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. [1]
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.[2] 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. [3] 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. [1]
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.[1] [3]
It is diagnosed more frequently in younger women,[4][5] women with BRCA1 mutations,[4] those belonging to African-American[4][5][6] and Hispanic[5][6] ethnic groups, and those having a recent birth.[7]
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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 cytokeratin 5/6 and EGFR staining. However no clear criteria or cutoff values have been standardized yet.[1] Also only about 75% of basal-type breast cancers are triple negative.
Some TNBC over expresses EGFR.[8][9] 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.[1] 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.
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 to the chemotherapy appears to improve outcome substantially.[1]
BRCA1 related triple negative breast cancer appear to be particularly susceptible to chemotherapy including platinum based agents.
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 inhibitors showed some promise in early trials[10] but failed in some later trials. [11] 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. [12]
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).[13] It is speculated that enhanced glycolysis in these tumors is probably related to their aggressive biology.
A number of new strategies are currently being tested in clinical trials,[14] including the PARP inhibitor BSI 201,[10] NK012,[15] and the GPNMB targeted CDX-011.
By 2009 a convergence of clinical and epidemiologic evidence linked hyperinsulinemia, insulin resistance, and diabetes to poor breast cancer outcomes.[16]
The widely-used diabetes drug metformin holds promise for the treatment of triple-negative breast cancer.[17] 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.[16]
According to Cancer Research UK, triple-negative breast cancer account for approximately 15% of all breast cancer cases.[18]
Younger women fall into the high risk group for this subtype of breast cancer.[5] Additionally, it is found to disproportionally affect African American and Hispanic women,[6] with African Americans facing worse prognosis than other ethnic groups.[5]
In 2009, a case-control study of 187 triple-negative breast cancer patients by the Fred Hutchinson Cancer Research Center 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.[19] 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.