Triple Negative Breast Cancer
Encyclopedia
Triple-negative breast cancer refers to any breast cancer
that does not express the genes for estrogen receptor
(ER), progesterone receptor
(PR) or Her2/neu
. Triple negative is sometimes used as a surrogate term for basal-like, however more detailed classification is possible providing better guidance for treatment and better estimates for prognosis.
Triple negative breast cancers is a very heterogeneous group of cancers. There is conflicting information over prognosis for the various subtypes but it appears that the Nottingham prognostic index is valid and hence general prognosis is rather similar with other breast cancer of same stage -- however more aggressive treatment is required. Some types of triple negative breast cancer are known to be more aggressive with poor prognosis, while other types have prognosis very similar or better than hormone receptor positive breast cancers. Pooled data of all triple negative subtypes suggest that with optimal treatment 20 year survival rates are very close to those of hormone positive cancer.
Triple negative breast cancers have a relapse pattern that is very different from hormone positive breast cancers: the risk of relapse is much higher for the first 3-5 years but drops sharply and substantially bellow that of hormone positive breast cancers after that. This relapse pattern has been recognized for all types of triple negative cancers for which sufficient data exists although the absolute relapse and survival rates differ across subtypes.
It is diagnosed more frequently in younger women, women with BRCA1
mutations, those belonging to African-American and Hispanic ethnic groups, and those having a recent birth.
5/6 and EGFR
staining. However no clear criteria or cutoff values have been standardized yet. Also only about 75% of basal-type breast cancers are triple negative.
Some TNBC over expresses EGFR
. Some TNBC over expresses transmembrane glycoprotein NMB (GPNMB).
On histologic examination triple negative breast tumors mostly fall into the categories secretory carcinoma or adenoid cystic types (both considered less aggressive), medullary cancers and grade 3 invasive ductal carcinomas with no specific subtype, and highly aggressive metastatic cancers. The medullary cancers are mostly BRCA1 related.
Rare forms of triple negative breast cancer are apocrine and squamous carcinoma.
Inflammatory breast cancer
is also frequently triple negative.
Many proteins such as Caveolin
1/2, Survivin
are researched as possible classification/prognostic factors.
Triple negative breast cancers are generally very susceptible to chemotherapy, however in some cases early complete response does not correlate with overall survival. This makes it particularly complicated to find the optimal chemotherapy. Adding a taxane
to the chemotherapy appears to improve outcome substantially.
BRCA1 related triple negative breast cancer appear to be particularly susceptible to chemotherapy including platinum based agents.
PARP inhibitor
s showed some promise in early trials but failed in some later trials. A novel antibody-drug conjugate known as Glembatumumab vedotin
(CDX-011), which targets the protein GPNMB
, has also shown very encouraging results in recent clinical trials.
It is speculated that enhanced glycolysis in these tumors is probably related to their aggressive biology.
BSI 201
, NK012
, and the GPNMB targeted CDX-011
.
The widely-used diabetes drug metformin
holds promise for the treatment of triple-negative breast cancer. 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.
, triple-negative breast cancer account for approximately 15% of all breast cancer cases.
Younger women fall into the high risk group for this subtype of breast cancer. Additionally, it is found to disproportionally affect African American and Hispanic women, with African Americans facing worse prognosis than other ethnic groups.
described a 2.5 increased risk for triple-negative breast cancer in women who used oral contraceptives (OCs) for more than one year compared to women who used OCs for less than one year or never. Interestingly, the increased risk for triple-negative breast cancer was 4.2 among women 40 years of age or younger who used OCs for more than one year, while there was no increased risk for women between the ages of 41 and 45. Also, as duration of OC use increased, triple-negative breast cancer risk increased.
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
that does not express the genes for estrogen receptor
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
(ER), progesterone receptor
Progesterone receptor
The progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...
(PR) or Her2/neu
HER2/neu
HER-2 also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Over expression of this gene is correlated with higher aggressiveness in breast cancers...
. Triple negative is sometimes used as a surrogate term for basal-like, however more detailed classification is possible providing better guidance for treatment and better estimates for prognosis.
Triple negative breast cancers is a very heterogeneous group of cancers. There is conflicting information over prognosis for the various subtypes but it appears that the Nottingham prognostic index is valid and hence general prognosis is rather similar with other breast cancer of same stage -- however more aggressive treatment is required. Some types of triple negative breast cancer are known to be more aggressive with poor prognosis, while other types have prognosis very similar or better than hormone receptor positive breast cancers. Pooled data of all triple negative subtypes suggest that with optimal treatment 20 year survival rates are very close to those of hormone positive cancer.
