Anthracyclines include daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone. The anthracyclines commonly used in treatment of breast cancer are either epirubicin or doxorubicin. Epirubicin is an epimer of doxorubicin with an important role in the chemotherapy treatment of both early and metastatic breast cancer [5]. The efficacy of epirubicin is similar to doxorubicin, while epirubicin has a different toxicity profile, particularly in regard to cardiotoxicity. The major side effects of anthracyclines are cardiotoxicity and myelosuppression. Doxorubicin is the most extensively studied anthracycline regarding cardiotoxicity [6]. Reported rare cardiac complications of doxorubicin treatment include acute reversible arrhythmias, subacute toxic myocarditis, and pericarditis. The most thoroughly evaluated cardiotoxicity of doxorubicin is cumulative progressive damage that leads to clinical events ranging from light reduction of left ventricular ejection fraction to irreversible life-threatening congestive cardiac failure [6]. Congestive cardiac failure due to anthracycline appears early, i.e., several days to months after treatment, peaking at 3 months following the last dose, or late appearing up to 10–12 years after the last anthracycline dose. Risk factors for anthracycline cardiotoxicity include cumulative dose (the strongest risk factor), age, prior irradiation, concomitant administration of other drugs, and previous history of drug disease. A maximum cumulative tolerant dose of 450–500 mg/m² has been recommended. Since the maximum cumulative dose in most breast cancer chemotherapeutic regimens ranges from 240 to 300 mg/m², breast cancer patients seem not to be affected by doxorubicin cardiotoxicity. Liposomal doxorubicin has been shown to have less cardiotoxicity. Epirubicin has been reported to have lower cardiotoxicity than doxorubicin, and a cumulative tolerable dose of 900–1,000 mg/m² has been suggested [6].

Epirubicin has been incorporated into most of the anthracycline-containing chemotherapy combinations in well-conducted clinical trials involving large numbers of patients. It has also been investigated in studies involving the administration of epirubicin in dose-dense chemotherapy schedules. Short-term follow-up of dose-dense clinical trials demonstrated safety comparable to that of doxorubicin.

Capecitabine is an oral prodrug of 5′-deoxy-5-fluorouridine (5′-DFUR). It is converted to 5-FU preferentially in tumor tissue through exploitation of high intratumoral concentrations of thymidine phosphorylase. After oral administration, capecitabine passes intact through the intestine, thus avoiding the direct release of 5-FU within the gastrointestinal tract. Capecitabine subsequently undergoes a three-step enzymatic conversion, the final stage of which relies on thymidine phosphorylase. This enzyme is overexpressed in a proportion of tumor tissues compared with normal tissues, thus resulting in the generation of 5-FU preferentially at the tumor site and decreasing systemic exposure to 5-FU. Bioavailability after oral administration is close to 100 % [7].

Capecitabine is effective and adequately tolerated, both as a monotherapy and as an addition to intravenous polychemotherapeutic to treat several types of cancers. Furthermore, the combination of capecitabine with taxanes is appropriate, because taxanes show synergistic effects with capecitabine. Capecitabine is effective for salvage treatment of patients with metastatic breast cancer. Thus, according to the Breast Cancer Guidelines Committee of the NCCN, capecitabine/docetaxel is considered a preferred combined chemotherapy regimen for recurrent or metastatic breast cancer after failure of anthracycline-based chemotherapy. The drug has also been approved for use as a single agent in metastatic breast cancer patients who are resistant to both anthracycline- and paclitaxel-based regimens or in whom further anthracycline treatment is contraindicated.

In addition, capecitabine has also been used in neoadjuvant breast cancer chemotherapy, with conflicting results. A very recently published meta-analysis including five trials of 3,257 patients with early or operable breast cancer without distant metastasis, treated in the neoadjuvant setting with capecitabine and anthracycline- and/or taxane-based therapy, found that adding capecitabine to neoadjuvant chemotherapy regimens is unlikely to improve outcomes in breast cancer patients without distant metastasis [8].

The most common dose-limiting adverse effects associated with capecitabine monotherapy are hyperbilirubinemia, diarrhea, and hand-foot syndrome. Myelosuppression, fatigue and weakness, abdominal pain, and nausea have also been reported. The dose of capecitabine approved by the US Food and Drug Administration (FDA) for both metastatic colorectal and breast cancer is 1,250 mg/m² given orally twice per day, usually separated by 12 h for the first 2 weeks of every 3-week cycle.

