Metastatic Breast CA.pdf

Pharmacotherapy Self-Assessment Program, 6th Edition 21 Metastatic Breast Cancer

Learning Objectives 1. Given an individuals medical history, distinguish

whether chemotherapy or hormonal therapy should be used to treat the patients metastatic breast cancer.

2. Develop a treatment approach using hormonal therapy for recurrent, hormone-positive metastatic breast cancer.

3. For a given patient with metastatic breast cancer, design an optimal chemotherapeutic regimen to manage the disease.

4. Assess the role of biologic therapies (single and combined therapy) in the treatment of metastatic breast cancer.

5. Analyze bisphosphonate use in the treatment of bone metastases in patients with metastatic breast cancer.

Overview of Metastatic Breast Cancer Patients who receive a diagnosis of early-stage breast cancer are treated with the intent to cure. Yet even with the best therapies available today, about 30% of patients will have recurrent breast cancer. A small proportion of patients (10%) will present with metastatic disease at their initial diagnostic examination. No standardized tools or techniques are available to determine which patients will have recurrent disease; therefore, clinicians treat all patients with a similar approach involving several modalities such as surgery, radiation, chemotherapy, and hormonal therapy. Unfortunately, the median survival time for a patient receiving a diagnosis of metastatic disease is only about 3 years. Some patients experience rapidly progressive disease, whereas others may live for many years. Despite a decline in overall mortality with breast cancer, metastatic breast cancer (MBC) is still incurable with the treatment options currently available.

Goals of Therapy in the Metastatic Setting When a patient is given a diagnosis of MBC, the treatment goal shifts from one end of the spectrum (cure, as in early-stage disease) to the other (palliation). In the metastatic setting, treatment modalities are given to improve quality of life, alleviate symptoms or complications of therapy, and prolong survival. The risks and benefits of therapy are weighed to determine the best option for the patient. Only a few patients remain disease free for prolonged periods, even if treated with doxorubicin, one of the most efficacious agents in breast cancer. This was demonstrated in a trial that spanned 20 years and compared use of fluorouracil, doxorubicin, and cyclophosphamide. The mean survival time for patients with MBC is about 24 years from diagnosis; however, this range may vary greatly depending on the site (e.g., bone metastases) and pathology (e.g., estrogen receptor/progesterone receptor [ER/PR] positivity) of the metastatic disease. Patients with bone-only disease, ER/PR-positive disease, or both tend to have cancer that is more indolent and that responds better to hormonal therapy.

Sites of Metastatic Disease Lung, liver, and bone are the most common metastatic sites for breast cancer. However, breast cancer can metastasize anywhere in the body. Invasive ductal carcinomas commonly spread to the lung, liver, bone, and brain, whereas invasive lobular carcinomas can also spread to serosal surfaces, meninges, and other unusual sites.

Therapy Selection Selecting the best form of therapy includes evaluating the prognostic and predictive features of the patients tumor to determine whether local treatment (radiation or surgery) or systemic treatment (hormonal or chemotherapy)

Metastatic Breast Cancer

Kellie L. Jones, Pharm.D., BCOPReviewed by J. Aubrey Waddell, Pharm.D., FAPhA, BCOP; Judy W.M. Cheng, Pharm.D., MPH, FCCP, BCPS (AQ Cardiology); and Benita E. Busch, Pharm.D., BCPS

Pharmacotherapy Self-Assessment Program, 6th Edition22Metastatic Breast Cancer

Abbreviations in This Chapter AI Aromatase inhibitorCT Computed tomography EGFR Epidermal growth factor receptorER Estrogen receptorHER2 Human epidermal growth

factor receptor 2LHRH Luteinizing hormone-

releasing hormoneMBC Metastatic breast cancerMRI Magnetic resonance imagingPR Progesterone receptor

in MBC is palliation, all of these factors are weighed before making a treatment decision.

