of
Research
This section needs to be updated.(September 2018) |
Triple-negative breast cancers (TNBC) have, on average, significantly higher
Another therapeutic marker of TNBC examines T-regulatory cells (Treg) and the presence of CCR2-positive Treg causing a decrease in CD8-positive cytotoxic T-cell activation resulting in promotion of tumor growth and metastasis as the tumor microenvironment is infiltrated with Treg.[38]
The widely used diabetes drug metformin holds promise for the treatment of triple-negative breast cancer.[39] In addition metformin may influence cancer cells through indirect (insulin-mediated) effects, or it may directly affect cell proliferation and apoptosis of cancer cells. Epidemiologic and preclinical lab studies indicate that metformin has anti-tumor effects, via at least two mechanisms, both involving activation of the AMP-activated protein kinase (AMPK). A large-scale phase III trial of metformin in the adjuvant breast cancer setting is being planned in 2009.[40]
Triple-negative breast cancer cells rely on glutathione-S-transferase Pi1, and an inhibitor (LAS17) shows encouraging results in a pre-clinical study.[41]
See also
References
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- ^ "Old drugs bring new hope to a cancer that lacks precision therapy". www.uchicagomedicine.org. Retrieved 2022-02-23.
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- ^ a b c d "Triple-negative Breast Cancer". Retrieved 22 Feb 2022.
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- ^ Reynolds, Sharon (2007-07-24). "Spotlight: Triple-Negative Breast Cancer Disproportionately Affects African American and Hispanic Women". National Cancer Institute. Archived from the original on 2010-12-21. Retrieved 2008-10-13.
- ^ Chustecka, Zosia (2007-03-19). "Survival Disadvantage Seen for Triple-Negative Breast Cancer". Medscape Medical News. Retrieved 2008-10-13.
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- ^ a b Commissioner, Office of the (2020-04-22). "FDA Approves New Therapy for Triple Negative Breast Cancer That Has Spread, Not Responded to Other Treatments". FDA. Retrieved 2020-11-19.
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- ^ a b "SABCS: PARP Inhibitor Data Called 'Spectacular' "; Dec 2009
- ^ "A Study of NK012 in Patients With Advanced, Metastatic Triple Negative Breast Cancer". 12 February 2015.
- ^ Burris (2009). "A Phase I/II Study of CR011-vcMMAE (CDX-011), an Antibody-Drug Conjugate, in Patients with Locally Advanced or Metastatic Breast Cancer" (PDF).
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- ^ Clinical trial number NCT01997333 for "Study of Glembatumumab Vedotin (CDX-011) in Patients With Metastatic, gpNMB Over-Expressing, Triple Negative Breast Cancer (METRIC)" at ClinicalTrials.gov
- ^ Finally, targeted therapies for triple-negative breast cancer. June 2016
- ^ "Study of Leronlimab (PRO 140) Combined With Carboplatin in Patients With CCR5+ mTNBC". 13 January 2022.
- ^ First Patient in CytoDyn's Triple-Negative Metastatic Breast Cancer Trial Shows Significant Reduction in Circulating Tumor Cells (CTC) and Reduced Tumor Size
- ^ "FDA Grants Fast Track Designation to Enobosarm in AR+, ER+, HER2- Metastatic Breast Cancer". Cancer Network. 10 January 2022. Retrieved 27 August 2023.
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Further reading
- Lehmann BD, Pietenpol JA (January 2014). "Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes". The Journal of Pathology. 232 (2): 142–50. PMID 24114677.