Breast Cancer Medication

Adjuvant treatment for breast cancer involves radiation therapy and a variety of chemotherapeutic and biologic agents. Adjuvant treatment of breast cancer is designed to treat micrometastatic disease, or breast cancer cells that have escaped the breast and regional lymph nodes but which have not yet had an established identifiable metastasis. Treatment is aimed at reducing the risk of future recurrence, thereby reducing breast cancer-related morbidity and mortality.

The 2011 NCCN guidelines include recommendations for the use of two new drugs, denosumab and eribulin, both of which received FDA approval in 2010. The 2011 guidelines support the use of biologic denosumab for the prevention of skeletal events. When compared with zoledronic acid, denosumab, which is administered subcutaneously, delayed the onset of skeletal events by 8% and the time to multiple skeletal events by 23%. In addition, toxicities, such as hypercalcemia and renal failure, were less frequent. The guidelines recommend eribulin, an antimicrotubular drug, as the "preferred single agent" in chemotherapy treatment for women with advanced disease. Trials have shown significant improvement in survival when compared with patients receiving "treatment by physician's choice."^[18]

In June 2011, an FDA panel recommended that bevacizumab (Avastin) no longer be used to treat breast cancer, and in November officially rescinded its approval.

Class Summary

Various chemotherapy regimens are recommended for the treatment of breast cancer. Common regimens include docetaxel, cyclophosphamide, doxorubicin, carboplatin, methotrexate, and trastuzumab, among others.

Docetaxel (Taxotere)

Docetaxel is indicated for use in combination with doxorubicin and cyclophosphamide for adjuvant treatment of operable node-positive breast cancer. It is also indicated for locally advanced or metastatic breast cancer after failure of prior chemotherapy. It is a semisynthetic taxane, a class of drugs that inhibits cancer cell growth by promoting assembly and blocking the disassembly of microtubules, thereby preventing cancer cell division, leading to cell death.

Carboplatin

Carboplatin is an analog of cisplatin. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA cross-links and inhibition of DNA replication. It binds to protein and other compounds containing the SH group. Cytotoxicity can occur at any stage of the cell cycle, but the cell is most vulnerable to the action of these drugs in the G1 and S phases. It has the same efficacy as cisplatin, but with a better toxicity profile. The main advantages over cisplatin include less nephrotoxicity and ototoxicity, not requiring extensive prehydration, and less likelihood of inducing nausea and vomiting; however, it is more likely to induce myelotoxicity.

Doxorubicin (Liposomal)

Doxorubicin is a cytotoxic anthracycline that inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA. It blocks DNA and RNA synthesis by inserting between adjacent base pairs and binding to the sugar-phosphate backbone of DNA, which causes DNA polymerase inhibition. It binds to nucleic acids, presumably by specific intercalation of the anthracycline nucleus with the DNA double helix. It is also a powerful iron chelator. The iron-doxorubicin complex induces production of free radicals that can destroy DNA and cancer cells. Maximum toxicity occurs during the S phase of the cell cycle.

Capecitabine (Xeloda)

Capecitabine is a pyrimidine analog, which, in combination with docetaxel, is indicated for metastatic breast cancer after the failure of prior anthracycline-containing chemotherapy. Monotherapy with capecitabine is indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline–containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated.^[12]

Paclitaxel

Paclitaxel is indicated for adjuvant treatment of node-positive breast cancer (ie, administered sequentially to doxorubicin-containing combination chemotherapy). Dose-dense regimens (ie, more frequent administration) are currently being studied and resulting disease-free interval examined. Mechanisms of action are tubulin polymerization and microtubule stabilization, which, in turn, inhibit mitosis and may result in the breakage of chromosomes.

Gemcitabine (Gemzar)

Gemcitabine is a pyrimidine analog that is metabolized intracellularly to an active nucleotide. It inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. It is cell-cycle specific for the S phase. Gemcitabine, in combination with paclitaxel, is indicated as a first-line treatment for metastatic breast cancer after the failure of prior anthracycline-containing adjuvant chemotherapy (unless anthracyclines were clinically contraindicated).

Cyclophosphamide

Cyclophosphamide is chemically related to nitrogen mustards. It is indicated for use in patients with carcinoma of the breast. It is activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type of reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

Methotrexate (Trexall)

Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction in malignant cells. Methotrexate is indicated alone or in combination with other anticancer agents for the treatment of breast cancer.

Epirubicin (Ellence)

Epirubicin is indicated as a part of adjuvant therapy in patients with evidence of axillary-node tumor involvement following resection of primary breast cancer.^[13] It is a cell cycle phase inhibitor–nonspecific anthracycline derivative of doxorubicin with maximum cytotoxic effects on the S and G2 phases of the cell cycle.

Vinorelbine (Navelbine)

Vinorelbine is a semisynthetic vinca alkaloid that inhibits tubulin polymerization during the G2 phase of cell division, thereby inhibiting mitosis.

Class Summary

Monoclonal antibodies have been engineered to react against specific antigens on cancer cells, which can help to enhance the patient’s immune response and prevent cancer cell growth.