Monitoring Response to Therapy Once a therapy is chosen, the patient should be assessed periodically to evaluate disease response. According to the American Society of Clinical Oncology, routine monitoring of tumor markers (specifically CA15.3 [normal concentration less than 30 U/mL] and CA27.29 [normal concentration less than 40 U/mL]), in conjunction with diagnostic imaging, is valuable in assessing disease status. Tumor markers CA15.3 and CA27.29 measure similar mucinous proteins and commonly are elevated in patients with MBC. An elevated tumor marker by itself does not warrant a change in therapy; therefore, the concentration should be evaluated in conjunction with radiologic findings to determine further therapy. Radiologic tests such as computed tomography (CT) of the abdomen or lungs or magnetic resonance imaging (MRI) of the brain can document stabilization or progression. By combining the clinical examination, radiologic findings, and tumor marker levels, the clinician can optimally prescribe the next line of therapy. Throughout the patients treatment, the pharmacist plays a valuable role in monitoring hematologic, kidney, and liver function for dosage adjustments of chemotherapy regimens. In addition, it is important to monitor common toxicities associated with treatment, such as nausea/vomiting, palmar-plantar erythrodysesthesia, mucositis, constipation/diarrhea, and pain. Knowledge of supportive care therapies is an invaluable asset in the treatment of oncology patients.

Hormonal Therapy Options Hormonal therapy plays a large role in the treatment of MBC. More than 60% of women with breast cancer have ER/PR-positive disease. Response rates to hormonal therapy for ER/PR-positive disease are 50% to 75%, but with ER/PR-negative disease, they are less than 10%.

Aromatase Inhibitors Aromatase inhibitors (AIs) work by inhibiting the aromatase enzyme responsible for converting androstenedione to estrone and testosterone to estradiol in postmenopausal women. Aminoglutethimide, a first-generation AI, was a nonspecific inhibitor of aromatase with numerous toxicities and adverse effects such as rash and drowsiness. Mineralocorticoids and glucocorticoids are depleted with this agent, and supplemental steroids (e.g., hydrocortisone) must be administered. Second-generation agents such as formestane and fadrozole are only available as injectable formulations and are not currently available in the United States. This leads to the third-generation AIs: anastrozole, letrozole, and exemestane. Anastrozole and letrozole are nonsteroidal AIs that bind reversibly to aromatase. Exemestane is a steroidal AI that exhibits weak androgenic properties because of its steroidal structure. These agents have superseded the use of first- and second-generation AIs. When AIs first came on the market, tamoxifen was considered the first-line treatment option for ER/PR-positive, postmenopausal MBC, followed by megestrol acetate

will provide the best outcome. Factors such as time to recurrence, extent of disease, location of metastatic sites, symptoms, ER/PR positivity, human epidermal growth factor receptor 2 (HER2) positivity, and performance status must be assessed.

Local vs. Systemic Therapy If the patient has a single metastatic lesion, a focal symptom, or a local crisis (e.g., impending fracture, spinal cord compression, brain metastasis), local therapy such as radiation or surgery may be initiated for immediate symptom relief. If the patient has several sites of metastasis and is experiencing symptoms from visceral disease, systemic therapy with hormonal therapy or chemotherapy should be used. Chemotherapy is chosen over hormonal therapy if an immediate response is desired because chemotherapy exhibits a quicker onset of action compared with hormonal therapy. Disease recurrence more than 5 years after the patients initial diagnosis and treatment is considered a favorable prognostic indicator. This reflects an indolent tumor instead of rapidly progressing disease. Other favorable features are ER and PR positivity. An ER- or PR-positive tumor is predictive of longer progression-free survival and can be treated with hormonal agents. The site of metastatic disease is also important. Patients with several sites of disease or disease that has spread to visceral organs (e.g., lung and liver) have a poorer prognosis and might benefit from chemotherapy.

Hormonal vs. Chemotherapy The decision to initiate hormonal therapy is supported if the patient has ER- and/or PR-positive breast cancer, a long disease-free interval, and/or a prior response to hormonal therapy. In patients with ER/PR-negative disease, a short disease-free interval, rapidly progressing visceral disease, and disease refractory to prior hormonal therapy, initiation of chemotherapy is appropriate. Any patient with HER2-positive disease should be considered for trastuzumab therapy, and patients with bone metastasis should be considered for bisphosphonate therapy. Two final decision points are treatment effects on the patients quality of life and the patients ability to tolerate therapy. Because the goal