The taxanes docetaxel and paclitaxel were initially introduced in metastatic breast cancer treatment. The taxanes exert their cytotoxicity through tubulin stabilization and cell cycle arrest [9]. They have also been shown to promote apoptosis, inhibit angiogenesis, and induce genes that mediate diverse cellular processes. Although in general the mode of action is similar, docetaxel has a longer plasma half-life and longer intracellular retention, in addition to greater potency in promotion of tubulin assembly and microtubule stabilization compared with paclitaxel. The major toxicities include neurotoxicity for paclitaxel, peripheral neuropathy with docetaxel, and neutropenia, which appears to be more prevalent with docetaxel than with paclitaxel. Other important toxicities include hypersensitivity reactions for paclitaxel and fluid retention and gastroenteric toxicity for docetaxel. In addition, asthenia, alopecia, and mouth ulcers are common adverse events with both agents. Taxane resistance, defined as progression while on therapy or ≤12 months in the adjuvant setting or 4 months in the metastatic setting, is a common problem.

Epothilones are cytotoxic macrolides with a similar mechanism of action to paclitaxel but with the potential advantage of activity in taxane-resistant settings in preclinical models. The antineoplastic activity of epothilones has been attributed to stabilization of microtubules, which results in mitotic arrest at the G2/M transition.

Ixabepilone is a semisynthetic analog of epothilone B designed to optimize the characteristics of its natural precursor. It is characterized by low susceptibility to common mechanisms of tumor resistance, including those mediated by the multidrug resistance protein, P-glycoprotein [10, 11]. In addition, microtubule-stabilizing agents such as ixabepilone prolong activation of the spindle assembly checkpoint, which may promote cancer cell death in mitosis or following mitotic exit. Furthermore, epothilone B analog, ixabepilone, has also been shown to induce apoptosis via a Bcl-2-suppressible pathway that controls a conformational change of the proapoptotic Bax protein. Ixabepilone is metabolized in the liver, and caution should be used when considering patients with liver impairment for therapy with this agent. Ixabepilone exposure is greater in patients with hepatic impairment and those receiving concomitant strong cytochrome P-450 CYP3A4 inhibitors.

In October 2007, ixabepilone was approved by the FDA for the treatment of locally advanced and metastatic breast cancer. Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. Ixabepilone is also indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.

Hematologic toxicities associated with ixabepilone use include neutropenia, leukopenia, anemia, and thrombocytopenia. Neutropenia is the most common toxicity of ixabepilone monotherapy. Dose reductions are recommended in patients who experience severe neutropenia or thrombocytopenia. Ixabepilone is contraindicated in patients with a neutrophil count <1,500 cells/mm³. Symptoms of peripheral neuropathy such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain have been reported in clinical trials of ixabepilone. Hypersensitivity reactions to ixabepilone treatment have also been reported. Although ixabepilone is not considered cardiotoxic, caution is recommended in patients with a history of cardiac disease, and ixabepilone should be discontinued in patients who develop cardiac ischemia or impaired cardiac function while on therapy.

Anthracycline- and taxane-based regimens are recommended as first-line treatment of metastatic breast cancer (Table 24.3). However, there are few options for the treatment of patients with anthracycline- and taxane-resistant or taxane-refractory metastatic breast cancer [12]. Single-agent capecitabine is approved for the treatment of patients after failure of anthracyclines and taxanes. Ixabepilone has demonstrated efficacy in patients with metastatic breast cancer resistant to multiple chemotherapeutic agents and is the only agent approved by the FDA as a monotherapy for anthracycline-, taxane-, and capecitabine-resistant metastatic breast cancer [12].

Endocrine treatment is the oldest targeted treatment of breast cancer. Selective estrogen receptor modulators (SERMs), such as tamoxifen, aromatase inhibitors, and GnRH agonists, are the drugs of choice. GnRH agonists suppress ovarian function, inducing a menopause-like condition in premenopausal women [13]. Fulvestrant and progestins are used in the treatment of metastatic breast cancer (Table 24.4).