Triple negative breast cancers have a relapse pattern that is very different from hormone positive breast cancers: the risk of relapse is much higher for the first 3-5 years but drops sharply and substantially bellow that of hormone positive breast cancers after that. This relapse pattern has been recognized for all types of triple negative cancers for which sufficient data exists although the absolute relapse and survival rates differ across subtypes.
It is diagnosed more frequently in younger women, women with BRCA1
BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
mutations, those belonging to African-American and Hispanic ethnic groups, and those having a recent birth.
Classification
Triple-negative breast cancers are sometimes classified into "basal-type" and other cancers, however there is no standard classification scheme. Basal type cancers are frequently defined by cytokeratinCytokeratin
Cytokeratins are proteins of keratin-containing intermediate filaments found in the intracytoplasmic cytoskeleton of epithelial tissue. The term "cytokeratin" began to be used in the late 1970s when the protein subunits of keratin intermediate filaments inside cells were first being identified and...
5/6 and EGFR
EGFR
EGFR is a four letter abbreviation that may refer to:* Epidermal growth factor receptor * Estimated glomerular filtration rate...
staining. However no clear criteria or cutoff values have been standardized yet. Also only about 75% of basal-type breast cancers are triple negative.
Some TNBC over expresses EGFR
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
. Some TNBC over expresses transmembrane glycoprotein NMB (GPNMB).
On histologic examination triple negative breast tumors mostly fall into the categories secretory carcinoma or adenoid cystic types (both considered less aggressive), medullary cancers and grade 3 invasive ductal carcinomas with no specific subtype, and highly aggressive metastatic cancers. The medullary cancers are mostly BRCA1 related.
Rare forms of triple negative breast cancer are apocrine and squamous carcinoma.
Inflammatory breast cancer
Inflammatory breast cancer
Inflammatory breast cancer is an especially aggressive type of breast cancer that can occur in women of any age .It is called inflammatory because it frequently presents with symptoms resembling an inflammation...
is also frequently triple negative.
Many proteins such as Caveolin
Caveolin
Caveolins are a family of integral membrane proteins which are the principal components of caveolae membranes and involved in receptor-independent endocytosis. Caveolins may act as scaffolding proteins within caveolar membranes by compartmentalizing and concentrating signaling molecules...
1/2, Survivin
Survivin
Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the BIRC5 gene....
are researched as possible classification/prognostic factors.
Treatment
Standard treatment is surgery with adjuvant chemotherapy and radiotherapy. As a variation neoadjuvant chemotherapy is very frequently used for triple negative breast cancers. This allows for a higher rate of breast conserving surgeries and by evaluating the response to the chemotherapy gives important clues about the individual responsiveness of the particular cancer to chemotherapy.Triple negative breast cancers are generally very susceptible to chemotherapy, however in some cases early complete response does not correlate with overall survival. This makes it particularly complicated to find the optimal chemotherapy. Adding a taxane
Taxane
The taxanes are diterpenes produced by the plants of the genus Taxus . As their name suggests, they were first derived from natural sources, but some have been synthesized artificially. Taxanes include paclitaxel and docetaxel . Paclitaxel was originally derived from the Pacific yew tree.Taxanes...
to the chemotherapy appears to improve outcome substantially.
BRCA1 related triple negative breast cancer appear to be particularly susceptible to chemotherapy including platinum based agents.
Experimental treatments
Angiogenesis and EGFR (HER-1) inhibitors are frequently tested in experimental settings and have shown great effectivity. Treatment modalities are not sufficiently established for normal use, it is unclear in which stage they are best used and which patients would profit.PARP inhibitor
PARP inhibitor
PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase . They are developed for multiple indications; the most important is the treatment of cancer...
s showed some promise in early trials but failed in some later trials. A novel antibody-drug conjugate known as Glembatumumab vedotin
Glembatumumab vedotin
Glembatumumab vedotin is an antibody-drug conjugate that targets cancer cells expressing transmembrane glycoprotein NMB ....
