Metastatic breast cancer treatment

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Assistant Editor-in-Chief Jack Khouri

Overview

With rare exception, metastatic breast cancer is an incurable but treatable illness. Currently, it is managed as a chronic disease, especially the category that is ER-positive with predominantly bone or soft tissue metastasis. Chemotherapy, biologic therapy and endocrine therapy are all considered in the treatment of metastatic breast cancer.

Principles of therapy

• The main aims of therapy are prolonging survival, improving quality of life and avoiding treatment-induced toxicity. Given that treatment is palliative, patients should be given treatment holidays in order to reduce drug-induced toxicity.
• HER2 overexpression and hormone receptor status are very important factors that guide therapy and influence prognosis.
• Multiagent chemotherapy regimens don't show significant survival benefit compared to single-drug regimens and augment toxicity.
• Chemotherapy is recommended for patients with ER-negative metastatic breast cancer and those with ER-positive breast cancer resistant to endocrine therapy or associated with visceral disease.
• Trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2.
• Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 overexpression.

Chemotherapy

• the most active single agents are Anthracyclines (Doxorubicin 60-75 mg/m2 IV every 21 days), Taxanes (paclitaxel 175 mg/m2 every 21 days or 80 mg/m2 IV days 1,8,15 every 21 days; docetaxel 60-100 mg/m2 IV every 21 days), Capecitabine (1000-1250 mg/m2 PO twice a day on days 1-14 every 21 days), Gemcitabine (800-1200 mg/m2 IV days 1,8,15 every 28 days), and Vinorelbine (25 mg/m2 weekly or days 1,8,15 every 28 days)
• Bevacizumab has been shown to improve the efficacy of taxanes in frontline treatment of patients with metastatic breast cancer.
• Combination chemotherapy include Gemcitabine combined with paclitaxel and docetaxel ombined with capecitabine.
• There is little evidence from trials reported from 2000 to 2007 that major survival differences exist between many commonly employed chemotherapy regimens.
• Trastuzumab should be added to chemotherapy. If progression of disease occurs, Lapatinib and capecitabine are recommended concomitantly.

Endocrine Therapy

• Endocrine therapy is based on the fact that estrogen receptor-positive tumors are highly estrogen-dependent for growth.
• Endocrine therapy agents for breast cancer are meant to block the effect the estrogen growth effect on breast cancer cells via several mechanisms:
  • Blocking the estrogen receptor (eg, Selective Estrogen Receptor Modulators like Tamoxifen)
  • Down-regulating and degrading the estrogen receptor (eg, Fulvestrant which is a pure estrogen antagonist)
  • Decreasing estrogen synthesis by blocking the enzyme called Aromatase, which converts androgens to estrogens. Aromatase inhibitors include many agents like Anastrozole, Letrozole and Exemestane
  • Decreasing estrogen level by:
    • Shutting down the hypothalamus-pituitary-ovarian axis by means of GnRH agonists, which block the hypothalamic signal that normally promotes etrogen synthesis by the ovaries
    • Ablating the ovaries (oophorectomy)
• Endocrine therapy should be the first-line treatment for ER-positive metastatic breast cancer unless there is significant visceral involovement (the so-called visceral crisis (ie, liver or lung disease)) where first-line chemotherapy should be offered first.
• There is no survival advantage for the combined administration of chemotherapy and endocrine therapy over either single therapy.

The factors that need to be taken into account when considering what endocrine therapy is appropriate for a particular patient include:

• Whether or not they have had previous endocrine therapy (including as an adjuvant)
• If so, which agent
• The extent and duration of any previous response to endocrine therapy
• Menopausal status

Tamoxifen

• Tamoxifen (TAM) is a SERM meaning that its effect on estrogen receptors depends on the target tissue. In fact, TAM inhibits breast cancer growth by competitive blockade of the estrogen receptor in breast tissue. The net result is a block in the G1 phase of the cell cycle and a slowing of cell proliferation. Tumors may then regress because of this altered balance between cell proliferation and ongoing cell loss. However, it has agonistic activiy in other tissues such as bone and uterus and blood vessels which is responsible for the side effects observed in patients on TAM, such as VTE and uterine cancer.
• TAM is the first-line recommended endocrine agent for premenopausal metastatic breast cancer patients and the second-line agent for postmenopausal patients relapsing on/after aromatase inhbitors.
• Small, randomized trials in premenopausal women have found that oophorectomy is not superior to TAM.
• Tamoxifen is a first-line treatment to men with ER-positive advanced breast cancer.
• An oral dose of 20 mg daily is the standard of care.

Aromatase Inhibitors

Aromatase Inhibitors (AIs) are drugs that suppress the enzyme aromatase present in many tissue such as the gonads, the adipose tissue, the placenta, and the endometrium. By blocking this enzyme, estrogen synthesis is suppressed and thus the trophic effects of estrogen on the breast tissue are rendered minimal. Aromatase inhibitor therapy is ONLY effective in suppressing estrogen levels in postmenopausal women. Because of that, measurement of serum follicle-stimulating hormone (FSH) levels can help selecting the proper patient population.

• In a randomized, double-blind, multicenter study designed to evaluate anastrozole (an AI), it was found that there was a significant increase in time to progression and a lower incidence of thromboembolic events and vaginal bleeding with anastrozole. These findings indicate that anastrozole should be considered as first-line therapy for postmenopausal women with advanced breast cancer.

Offer an AI to:

• postmenopausal women with ER-positive breast cancer and no prior history of endocrine therapy
• postmenopausal women with ER-positive breast cancer previously treated with tamoxifen

All aromatase inhibitors appear to be equally effective in terms of primary outcome (overall survival).

The most commonly used AIs are the following:

• Letrozole (Femara): 2.5 mg PO daily
• Anastrozole (Arimidex): 1 mg PO daily
• Exemestane (Aromasin) 25 mg PO daily

Ovarian suppression with GnRH agonists

Ovarian suppression is indicated for premenopausal and perimenopausal women who have previously been treated with tamoxifen and then experience disease progression. The combination of a GnRH agonist and tamoxifen is superior to GnRH agonist alone in premenopausal women with advanced breast cancer. Therefore, if a premenopausal woman with advanced breast cancer is thought to be suitable for endocrine treatment, the combination of a GnRH agonist plus tamoxifen be considered as the new standard treatment. .