as second-line therapy. The clinical importance of AIs started to become clear when initial studies were conducted comparing their efficacy with megestrol acetate. Although only marginal benefits were demonstrated with the third-generation AIs compared with megestrol acetate, all of the agents were associated with a lower incidence of adverse effects (Table 2-1). These data catapulted AIs to the first-line treatment position, and studies were initiated comparing AIs head to head with tamoxifen. Aromatase inhibitors are now standard first-line therapy in postmenopausal patients. A combined analysis of two studies evaluating anastrozole and tamoxifen has been published. One trial took place in the United States and the other, in Europe; 1021 patients were included in the analysis. With a median follow-up of 18.2 months, anastrozole was considered at least equivalent to tamoxifen; the median time to progression was 8.5 versus 7 months, respectively. Clinical benefit rates (complete response plus stable disease plus stabilization of disease for 24 weeks or more) were also higher for anastrozole compared with tamoxifen (57.1% vs. 52%, respectively), but the difference was not statistically significant. Individual trial results are listed in Table 2-1. Data demonstrated that anastrozole was as effective as tamoxifen; however, patients receiving anastrozole exhibited significantly fewer venous thromboembolic events than those receiving tamoxifen.

Despite differences in response rates among studies (because of the lack of standard testing for ER/PR status in Europe), the U.S. Food and Drug Administration (FDA) approved anastrozole for labeling as a first-line treatment of patients with ER/PR-positive MBC. When letrozole was compared with tamoxifen, it received the same approval by the FDA. Exemestane is the newest agent to be marketed. In a recent Phase III trial, exemestane was superior to tamoxifen in response rate and progression-free survival in patients with MBC. Exemestane is also approved for use in MBC after tamoxifen failure. If a patient receives a nonsteroidal AI (anastrozole or letrozole) and achieves stable disease, the patient may be offered the steroidal agent exemestane if his or her disease progresses. Cross-resistance has not been reported between steroidal and non-steroidal AIs. The use of AIs in patients with ER/PR-positive MBC has substantially changed during the past 10 years, with tamoxifen use dramatically falling because AIs offer similar efficacy with fewer toxicities.

Pure Antiestrogens Pure antiestrogens offer a specific mechanism for inhibiting the growth of ER/PR-positive MBC. Fulvestrant is the only agent in this class; it works by binding and blocking the ER and increasing the degradation of the ER protein. This activity ultimately leads to the inhibition of

Table 2-1. Comparison of Aromatase Inhibitors with Tamoxifen and Megestrol Acetate Objective Response (%) Clinical Benefit Ratea (%) TTP (months)

Anastrozole vs. megestrol acetate Study 1 (n=256)

10.2 vs. 5.5 36.7 vs. 35.2 5.6 vs. 5.0

Study 2 (n=260)

10.4 vs. 10.4 34.1 vs. 32.8 4.3 vs. 3.9

Letrozole vs. megestrol acetate Study 1 (n=363)

23.6 vs. 16.4 34.5 vs. 31.7 5.6 vs. 5.5

Study 2 (n=400)

16.1 vs. 14.9 26.7 vs. 23.4 3 vs. 3

Exemestane vs. megestrol acetate (n=769) 15.0 vs. 12.4 37.4 vs. 34.6 4.7 vs. 3.8

Anastrozole vs. tamoxifen Study 1 (n=353)

21.1 vs. 17.0 59.1 vs. 45.6 11.1 vs. 5.6

Study 2 (n=668)

32.9 vs. 32.6 56.2 vs. 55.5 8.2 vs. 8.3

Letrozole vs. tamoxifen (n=907) 32.0 vs. 21.0 50.0 vs. 38.0 9.4 vs. 6.0

Exemestane vs. tamoxifen

(n=120) 40.9 vs. 13.6 55.7 vs. 42.4 8.9 vs. 5.2aClinical benefit rate = complete response plus stable disease plus stabilization of disease for 24 weeks or longer. TTP = time to treatment progression.


