Breast Cancer Medication

Updated: Oct 24, 2017
  • Author: Pavani Chalasani, MD, MPH; Chief Editor: John V Kiluk, MD, FACS  more...
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Medication

Medication Summary

Adjuvant treatment for breast cancer involves radiation therapy and a variety of chemotherapeutic and biologic agents. It 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.

In patients receiving adjuvant aromatase inhibitor therapy for breast cancer who are at high risk for fracture, the monoclonal antibody denosumab or either of the bisphosphonates zoledronic acid and pamidronate may be added to the treatment regimen to increase bone mass. These agents are given along with calcium and vitamin D supplementation.

Bevacizumab, a humanized monoclonal antibody that inhibits angiogenesis, had been approved for use in combination therapy for metastatic breast cancer. In November 2011, however, the US Food and Drug Administration (FDA) revoked its approval for this indication, after concluding that bevacizumab had not been shown to be safe and effective for that use. [175]

In December 2013, Hoffmann-La Roche, manufacturer of capecitabine (Xeloda), an oral agent for the treatment of breast and colorectal cancers, reported that in rare cases, patients using the drug may develop potentially fatal cutaneous disease, such as Stevens-Johnson syndrome or toxic epidermal necrolysis. Signs and symptoms of severe skin reactions may include flu-like symptoms, fever, itching, mouth sores, and burning eyes, as well as a painful, red or purplish rash that causes the skin to shed. [176]

Fulvestrant (Faslodex) was approved by the FDA for hormone receptor (HR)-positive, HER2-negative locally-advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy.

The approval is based on results from the phase III FALCON trial, a total of 462 treatment-naïve patients were randomly assigned to 500 mg of fulvestrant on days 0, 14, 28 or 1 mg daily of anastrozole. Eligible patients had received no prior endocrine therapy, although treatment with 1 prior chemotherapy. 

Data from FALCON showed that fulvestrant extended median progression-free survival (PFS) by 2.8 months compared with the aromatase inhibitor anastrozole. Overall response rate and clinical benefit rate did not differ significantly between groups. Fulvestrant resulted in a median duration of response of 20 months as compared with 13.2 months with anastrozole. Median duration of clinical benefit was 22.1 months with fulvestrant and 19.1 months with anastrozole. Expected duration of response also favored fulvestrant, as did expected duration of clinical benefit. [181]

Palbociclib is also used in combination with fulvestrant for the treatment of women with hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic breast cancer with disease progression following endocrine therapy. A total of 521 pre- and postmenopausal women were randomly assigned either palbociclib plus fulvestrant or placebo plus fulvestrant until disease progression or unacceptable toxicity. Palbociclib was administered 125 mg orally daily for 21 consecutive days followed by 7 days off treatment. Fulvestrant was administered 500 mg IM on days 1, 15, and 29, and once monthly thereafter. The median progression-free survival was 9.5 months compared to 4.6 months for patients treated in the palbociclib-plus-fulvestrant and placebo-plus-fulvestrant arms, respectively. [134, 182]

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Antineoplastics, Antimicrotubular

Class Summary

Use of antimicrotubular therapy may be considered in patients who have received at least 2 chemotherapeutic regimens for metastatic disease.

Eribulin (Halaven)

Eribulin inhibits the growth phase of microtubules, leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death. It is 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 the metastatic setting.

Docetaxel (Taxotere, Docefrez)

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 and leading to cell death.

Paclitaxel (Taxol)

Paclitaxel is indicated for adjuvant treatment of node-positive breast cancer; it is administered sequentially after 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.

Ixabepilone (Ixempra)

Ixabepilone is a semisynthetic analogue of epothilone B that inhibits microtubules, halting cell division in the mitotic phase and resulting in cell death. It is used mostly in combination with capecitabine in patients with recurrent or metastatic breast cancer in whom therapy with other first-line agents (eg, an anthracycline and a taxane) has failed.

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Antineoplastics, Alkylating

Class Summary

Alkylating agents constitute one of the earliest classes of antineoplastic agents used to treat cancer. They work by cross-linking DNA, which impedes cellular growth. They can be used alone or in combination with other chemotherapeutic agents.

