Carcinoma of the Breast: A Review of Pharmacologic Treatment

Breast cancer is the most prevalent type of cancer affecting women (aside from skin cancer), and it is the second leading cause of cancer-related deaths in women after lung cancer. In 2004, an estimated 215,900 women will be diagnosed with carcinoma of the breast in the United States, and approximately 40,110 will die from the disease. Currently, there are over 2 million women in the United States who have been treated for breast cancer.¹ More than 80% of breast cancer cases occur in women over 50 years of age. Although the number of cases of breast cancer appears alarming, there has been a decline in the number of cancer-related deaths, due to early detection, intervention, and the treatment options available. Breast cancer is not limited to just women. Approximately 1500 men annually are afflicted by the disease.

Treatment options are available for each stage of breast cancer. Surgery is typically the initial line of defense. Depending on the disease stage, however, adjuvant therapies?such as radiation, chemotherapy, hormone/endocrine, or biological?are employed to prevent or delay the possibility of metastasis.

Chemotherapy Agents

The management and treatment of breast cancer has progressed in the last few years. Women who have stage I of the disease (negative axillary lymph node dissections and small primaries) usually are treated via surgery alone and have an 80% survival rate.² In cases where patients have node-positive disease, there is a high risk of recurrence.

A variety of chemotherapy agents are accessible for the treatment of breast cancer. Carcinoma of the breast may respond to various cytotoxic agents, hormonal therapies, and various other endocrine treatments. Most chemotherapy protocols involve a combination of one or more agents to aggressively treat the breast cancer. Some of the most common chemotherapeutic agents are listed in the Table.³

The use of cytotoxic agents is recommended for women who have positive nodes. The chemotherapy combination regimens most commonly used to treat breast cancer include the following:

CAF (FAC): Combination of cyclophosphamide, Adriamycin (doxorubicin), and 5-fluorouracil

• Cyclophosphamide 100 mg/m² by mouth (PO) daily on days 1 to 14 (given as a single daily dose)
• Doxorubicin 30 mg/m² by intravenous (IV) push on days 1 and 8
• 5-fluorouracil 500 mg/m² by IV push on days 1 and 8
• Cycle repeated for 6 cycles every 28 days

CMF: Combination of cyclophosphamide, methotrexate, and 5-fluorouracil

• Cyclophosphamide 100 mg/m² PO on days 1 to 14
• Methotrexate 40 mg/m² IV on days 1 and 8
• 5-fluorouracil 600 mg/m² IV on days 1 and 8
• Given every 28 days for 6 cycles

CAF is often used in women with a high risk of recurrence. Both of the above protocols have been shown to significantly reduce relapse rate and to increase chances of survival. These agents may be very effective for patients in locally advanced disease stages, and they can actually increase chances of survival and/or possibly remission. They are less effective in patients with rapidly growing tumors or in cases of metastasized cancers.

Other alternative protocols include the following:

• AC: Adriamycin (doxorubicin) and cyclophosphamide
• ACT: Adriamycin (doxorubicin), cyclophosphamide, and Taxol (paclitaxel)
• FEC: fluorouracil, epirubicin, and cyclophosphamide²

In the past few years, oncologists have had several new choices of therapies to combat resistant tumors or cases of advanced cancer. The taxenes and platinum-based agents are 2 very well-known classes. Examples of taxenes include paclitaxel and docetaxel. Oxaliplatin, cisplatin, and carboplatin are members of the platinum-based class, also known as alkylating agents. The most common adverse effects of all the therapies listed above include nausea, vomiting, hair loss, neutropenia, neurotoxicity, thrombocytopenia, fatigue, and diarrhea.

Paclitaxel

Paclitaxel is an alkaloid ester derived from the Pacific (or Western) yew tree (Taxus brevifolia) and the European yew tree (Taxus baccata). It is used as an adjuvant therapy for node-positive breast cancer administered subsequently to doxorubicin-containing chemotherapy and for the treatment of metastatic breast cancer after a failure of combination chemotherapy or in relapse within 6 months of adjuvant therapy.³ It is metabolized primarily by the liver P-450 system. This agent usually is administered as 100 mg/m ² IV over 1 hour every 3 weeks for 4 courses.

Docetaxel

This agent is a synthetic taxene derived from the European yew tree. The mechanism of action is identical to that of paclitaxel. It is approved for the treatment of locally advanced or metastatic breast cancer after the failure of prior chemotherapy. It usually is administered as 60 to 100 mg/m ² every 3 weeks.