estrogen signaling to the ER. Unlike tamoxifen, fulvestrant does not exhibit any estrogen agonistic activity. This agent must be administered by intramuscular injection. Fulvestrant is currently approved at a dosage of 250 mg once monthly. The current formulation is available in a 50-mg/mL concentration as 2.5- and 5.0-mL prefilled syringes. Administering 5 mL of the drug by intramuscular injection can be painful; however, doses can be given in one injection or in two smaller injections of 125 mg each. Like the AIs, fulvestrant was tested as a second-line agent for MBC. In trials conducted concurrently in North America and in other countries, fulvestrant 250 mg/month was tested against anastrozole 1 mg/day in patients whose previous antiestrogen therapy had failed. Fulvestrant demonstrated efficacy similar to anastrozole regarding time to progression and objective response rates. In subsequent survival analysis of the combined trials, no significant difference was identified between agents, and both drugs were well tolerated. Based on data from these trials, fulvestrant was approved by the FDA for use in patients whose antiestrogen therapy had failed in the metastatic setting. In the first-line setting, fulvestrant did not exhibit a statistically significant decrease in time to progression and did not meet criteria for noninferiority compared with tamoxifen. In a preplanned subgroup analysis of patients with ER/PR-positive disease, the median time to progression was similar to tamoxifen. As with many drugs, clinicians try to find better ways of administering a drug to optimize efficacy and decrease toxicity. Because hormonal therapy is slower in onset compared with chemotherapy, fulvestrant has been tested using a loading dose to allow quicker steady-state values and earlier patient benefit. Studies under way are using 500 mg on day 1 and 250 mg on days 14 and 28, followed by 250 mg once monthly; or another dosing schedule of 500 mg on days 1, 14, and 28, followed by 500 mg monthly. In addition, clinicians are evaluating the use of other agents in combination with fulvestrant. One proposed

mechanism is to add an agent that exhibits a different pathway of inhibiting estrogen (e.g., AIs). Fulvestrant is also being studied in combination with trastuzumab. Previous data demonstrated cross-communication between the human epidermal growth factor receptor (EGFR) and ER signal transduction pathways. As these data mature, new combinations and dosages may be warranted in the treatment of ER/PR-positive MBC. Table 2-2 describes fulvestrant combinations in ongoing trials.

Luteinizing HormoneReleasing Hormone Agonists The idea of ovarian ablation has been used for more than 100 years in the treatment of early and advanced stages of breast cancer. Knowing that estrogen plays a large role in breast cancer, using an agent that induces chemical ovarian ablation is well founded. Meta-analysis data are available evaluating luteinizing hormone-releasing hormone (LHRH) agonists for MBC. With an LHRH agonist alone (e.g., goserelin), response rates were comparable with historic outcomes from oophorectomy or irradiation. Tamoxifen in combination with an LHRH agonist demonstrated significant improvements in objective response rates and survival compared with tamoxifen alone. These data reveal that combination therapy using tamoxifen and an LHRH agonist is the preferred method of hormonal manipulation in treating patients with premenopausal, hormone receptorpositive MBC. Studies are under way to evaluate the use of AIs in combination with LHRH agonists for use in premenopausal women. The logic is to induce menopause with the LHRH agonist and then give the patient an AI after the patient has achieved chemical menopause. Recent studies demonstrated improved complete and partial response, clinical benefit, and stabilization of disease with such sequential treatment.

Table 2-2. Current Trials Evaluating the Sequence of Fulvestrant and Other Hormonal TherapiesTrial Name Phase Randomization Fulvestrant Dosing Schedule CommentsEFECT(n=660)

III Fulvestrant vs. exemestane

250 mg on days 0, 14, and 28, then monthly

For patients with recurrent disease after an NSAI

SOFEA(n=750)

III Fulvestrant vs.Anastrozole + fulvestrantvs.Exemestane

250 mg monthly For patients with recurrent disease after an NSAI

FACT(n=512)

III Anastrozole + fulvestrantvs.Anastrozole

500 mg on day 0, then 250 mg on days 14 and 28, then 250 mg monthly

FIRST(n=200)

II Anastrozole + fulvestrant 500 mg on day 1 (then monthly) First-line treatment

EFECT = Evaluation of Faslodex versus Exemestane Clinical Trial; FACT = Fulvestrant and Anastrozole in Combination Trial; FIRST = Study to Compare the Efficacy and Tolerability of Fulvestrant with Anastrozole as First Line Hormonal Treatment for Postmenopausal Women with Hormone Positive Metastatic Breast Cancer; n = number of people included in the study; NSAI = nonsteroidal aromatase inhibitor; SOFEA = Study of Faslodex with or Without Concomitant Arimidex vs. Exemestane After Progression on Nonsteroidal Aromatase Inhibitors.