Carboplatin

Carboplatin is an analogue of cisplatin. It 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.

Carboplatin has the same efficacy as cisplatin but a better toxicity profile. Its main advantages over cisplatin include less nephrotoxicity and ototoxicity, absence of a need for extensive prehydration, and reduced likelihood of inducing nausea and vomiting; however, it is more likely to induce myelotoxicity.

Cyclophosphamide (Cytoxan)

Cyclophosphamide is chemically related to nitrogen mustards. It can be used as a single agent or in various combination chemotherapy regimens for recurrent or metastatic breast cancer.

Cyclophosphamide 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. 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.

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Antineoplastics, Anthracycline

Class Summary

Anthracyclines work in multiple ways, including intercalation between DNA base pairs and inhibition of type II topoisomerase function, resulting in inhibition of cell replication and transcription. They also work by inhibition of DNA helicase, resulting in DNA cleavage.

Doxorubicin

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.

This agent 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.

Epirubicin (Ellence)

Epirubicin is indicated as a part of adjuvant therapy in patients with evidence of axillary-node tumor involvement after resection of primary breast cancer. [142] It can be used as a single agent, but such use is much less common in the setting of recurrent or metastatic disease. Epirubicin 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.

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Antineoplastics, Antimetabolite

Class Summary

Antimetabolite therapy can stop cancer cell growth and cell division by interfering with DNA replication of these cells. These drugs are often first-line agents for breast cancer.

Capecitabine (Xeloda)

Capecitabine is a pyrimidine analogue that, 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 that either is resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or is resistant to paclitaxel in a situation where further anthracycline therapy is not indicated. [143] It is the preferred first-line agent for human epidermal growth receptor 2 (HER2)-positive disease, along with trastuzumab.

Gemcitabine (Gemzar)

Gemcitabine is a pyrimidine analogue 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).

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.

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Antineoplastics, Vinca Alkaloid

Class Summary

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

Vinorelbine (Navelbine)

Vinorelbine is a semisynthetic vinca alkaloid that inhibits tubulin polymerization during the G2 phase of cell division, thereby inhibiting mitosis. This agent is a preferred first-line agent, with trastuzumab, for HER2-positive breast cancer. It is also used alone to treat recurrent or metastatic disease.

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Monoclonal Antibodies

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. The combination of both HER2 receptor antibodies (pertuzumab plus trastuzumab) is superior to either agent alone.

The indication for metastatic breast cancer (HER2-negative) was revoked by the FDA in November 2011 due to failure to delay tumor growth or provide survival benefit. The NCCN 2011 guidelines still recommend bevacizumab for targeted therapy despite concerns expressed by the FDA.

ado-trastuzumab emtansine (Kadcyla)

Ado-trastuzumab emtansine is an HER2-targeted antibody (trastuzumab) covalently linked to a microtubule inhibitor (DM1, a maytansine derivative). It is indicated for the treatment of HER2-positive metastatic breast cancer after prior trastuzumab and taxane therapy.

Upon binding to sub-domain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in intracellular release of DM1-containing cytotoxic catabolites. Binding of DM1 to tubulin disrupts microtubule networks in the cell, which results in cell cycle arrest and apoptotic cell death

Denosumab (Prolia, Xgeva)

Denosumab is a monoclonal antibody that specifically targets RANK ligand, an essential regulator of osteoclasts. This agent is indicated to prevent skeletal-related events (ie, bone fractures, spinal cord compression, or hypercalcemia) in patients with bone metastases from solid tumors whose expected survival exceeds 3 months.

Osteonecrosis of the jaw in patients receiving denosumab has often been associated with dental procedures. Consequently, patients should undergo a dental examination before the initiation of denosumab therapy to determine whether they might benefit from preventive dentistry procedures.

Trastuzumab (Herceptin)

Trastuzumab is a monoclonal antibody that binds to extracellular HER2. It mediates antibody-dependent cellular cytotoxicity against cells that overproduce HER2.

