US Pharm. 2012;37(1)(Oncology suppl):8-11.

ABSTRACT: Breast cancer, the most prevalent type of cancer among women in the United States, is the second leading cause of cancer-related death (after lung cancer). One of the most lethal forms of breast cancer is triple-negative breast cancer (TNBC). On immunohistochemical analysis, TNBC does not express genes for estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2. Histologically, TNBC is poorly differentiated and is characterized by an aggressive clinical history. A significant overlap exists in biological and clinical characteristics of basal-like breast cancer and TNBC. Treatment options are limited at present, as TNBC lacks a therapeutic target and is naturally resistant to existing targeted therapies (i.e., endocrine treatment and trastuzumab). As no specific treatment guidelines exist, TNBC frequently is treated with surgery, radiation, and selected chemotherapy.

The most prevalent form of cancer among U.S. women, breast cancer is second only to lung cancer as a primary cause of cancer-related death.1 The encouraging news is that there are 2.5 million breast cancer survivors in the U.S., possibly because of greater awareness, earlier detection, and newer treatment options.1 It has been reported that if yearly mammography screenings are begun at age 40 years, breast cancer deaths are reduced by an estimated 40%.2,3 Conversely, when screening begins at age 50 years and takes place every other year, breast cancer deaths are reduced by only 23%.2 Over the years, mammography screening in women aged 40 to 74 years has been correlated with a reduction in mortality rate associated with breast cancer.4

Breast cancer susceptibility genes 1 (BRCA1) and 2 (BRCA2) belong to a class of human genes known as tumor suppressors. In normal cells, BRCA1 and BRCA2 help ensure the stability of the cell’s genetic material (DNA) and help prevent uncontrolled cell growth. Mutation of these genes has been linked to the development of hereditary breast and ovarian cancer. The presence of BRCA1 and BRCA2 mutations can be determined by genetic testing.

In triple-negative breast cancer (TNBC), the tumor does not express estrogen receptors (ERs), progesterone receptors (PRs), or human epidermal growth factor receptor 2 (HER2) on immunohistochemical analysis. TNBC has many histologic and genetic similarities to BRCA1-associated breast cancer, suggesting a shared pathogenesis and the potential use of common chemotherapeutics. This review discusses the pathophysiology of TNBC, as well as current treatment options and drugs of interest that may prove beneficial.

Prevalence

One in eight women is projected to develop some type of breast cancer in her lifetime.5,6 In 2010, there were 207,090 new cases of breast cancer in women and 1,970 new cases in men, resulting in 39,840 deaths and 390 deaths, respectively.7 Researchers report that the TNBC subgroup accounts for approximately 15% to 20% of all cases of breast cancer.8 Younger women fall into the high-risk group for TNBC, as do those with BRCA1 mutations.2,8,9,10 Women with an inherited BRCA1 mutation gene may develop TNBC before age 50 years. African American women, who are three times more likely than white women to develop TNBC, face a worse prognosis than other ethnic groups.11,12 TNBC primarily affects African American women, followed by Hispanic, Asian, and non-Hispanic white women, women who recently gave birth, and obese women. In a study of more than 50,000 women with all stages of breast cancer, 77% of those with TNBC survived at least 5 years, versus 93% of those with other types of breast cancer.12

A case–control study of 187 TNBC patients reported a 2.5 increased risk of TNBC in women who used oral contraceptives (OCs) for more than 1 year compared with those who used OCs for less than 1 year or never, and the increased risk was 4.2 among women aged 40 years and younger who used OCs for more than 1 year.13

Etiology

Any woman can get TNBC, and the disease typically occurs before age 40 to 50 years, versus age 60 years or older for other forms of breast cancer. To better comprehend TNBC, it is important to have an understanding of the receptor proteins found on the surface of and inside healthy breast cells.10 These receptors function as sentinel cells, receiving messages from estrogen and progesterone in the bloodstream and then directing cell growth and function. Classification of breast cancer is often based on an assessment of tumor biology (e.g., status or presence of ER and PR) and human epidermal growth factor receptor (EGFR; also known as ErbB2 or HER2/neu) overexpression.14-18 About 15% to 20% of breast cancer test results are negative for ER, PR, and HER2/neu, denoting a diagnosis of TNBC.10 When all three factors are negative, cancer growth is not supported by estrogen and progesterone or by the presence of too many HER2 receptors, and other factors are supporting cell proliferation.10 About 20% to 30% of breast cancers have too many HER2 receptors.10 In healthy breast cells, HER2 receptors receive signals that stimulate the cells’ growth. When there are too many HER2 receptors, however, breast cancer cells multiply too quickly.