Drug Selection If the patient had a long disease-free survival with prior hormonal therapy, the likelihood of having a positive response to another hormonal agent is high. The next issue to evaluate is the patients menopausal status. Aromatase inhibitors cannot be used in premenopausal patients because they are still producing robust amounts of estrogen in their ovaries. If the patient is premenopausal, has had prior endocrine therapy (tamoxifen), and is within 1 year of antiestrogen exposure, the preferred second-line therapy choices are oophorectomy, radiation-induced ovarian ablation, or LHRH agonists and endocrine therapy. In a premenopausal patient who has not been exposed to antiestrogen therapy, treatment with an antiestrogen with or without ovarian ablation is preferred. For patients who are postmenopausal and antiestrogen nave, or even those who received previous antiestrogen therapy but had recurrent tumors within 1 year of therapy, an AI is considered the first-line treatment. There are no data to stipulate which AI should be used first because no head-to-head trials have been conducted. If the patient was initially prescribed a nonsteroidal AI and had progression of disease, the patient may be switched to a steroidal AI. If the cancer continues to progress after these treatments, the next treatment option could include tamoxifen, fulvestrant, progestins, androgens, and even estrogens. Table 2-3 describes different treatment options. After a patient has received second-line hormonal therapy, choices for sequential therapy are not based on high levels of evidence.

Chemotherapy Options Several clinical factors should be considered to help predict the likelihood of response to chemotherapy. Patients with a better performance status, less extensive prior treatment, a prolonged disease-free interval, and less extensive metastatic disease are more likely to respond to this treatment. Chemotherapy is typically continued as long as the patient responds to the regimen and tolerates the adverse effects. Patients may be granted a chemo holiday (i.e., a break with no chemotherapy) if they have long periods

of response or stable disease or if they experience numerous toxicities. If a patient has exhausted the treatment options (both hormonal and chemotherapy), then best supportive care is a reasonable choice. The National Comprehensive Cancer Network recommends that clinicians consider no further cytotoxic therapy when the patient has had no response to three sequential regimens or has a performance status greater than 3 (i.e., the person is capable of only limited self-care and confined to a bed or chair for more than 50% of waking hours). This classification is based on the Eastern Cooperative Oncology Group performance status grading scale.

Sequential vs. Combination Therapy In MBC, response rates can vary with single or combination chemotherapy in nave or previously treated patients. A meta-analysis demonstrated that combination chemotherapy is associated with higher response rates and a longer time to progression, but, understandably, it has greater toxicity. Few studies, however, have demonstrated an improvement in survival with combination therapy. The only combination regimens that have demonstrated survival benefits are docetaxel and capecitabine, paclitaxel and gemcitabine, and doxorubicin and paclitaxel. There is little compelling evidence that combination therapy should be given rather than sequential therapy. If a patient requires a rapid response to shrink the disease as fast as possible, combination therapy can be used even if it produces greater toxicity. Table 2-4 lists single and combination treatment options.

Anthracyclines Before the introduction of taxanes, anthracyclines were considered the most active class of chemotherapeutic agents for the treatment of breast cancer. For patients who had not received treatment in the metastatic setting, single-agent therapy with an anthracycline resulted in response rates of 35% to 50%. Today, most patients with metastatic disease have previously been treated with an anthracycline in the adjuvant setting. This limits the use of these agents for metastatic disease. However, if there is a long disease-free interval between uses, anthracyclines can be reintroduced.

Table 2-3. Treatment Options for Patients with Hormone-Positive Metastatic Breast Cancer DiseasePremenopausal Postmenopausal

Previous Tamoxifen Previous NSAITamoxifen NSAI ExemestaneOophorectomy Exemestane FulvestrantLHRH agonist Fulvestrant TamoxifenRadiation-induced oophorectomy Megestrol acetate Megestrol acetateMegestrol acetate Androgens AndrogensAndrogens Ethinyl estradiol High-dose estrogensHigh-dose estrogensIf patient becomes postmenopausal, treatment options for postmenopausal women can be considered.