Trastuzumab is indicated for adjuvant treatment of HER2-overexpressing, node-positive or node-negative (estrogen receptor [ER]/progesterone receptor [PR]-negative or with 1 high-risk feature) breast cancer, either as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel or as part of a regimen that also includes docetaxel and carboplatin.

Trastuzumab is also indicated for use as a single agent after multimodality anthracycline-based therapy. The combination of trastuzumab and an anthracycline is associated with significant cardiac toxicity.

This agent 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 1 or more chemotherapy regimens for metastatic disease. [144]

Pertuzumab (Perjeta)

Pertuzumab is a monoclonal antibody that binds to the extracellular domain of the HER2 receptor. It is indicated for the treatment of metastatic HER2-positive breast cancer in combination with trastuzumab and docetaxel. It is also the first drug approved for neoadjuvant treatment of breast cancer for patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer. It is also used in combination with trastuzumab and docetaxel for neoadjuvant treatment.

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Tyrosine Kinase Inhibitors

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 the intracellular tyrosine kinase domains of epidermal growth factor receptor (EGFR [ErbB1]) and HER2 (ErbB2). This agent is indicated in combination with capecitabine for advanced or metastatic breast cancer in patients with tumors that overexpress HER2 and for which previous therapy (ie, anthracycline, taxane, and trastuzumab) was not effective.

This agent is also used in combination with letrozole for the treatment of postmenopausal women with hormone receptor–positive metastatic breast cancer tumors that overexpress the HER2 receptor, for whom hormonal therapy is indicated. [145]

Neratinib (Nerlynx)

Tyrosine kinase inhibitor indicated for extended adjuvant therapy following trastuzumab-based therapy with early stage HER2 overexpressed/amplified breast cancer. It irreversibly binds to EGFR, HER2, and HER4. In vitro, inhibition reduces EGFR and HER2 autophosphorylation, subsequently inhibits signal transduction pathways and demonstrates antitumor activity in overexpressed EGFR and/or HER2 carcinoma cells; neratinib human metabolites (M3, M6, M7, and M11) inhibits EGFR, HER2 and HER4 activity.

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Aromatase Inhibitors

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. All 3 selective aromatase inhibitors (anastrozole, letrozole, and exemestane) have similar antitumor efficacy and similar toxicity profiles.

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 after 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 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.

Letrozole is also indicated for treatment of advanced breast cancer in postmenopausal women with disease progression after antiestrogen therapy and for extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy. [146]

Exemestane (Aromasin)

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.

Exemestane differs from tamoxifen in that it inhibits estrogen production, whereas tamoxifen inhibits estrogen at the receptor site. It may be superior to tamoxifen for breast cancer chemoprevention, with a better safety profile. However, exemestane is not yet indicated for this application by the American Society of Clinical Oncology (ASCO). It is indicated for advanced breast cancer in postmenopausal women whose disease has progressed after tamoxifen therapy. Off-label use of exemestane is suggested as an alternative to tamoxifen or raloxifene in the 2013 ASCO guidelines to reduce the risk of ER-positive breast cancer in high-risk postmenopausal women. [135]

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CDK Inhibitors

Class Summary

Palbociclib and ribociclib are cyclin dependent kinases (CDK) 4, 6 inhibitors indicated in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

Approval of palbociclib for initial endocrine-based therapy in postmenopausal women was based on the phase II trial (PALOMA-1) which measured median progression-free survival (PFS) duration. The mean PFS was 10.2 months in the letrozole group and 20.2 months for palbociclib plus letrozole group. [134]

The approval of palbociclib for ER+/HER2- advanced breast cancer in combination with fulvestrant in women (regardless of menopausal status) with disease progression following endocrine therapy was based on the PALOMA-3 trial (n=521). PFS was prolonged with palbociclib plus fulvestrant compared with fulvestrant alone (9.2 mo vs 3.8 mo). [177]

Approval of ribociclib was based on interim analysis results from the pivotal phase 3 MONALEESA-2 trial in postmenopausal women who received no prior systemic therapy for their advanced breast cancer. The trial demonstrated that ribociclib plus the aromatase inhibitor letrozole reduced the risk for progression or death compared with letrozole alone. The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63% with a duration of 19.3 months in the ribociclib group and 42.2% with a duration of 14.7 months in the letrozole alone group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively. [135] Since these data were published, a subsequent analysis with an additional 11 months of follow-up showed that the median PFS was 25.3 months with the ribociclib combination vs 16 months with letrozole alone, according to a company statement.