Hormonal Therapy

Because some breast cancers progress with excess estrogen or progesterone, hormone therapy often is utilized. The goal of therapy is to prevent hormones from aiding the growth of cancer cells. This therapy works primarily by blocking estrogen that causes cell proliferation. These agents frequently are used as adjunctive therapy for women with advanced-stage estrogen-receptor-positive cancer. The hormonal therapy agents fall into the following classes:

• Estrogen-receptor antagonists
• Aromatase inhibitors
• Gonadotropin-releasing hormone agonists

Estrogen-Receptor Antagonists

The most commonly used hormone therapy is the antiestrogen tamoxifen. Tamoxifen is a synthetic hormone that has been utilized for more than 25 years to treat breast cancer. It can decrease the chances of some earlystage cancers recurring and can prevent further metastasis. It also is approved as a chemopreventive agent for women who have a high risk of developing breast cancer. It can be beneficial in postmenopausal women when used as monotherapy or in combination with cytotoxic chemotherapy. Experts recommend that women take tamoxifen for 5 years following surgical resection.²

Tamoxifen exerts its pharmacologic effect by acting as a competitive partial agonist?inhibitor of estrogen and binds to the estrogen receptors of estrogen-sensitive tumors. Common adverse effects include an increased risk of endometrial cancer, vaginal bleeding and discharge, edema, hot flashes, and nausea. Tamoxifen, although effective, targets all estrogen receptors.

A generation of agents known as selective estrogen receptor modulators (SERMs) also can act as estrogen blockers. SERMs, such as raloxifene and toremifene, are more specific in targeting breast cancer cells and have a lesser antiestrogenic effect. Although raloxifene and toremifene are not approved for the treatment of breast cancer, a clinical study that began in 1999, known as STAR (Study of Tamoxifen and Raloxifene), is still under way to determine the effectiveness of raloxifene in relation to tamoxifen.

Aromatase Inhibitors

Aminoglutethimide is an adrenal steroid inhibitor used primarily in treating metastatic breast cancer in postmenopausal women whose tumors have significant levels of estrogen receptors. It is usually administered with hydrocortisone to decrease the incidence of adrenal insufficiency.

Newer agents approved by the FDA for the treatment of metastatic breast cancer include anastrozole and letrozole, which are classified as nonsteroidal inhibitors, and exemestane, which is a steroidal hormonal agent. These agents exert their therapeutic effect by inhibiting aromatase, an enzyme that is a primary source of estrogen production in many tissue areas, including the breast. They are approved as firstline therapy, and they can be used in women whose tumors have progressed and have not responded well to tamoxifen treatment. They significantly lower serum estradiol concentrations and have no detectable effect on the formation of adrenal corticosteroids or aldosterone. Common adverse effects include vasodilation, an increased risk of osteoporosis, arthralgia, hot flashes, and headache.

Gonadotropin-Releasing Hormone (GnRH) Agonists

Goserelin and leuprolide are classified as synthetic peptide analogues of GnRH, and they are sometimes used as palliative treatments in advanced breast cancer. These agents are similar in structure to luteinizing hormone?releasing hormone (LH-RH). They cause the endocrine system to act as if sufficient LH-RH is present, thus preventing further synthesis of estrogen, which in turn reduces the hormones needed by the breast tumors to continuing growing.

Biological Therapy

Approximately 25% to 30% of individuals with breast cancer have tumors that cause an excess of human epidermal growth factor receptor 2 protein (HER-2/neu protein), which stimulates cancer cells to grow at an aggressive rate and to become resistant to some of the standard treatment options available. These individuals may receive trastuzumab. Trastuzumab is a monoclonal antibody that binds to the extracellular domain of the HER-2, and it mediates antibody-dependent cellular cytotoxicity against cells, which overproduce HER-2.² This drug is administered via IV infusion. The initial dosage is usually 4 mg/kg over 90 minutes, and the maintenance dose is 2 mg/kg by IV infusion. The most common adverse effects include leukopenia, diarrhea, anemia, fever, and chills.

Conclusion

Although the incidence of breast cancer has increased, the number of deaths related to this type of cancer is declining, due to early screening and medical advances in therapy. Many treatment options have become available to patients in the past 2 decades. Various other treatment options are currently being researched. For health care professionals, the best line of defense in combating breast cancer is patient education and encouraging patients to follow the recommended screening guidelines.

Ms. Terrie is a clinical pharmacy writer based in Slidell, La.

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