Denosumab

Monoclonal antibody that specifically targets RANK ligand, an essential regulator of osteoclasts. Indicated to prevent SREs (ie, bone fractures and pain) in patients with bone metastases from solid tumors.

Trastuzumab (Herceptin)

Trastuzumab is a monoclonal antibody that binds to the extracellular human epidermal growth receptor 2 (HER2). It mediates antibody-dependent cellular cytotoxicity against cells that overproduce HER2. It is indicated for adjuvant treatment of HER2-overexpressing, node-positive or node-negative (ER/PR negative or with one high-risk feature) breast cancer, as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; with docetaxel and carboplatin; or as a single agent following multimodality anthracycline-based therapy. It is also used in combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer and as a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.^[14]

Class Summary

Tyrosine kinase inhibitors play an important role in the modulation of growth factor signaling. They are commonly combined with other forms of chemotherapy or radiation therapy.

Lapatinib (Tykerb)

Lapatinib is a 4-anilinoquinazoline kinase that inhibits intracellular tyrosine kinase domains of epidermal growth factor receptors (EGFR [ErbB1]) and HER2 (ErbB2). It is indicated in combination with capecitabine for advanced or metastatic breast cancer with tumors that over-express HER2 for which previous therapy (ie, anthracycline, taxane, and trastuzumab) was not effective. It is also used in combination with letrozole for the treatment of postmenopausal women with hormone receptor–positive metastatic breast cancer tumors that over expresses the HER2 receptor for whom hormonal therapy is indicated.^[15]

Class Summary

Aromatase inhibitors play a role in adjuvant therapy in breast cancer. These agents work by inhibiting aromatase, the enzyme responsible for converting other steroid hormones into estrogen.

Anastrozole (Arimidex)

Anastrozole significantly lowers serum estradiol concentrations by inhibiting the conversion of adrenally generated androstenedione to estrone. It is used as first-line treatment of breast cancer in postmenopausal women with hormone receptor–positive or hormone receptor–unknown locally advanced or metastatic disease. It is also used to treat advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy.

Letrozole (Femara)

Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system. It inhibits the conversion of androgens to estrogens. Letrozole is indicated for the adjuvant treatment of postmenopausal women with hormone receptor–positive early breast cancer. It is also used for first-line treatment of postmenopausal women with hormone receptor–positive or hormone receptor–unknown locally advanced or metastatic breast cancer. It is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy and for the extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy.^[16]

Exemestane

Exemestane elicits irreversible steroidal aromatase inactivation by acting as a false substrate for the aromatase enzyme. It binds irreversibly to the aromatase enzyme active site, causing inactivation (ie, suicide inhibition). It significantly lowers circulating estrogen concentrations in postmenopausal women. It differs from tamoxifen in that it inhibits estrogen production, whereas tamoxifen inhibits estrogen at the receptor site. It is indicated for advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.

Class Summary

Bisphosphonates are complementary to chemotherapy and hormone therapy because they may lessen the damage to bone from metastatic disease. Bisphosphonates inhibit osteoclast function and reduce the resorption of bone.

Zoledronic Acid (Zometa, Reclast)

Zoledronic acid inhibits bone resorption, possibly by acting on osteoclasts or osteoclast precursors.

Class Summary

SERMs stimulate or inhibit the estrogen receptors of various target tissues. Examples of SERMs include tamoxifen, raloxifene, and toremifene.

Tamoxifen

SERMs stimulate or inhibit the estrogen receptors of various target tissues. Examples of SERMs include tamoxifen, raloxifene, and toremifene.

Raloxifene (Evista)

Raloxifene is a selective nonsteroidal benzothiophene, estrogen receptor modulator. It is indicated for risk reduction for invasive breast cancer in postmenopausal women with osteoporosis. In addition, it is indicated for risk reduction in invasive breast cancer in postmenopausal women at high risk of invasive breast cancer.

Toremifene (Fareston)

Toremifene is a nonsteroidal triphenylethylene derivative that binds to estrogen receptors. It may exert estrogenic activities, antiestrogenic activities, or both activities. It is indicated for metastatic breast cancer in postmenopausal women with estrogen-receptor–positive or unknown tumors.^[17]

Class Summary

May consider use in patients who have received at least 2 chemotherapeutic regimens for metastatic disease.

Eribulin (Halaven)

Microtubule inhibitor. Inhibits growth phase of microtubules, leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death.

Indicated for metastatic breast cancer in patients who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Class Summary

The NCCN 2011 guidelines still recommend bevacizumab for targeted therapy^[18] despite concerns expressed by the FDA.^{[19, 20]}

Bevacizumab

Indicated as a first-line treatment for metastatic colorectal cancer. Murine derived monoclonal antibody that inhibits angiogenesis by targeting and inhibiting vascular endothelial growth factor (VEGF). Inhibiting new blood vessel formation denies blood, oxygen, and other nutrients needed for tumor growth. Used in combination with standard chemotherapy.