(CDX-011), which targets the protein GPNMB
GPNMB
Transmembrane glycoprotein NMB is a protein that in humans is encoded by the GPNMB gene. The mouse and rat orthologues of GPNMB are known as DC-HIL and Osteoactivin , respectively. Two transcript variants encoding 560 and 572 amino acid isoforms have been characterized for this gene in humans...
, has also shown very encouraging results in recent clinical trials.
Future diagnostic possibility
Triple-negative breast cancers have, on average, significantly higher fluorine-18 fluorodeoxyglucose (FDG) uptake (measured by the SUVmax values) compared with uptake in ER+/PR+/HER2- tumors using fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET).It is speculated that enhanced glycolysis in these tumors is probably related to their aggressive biology.
Clinical trials
A number of new strategies are currently being tested in clinical trials, including the PARP inhibitorPARP inhibitor
PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase . They are developed for multiple indications; the most important is the treatment of cancer...
BSI 201
BSI 201
Iniparib is a drug that acts as an irreversible inhibitor of PARP1 and possibly other enzymes through covalent modification. It is undergoing clinical trials for treatment of some types of breast cancer.It is the first PARP inhibitor to commence phase III clinical trials...
, NK012
NK012
NK012 is a 'nanodevice' formulation of SN-38 . NK012 is an SN-38-releasing nanodevice constructed by covalently attaching SN-38 to the block copolymer PEG-PGlu, followed by self-assembly of amphiphilic block copolymers in aqueous media....
, and the GPNMB targeted CDX-011
Glembatumumab vedotin
Glembatumumab vedotin is an antibody-drug conjugate that targets cancer cells expressing transmembrane glycoprotein NMB ....
.
Preclinical Research
By 2009 a convergence of clinical and epidemiologic evidence linked hyperinsulinemia, insulin resistance, and diabetes to poor breast cancer outcomes.The widely-used diabetes drug metformin
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
holds promise for the treatment of triple-negative breast cancer. 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
AMP-activated protein kinase
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. It consists of three proteins that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of...
(AMPK).
A large-scale phase III trial of metformin in the adjuvant breast cancer setting is being planned.
Distribution
According to Cancer Research UKCancer Research UK
Cancer Research UK is a cancer research and awareness charity in the United Kingdom, formed on 4 February 2002 by the merger of The Cancer Research Campaign and the Imperial Cancer Research Fund. Its aim is to reduce the number of deaths from cancer. As the world's largest independent cancer...
, triple-negative breast cancer account for approximately 15% of all breast cancer cases.
Younger women fall into the high risk group for this subtype of breast cancer. Additionally, it is found to disproportionally affect African American and Hispanic women, with African Americans facing worse prognosis than other ethnic groups.
Oral contraceptive a risk factor
In 2009, a case-control study of 187 triple-negative breast cancer patients by the Fred Hutchinson Cancer Research CenterFred Hutchinson Cancer Research Center
The Fred Hutchinson Cancer Research Center, is one of the world’s leading cancer research institutes...
described a 2.5 increased risk for triple-negative breast cancer in women who used oral contraceptives (OCs) for more than one year compared to women who used OCs for less than one year or never. Interestingly, the increased risk for triple-negative breast cancer was 4.2 among women 40 years of age or younger who used OCs for more than one year, while there was no increased risk for women between the ages of 41 and 45. Also, as duration of OC use increased, triple-negative breast cancer risk increased.
See also
- Collaboration of Scientists for Critical Research in Biomedicine. Inc.
- The Triple Negative Breast Cancer FoundationThe Triple Negative Breast Cancer FoundationThe Triple Negative Breast Cancer Foundation is a nonprofit organization dedicated to raising awareness of triple-negative breast cancer...
External links
- The Official Triple Negative Breast Cancer Foundation Site
- Triple Negative Breast Cancer Discussion Forum
- Information about Triple Negative Breast Cancer
- Susan G. Komen for the Cure - Subtypes of breast cancer
- Breast Cancer Network of Strength - Information about Triple Negative Breast Cancer
- Living Beyond Breast Cancer's Guide to Understanding Triple-Negative Breast Cancer
- No Surrender Breast Cancer Foundation - Review of TNBC treatments
- Breast Cancer Watch (Click on "triple negative" at top for Feb 2009 review with links to references)
- No Surrender Breast Cancer Foundation - PARP inhibitors
- Current clinical trials for TNBC
- Phase III or IV trials for TNBC
- The Collaboration of Scientists for Critical Research in Biomedicine