A third inhibitor, abemaciclib was FDA approved in September 2017. Approval was based on results from the MONARCH 1 and 2 trial. The Monarch 1 trial studied the safety and efficacy of abemaciclib as a stand-alone treatment in a single-arm trial of 132 patients with HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and chemotherapy after the cancer metastasized. Abemaciclib was administered at 200 mg orally twice daily until disease progression or unacceptable toxicity. At the 8-month interim analysis, 35.6% of patients had received at least 8 cycles of the CDK4/6 inhibitor.The investigator-assessed, confirmed ORR was 19.7%, which included all partial responses (PR). The rate of patients with stable disease (SD) ≥6 months was 22.7%, leading to a clinical benefit rate of 42.4%. The median time to response was 3.7 months and the median duration of response was 8.6 months.  [178]

Palbociclib (Ibrance)

Palbociclib is a cyclin dependent kinases (CDK) 4,6 inhibitor. It reduces cellular proliferation of ER-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle. It is indicated in combination with letrozole for treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. It is also approved for ER+/HER2- advanced breast cancer in combination with fulvestrant in women (regardless of menopausal status) with disease progression following endocrine therapy.

Ribociclib (Kisqali)

Cyclin dependent kinases (CDK) 4 and 6 inhibitor. CDK inhibitors block cellular proliferation of G1 into S phase of the cell cycle. It is indicated in combination with an aromatase inhibitor (eg, letrozole) as initial endocrine-based therapy for postmenopausal women with HR+/HER- advanced or metastatic breast cancer.

Abemaciclib (Verzenio)

CDK 4 and 6 inhibitor. These kinases are activated upon binding to D cyclins and play a crucial role in signaling pathways which lead to cell cycle progression and cellular proliferation. In ER-positive breast cancer cells, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation. It is indicated for HR+/HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy as either monotherapy or in combination with fulvestrant.

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Calcium Metabolism Modifiers

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. An intravenous bisphosphonate should be used in combination with oral calcium citrate and vitamin D supplementation in bone metastasis, according to the National Comprehensive Cancer Network (NCCN) 2012 guidelines. [69]

Pamidronate (Aredia)

Pamidronate disodium is a bone resorption inhibitor that absorbs calcium phosphate crystals and prevents the dissolution of this mineral. It also inhibits osteoclast activity in the bone.

Zoledronic Acid (Zometa, Reclast)

Zoledronic acid inhibits bone resorption by acting on osteoclasts or osteoclast precursors. It may be superior to pamidronate in patients with lytic bone metastases.

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Antineoplastics, Estrogen Receptor Antagonist

Class Summary

Selective estrogen receptor modulators (SERMs) stimulate or inhibit the estrogen receptors of various target tissues. Examples of SERMs include tamoxifen, raloxifene, and toremifene.

Tamoxifen (Soltamox)

Tamoxifen is a nonsteroid with potent antiestrogenic effects in the breast; however, it may be an estrogen agonist in the uterus. CYP2C19 heterozygous*2 carriership may be a predictive factor for longer survival in patients with breast cancer who are taking tamoxifen. [147] Tamoxifen is considered the gold standard for prevention of breast cancer in high-risk women, as adjuvant treatment for breast cancer, and in metastatic breast cancer.

Raloxifene (Evista)

Raloxifene is a selective nonsteroidal benzothiophene ER modulator. It is indicated for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis. In addition, it is indicated for risk reduction in postmenopausal women at high risk for 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. It is indicated for metastatic breast cancer in postmenopausal women with ER-positive or ER-unknown tumors. [148]

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