Treatment Options for Metastatic Breast Cancer

Breast cancer is the most common malignancy in women. An estimated 211,240 new cases will be diagnosed in 2005, with ~40,410 deaths resulting.¹ Established risk factors associated with the development of breast cancer include age >50 years; positive family history of breast cancer (first-or second-degree relative); early onset of menarche (age <12 years); late onset of menopause (age >55 years); later age at first live birth (age >30 years); and history of benign breast disease (atypical hyperplasia).² Other associated risk factors include exogenous estrogen exposure (hormone replacement therapy); the presence of breast cancer susceptibility genes (BRCA1 and BRCA2); and the presence of the human epidermal growth factor-2 (HER-2/neu) protein.^2,3

The American Cancer Society recommends the following screening for early detection of breast cancer: women ?40 years of age should have a clinical breast exam (CBE) and mammogram each year; women in their 20s and 30s should have a CBE every 3 years; and women in their 20s should start breast self-examinations.¹ To date, tamoxifen is the only FDA-approved risk-reduction option that may be offered to postmenopausal women at high risk of developing breast cancer, potentially offering a 49% reduction in breast cancer events.⁴

Breast lesions often present as a painless lump and in the majority of cases are benign. Ultimately, the diagnosis of breast cancer requires a pathologic determination (biopsy of the lesion), which often indicates adenocarcinoma. A further diagnostic workup includes laboratory studies (complete blood count, liver function tests); a chest x-ray; determination of tumor estrogen/progesterone receptor (ER/PR) status; and HER-2/neu status. Further studies (eg, bone scan, abdominal computed tomography scan) are indicated if there are abnormal findings in the initial workup that are possibly suggestive of more advanced disease.

The most common sites of metastatic spread include lymph nodes, bone, bone marrow, brain, lungs, and liver. In terms of treatment, invasive breast cancer can be divided into (1) operable locoregional invasive carcinoma, (2) inoperable locoregional invasive carcinoma, and (3) metastatic or recurrent carcinoma.⁵

Treatment of Metastatic Breast Cancer

The treatment of metastatic breast cancer prolongs survival and enhances the quality of life; however, it is not curative. The presence of ER/PR receptors in the primary breast tumor is the determining factor for endocrine therapy versus cytotoxic chemotherapy. Trastuzumab is indicated for the subset of patients whose tumor is positive for HER-2/neu protein overexpression. Patients with bone metastasis and radiographic evidence of bone destruction should receive a bisphosphonate for the prevention of further bone complications. Supportive care should be considered for those patients with poor performance status and/or those who have had no response to 3 sequential chemotherapy regimens.^5,6

Endocrine Therapy

Endocrine therapy is indicated for patients with ER/PR-positive tumors; those with bone or soft tissue disease only; and those with limited, asymptomatic visceral disease. The most appropriate endocrine therapy often will be determined by the patient's menopausal status and whether or not the patient has received previous antiestrogen therapy.

Treatment options for postmenopausal patients include antiestrogens (tamoxifen, toremifene, and fulvestrant) and aromatase inhibitors (anastrozole, letrozole, and exemestane). Postmenopausal patients previously exposed to antiestrogen therapy should receive an aromatase inhibitor as first-line treatment. For premenopausal women, treatment options consist of an antiestrogen (as above) or ovarian ablation (surgical or radiotherapeutic oophorectomy) with or without a luteinizing hormone-releasing hormone (LHRH) agonist (such as leuprolide). Ovarian ablation is indicated primarily for premenopausal women previously exposed to antiestrogen therapy.^5,7-9

Tamoxifen exerts its antiestrogen effects by binding to intracytosolic estrogen receptors, blocking the effects of endogenous estrogen. Common adverse effects associated with tamoxifen include hot flashes, atrophic vaginitis, irregular menses, ocular toxicity, thromboembolic events, and risk of endometrial cancer (secondary to agonist effects on endometrial tissue).¹⁰ Toremifene is similar to tamoxifen, offering a similar efficacy and toxicity profile. Fulvestrant also is an antiestrogen; however, it does not possess the estrogen agonist effects of tamoxifen. This agent is indicated only for postmenopausal ER/PR-positive patients previously treated with an antiestrogen. Compared with anastozole, it has similar efficacy.¹¹