It has been determined that 92% of TNBCs express the mucin 1 (MUC1) oncoprotein target. This protein serves a protective function by binding to pathogens, and it also acts in a cell-signaling capacity. Overexpression, aberrant intracellular localization, and changes in glycosylation of this protein have been associated with carcinomas.19

TNBC is believed to be a subgroup of basal-type breast cancers, which means that the cells resemble the basal cells that line the breast ducts.2,3,10,15,17,18 Approximately 70% of TNBCs express basal markers.19-21 As with other types of breast cancer, basal-like cancers may be linked to family history or may occur without an apparent family link. TNBCs and basal-type cancers tend to be more aggressive than other types of breast cancer, have a higher grade, and have an early relapse; they also are less responsive to standard treatment, more likely to spread beyond the breast, and more likely to recur after treatment.9-12 These risks appear to be greatest in the first few years after treatment. A study involving more than 1,600 women found that those with TNBC had a higher risk of the cancer recurring outside the breast within the first 3 years.8

Treatment Overview

Once a tumor or lump is detected in the breast tissue, it usually is biopsied, and a pathology report is generated to help provide a working diagnosis. TNBC is typically treated with a combination of surgery, radiation, and chemotherapy.22,23 Since hormones are not supporting the tumor’s growth, TNBC is unlikely to respond to molecularly targeted therapy—i.e., endocrine agents including anastrozole (Arimidex), exemestane (Aromasin), letrozole (Femara), and fulvestrant (Faslodex). TNBC is also unlikely to respond to drugs that target HER2, such as trastuzumab (Herceptin) and lapatinib (Tykerb). This leaves a few chemotherapy agents and radiation as the only therapeutic options. Most BRCA1-associated breast cancers are triple-negative, and BRCA1 dysfunctions render most cancer cells deficient in double-stranded DNA break-repair mechanisms.24 This makes the cells more sensitive to DNA-damaging agents such as platinum salts and topoisomerase I inhibitors.10

Treatment Options

Neoadjuvant Chemotherapy: Chemotherapy administered prior to surgery is being used increasingly to manage large ( >3 cm) and locally advanced (T3, T4, or N2) breast cancers.25 It is most often performed to shrink the tumor and to determine whether the cancer is sensitive to the particular combination of drugs being tried.

In a study of 14 women with locally advanced TNBC, nine patients achieved pathologic complete response with neoadjuvant carboplatin-docetaxel chemotherapy.26 All 14 patients had clinical T2 tumors (>2-<5 cm), which were grade 3 in most cases. Patients received six 3-week cycles of chemotherapy. In patients with complete response, no living cancer cells were found in the tumor upon removal. The addition of platinum agents has produced high response rates in ER-negative breast cancer and in patients with and without TNBC associated with BRCA1 mutations.23,24,27,28

VEGF (Vascular Endothelial Growth Factor) Inhibitors: Angiogenesis is the process by which tumors create new blood vessels to get the oxygen and nutrients they need to grow and proliferate.29 However, when one angiogenesis promoter is blocked by drugs, the cancer eventually grows blood vessels through another angiogenesis promoter. Bevacizumab (Avastin) interferes with the activity of the VEGF protein by attaching itself to VEGF, thereby preventing it from interacting with receptors on the blood vessels and stimulating angiogenesis.30

In clinical trials, bevacizumab used in combination with chemotherapy demonstrated significantly improved progression-free survival (PFS), but no overall survival benefit was seen in any of the phase III trials or in any subgroup.30 Without an overall survival advantage, it is unclear whether the level of improvement in PFS (2.5 months) is clinically meaningful given the excessive toxicity and expense of the drug.

EGFR-Targeted Therapies: Newer treatments target EGFR to block signals that modulate cancer growth.27,28,31 Many TNBC cells are known to overexpress EGFR. Cetuximab (Erbitux) attaches to the EGFR protein, and growth signals cannot attach to EGFR on the cancer cell; therefore, the signals cannot stimulate the cell to grow. Some studies that used cetuximab alone or in combination with platinum-based chemotherapy to treat metastatic TNBCs reported only modest activity.

Drugs of Interest: This group of promising drugs for the treatment of TNBC (TABLE 1) includes epigenetic reprogramming breast cancer cells; leptin receptor antagonist peptide; metformin; MUC1 vaccine; platinum; poly adenosine diphosphate–ribose polymerase inhibitors; and carboplatin (combined with other chemotherapy agents).32-39 These agents, which are being studied to determine their efficacy and role in the treatment of TNBCs and other cancers, offer unique approaches to treating cancer.

The Pharmacist’s Role

Because they are highly accessible and trusted health care professionals, pharmacists are ideally positioned to answer questions about breast cancer—including TNBC—and to raise patients’ awareness of detection, screening, and treatment. Pharmacists should take every opportunity to encourage and remind patients about the importance of routine breast cancer screening, including mammography, routine medical checkups, yearly clinical breast examinations, and monthly breast self-examinations, since early detection can save lives.

Pharmacists can answer questions about the risk factors and the symptoms associated with breast cancer, as well as direct patients to various health-related resources and agencies. As health care professionals, pharmacists can provide patients with the information they need to make informed decisions about their health. Pharmacists also should encourage patients to take a proactive approach to maintaining good health and to always ask questions when in doubt.

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