Triple-negative breast cancer

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. This subtype of breast cancer is clinically characterised as more aggressive and less responsive to standard treatment and is associated with poorer overall patient prognosis. 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.

It has a poor prognosis (due to lack of a targeted therapy). PARP inhibitors showed some promise in early trials but failed in some later trials. A novel, targeted antibody-drug conjugate, Glembatumumab vedotin (CDX-011), has also shown very encouraging results in recent clinical trials.

Characteristics
Triple-negative breast cancers are themselves a subgroup of "basal-type" breast cancers. As triple-negative breast cancers make up the overwhelming majority of this subgroup, what limited data that is available typically deals with triple-negative breast cancers.

Most TNBC over expresses EGFR. Some TNBC over expresses transmembrane glycoprotein NMB (GPNMB).

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.

Treatment
Breast cancers are classified by whether or not they express the genes for estrogen receptor, progesterone receptor or Her2/neu. These three receptors are known to help the cancer develop, and the most successful breast cancer treatments are hormone-based drugs that directly target these receptors. It is important to know what subtype the cancer is before commencing treatment as different drugs target different receptors.

"Triple-negative" breast cancer cells do not express any of these receptors. This means they are generally unresponsive to such standard receptor-mediated treatments. However, other forms of chemotherapy can still generate positive outcomes. Some reports even suggest they are more susceptible to non-receptor mediated therapies than other tumours.

Although triple-negative breast cancer can be treated with chemotherapy, early relapse and metastasis (spread to other tissues) is common.

Clinical trials
A number of new strategies are currently being tested in clinical trials, including the PARP inhibitor BSI 201, NK012, and the  GPNMB targeted CDX-011.

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 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.

Distribution
According to Cancer Research UK, 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 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. 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.