The aromatase inhibitors (anastrozole, letrozole, and exemestane) suppress ovarian and peripheral estrogen production by inhibiting aromatase, the enzyme responsible for the conversion of androgens to estrogens. If this pathway is inhibited in premenopausal women, suppression of estrogen will not be maintained due to the negative feedback mechanism of the endocrine loop. After menopause, however, the primary source of estrogens is adipose tissue. Therefore, administration of an aromatase inhibitor will suppress the peripheral conversion of androgens to estrogens.¹² For these reasons, aromatase inhibitors are efficacious only in postmenopausal women.

Anastrozole and letrozole are at least equally effective as, if not superior to, tamoxifen when utilized as first-line therapy in metastatic breast cancer.^13-15 Exemestane currently is indicated as a second-or third-line treatment option in postmenopausal patients whose disease has progressed following tamoxifen therapy.¹⁶

The side-effect profile of the aromatase inhibitors is similar to that of tamoxifen. A lower frequency of thromboembolic events has been reported in these initial studies, however.

Leuprolide is an LHRH agonist utilized in premenopausal metastatic breast cancer patients. The mechanism of action is downregulation of LHRH receptors in the pituitary, resulting in decreased circulating levels of LH and subsequently a decline in circulating estrogen levels. Studies have suggested that the combination of tamoxifen and an LHRH agonist may be superior to tamoxifen alone. Side effects include tumor flare (due to estrogen surge prior to LHRH downregulation) and menopausal symptoms.⁹

Cytotoxic Chemotherapy

Systemic chemotherapy is indicated for women with ER/PR-negative tumors, symptomatic visceral metastasis, or hormone-refractory disease. There are many active agents for the treatment of metastatic breast cancer, used either singly or in combination. Often, the choice is dependent upon physician preference, adverse-effect profile, and/or patient performance status. Recommended single-agent therapy may include any one of the following: doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, docetaxel, capecitabine, vinorelbine, or gemcitabine. Combination chemotherapy regimens are listed in the Table.⁵

Side effects of chemotherapy may include nausea and vomiting, alopecia, neutropenia, anemia, thrombocytopenia, febrile neutropenia, infectious complications, and mucositis. Many other drug-specific toxicities may result as well, such as cardiotoxicity, peripheral neuropathies, and secondary leukemias.

Trastuzumab

In ~20% to 30% of patients diagnosed with breast cancer, overexpression of HER-2/neu is present, and it often is associated with a poorer prognosis and a decrease in disease-free survival. Trastuzumab is a murine-human chimeric monoclonal antibody targeted against the HER-2/neu protein. This drug may be utilized in HER-2/neu- positive tumors either as a single agent or in combination with paclitaxel, docetaxel, vinorelbine, or platinum agents (Table).⁵ Previous studies of trastuzumab combined with doxorubicin and cyclophosphamide indicated a significant amount of cardiac toxicity, and therefore this combination is no longer recommended. Side effects associated with trastuzumab are generally mild, including mild pain, fever, chills, and nausea.^5,7

Bisphosphonates

Bisphosphonates (either pamidronate or zoledronic acid) are recommended for patients with metastatic breast cancer who have imaging evidence of lytic bone destruction, who are currently receiving systemic hormonal therapy or chemotherapy, and who are expected to survive ?3 months. One of the most significant benefits from the administration of a bisphosphonate is an overall reduction in skeletal complications associated with bone metastasis in breast cancer patients. Such complications include pathologic fractures, spinal cord compression, hypercalcemia, and pain.

Side effects generally are mild? fever, chills, and myalgias have been reported most commonly. Increases in serum creatinine (SCr) and renal dysfunction may result, especially in patients with an elevated SCr (?3 mg/dL), preexisting renal insufficiency, or infusion durations shorter than those recommended by the manufacturer. Regular monitoring of SCr and electrolytes is strongly recommended. Osteonecrosis of the jaw recently has been reported as well.⁶

Dr. Saadeh is an associate professor of pharmacy practice at Ferris State University, Sparrow Health System.

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