LHRH = luteinizing hormone releasing-hormone; NSAI = nonsteroidal aromatase inhibitor.


The anthracyclines most commonly used are doxorubicin, liposomal doxorubicin, and epirubicin. Numerous combination regimens with or without anthracyclines have been shown to be effective and are included in Table 2-4.

Taxanes Up to 50% of patients with MBC respond to single-agent treatment with paclitaxel or docetaxel. There has been considerable research on different dosing and scheduling regimens. The Cancer and Leukemia Group B compared a weekly regimen with an every-3-week regimen of paclitaxel in women with metastatic, HER2-positive breast disease. Weekly paclitaxel administration (80 mg/m2 for 1 hour) was superior to every-3-week administration (175 mg/m2 for 3 hours), producing statistically significant better response rates, time to progression, and survival. The toxicities identified were slightly different depending on the schedule, with every 3-week therapy having more grade 3 granulocytopenia, myalgias, and arthralgias and weekly administration resulting in more grade 3 sensory and motor neuropathies. A head-to-head trial comparing paclitaxel (175 mg/m2) with docetaxel (100 mg/m2) given every 3 weeks for MBC found docetaxel to be superior in overall survival and time to progression. More hematologic and nonhematologic toxicities were noted with docetaxel. It is difficult to interpret this information and the data for weekly paclitaxel versus paclitaxel given every 3 weeks. It is not known whether docetaxel given every 3 weeks would provide results similar to weekly paclitaxel. Nanoparticle albuminbound paclitaxel, a novel formulation created through nanotechnology, has an improved toxicity profile. Regular paclitaxel requires polyethoxylated castor oil for solubility; however, nanoparticle albuminbound paclitaxel does not. Therefore, there is little risk of hypersensitivity reactions. Albumin is a natural carrier of lipophilic molecules in humans; it allows nanoparticle albuminbound paclitaxel to be administered at higher doses and for a shorter infusion time (i.e., 30 minutes) than paclitaxel.

Nanoparticle albuminbound paclitaxel has been compared with both paclitaxel and docetaxel. Compared with every-3-week paclitaxel administration, nanoparticle albuminbound paclitaxel (260 mg/m2 infused for 30 minutes every 3 weeks) resulted in significantly higher response rates and longer time to progression. More grade 3 neuropathies were identified with nanoparticle albuminbound paclitaxel compared with paclitaxel; however, the neuropathy experienced was for a shorter duration than with paclitaxel. Data comparing nanoparticle albuminbound paclitaxel with docetaxel, although presented, have not been published in full. Nanoparticle albuminbound paclitaxel (given either weekly or every 3 weeks) demonstrated better progression-free survival and a better safety profile than docetaxel given every 3 weeks. This has led investigators to evaluate weekly dosing with nanoparticle albuminbound paclitaxel versus every-3-week administration of docetaxel in a large Phase III trial. The epothilones, which have a mechanism of action similar to taxanes, are a novel class of agents being used and studied in MBC. Ixabepilone is a semisynthetic analog of epothilone B that binds to a specific site on tubulin; this differs from the taxanes and results in microtubule stabilization. Ixabepilone at a dose of 40 mg/m2 is approved in combination with capecitabine for patients with MBC whose anthracycline and taxane therapy has failed or as a single agent for patients whose disease has progressed after treatment with anthracyclines, taxanes, and capecitabine. Progression-free survival (25% reduction in risk of disease) was significantly better with combined ixabepilone and capecitabine therapy compared with capecitabine alone. This benefit was similar to that observed with upfront taxane therapy in chemotherapy-nave patients. Greater toxicity was identified in the combination arm (i.e., sensory neuropathy, fatigue, and neutropenia). These study results are the first to be published regarding epothilone therapy in the treatment of MBC, but additional studies are planned (see Table 2-4).

Table 2-4. Single and Combination Chemotherapy Regimens for Patients with Metastatic Breast CancerSingle Agent Combination Other Active AgentsDoxorubicinEpirubicinLiposomal doxorubicinPaclitaxelDocetaxelCapecitabineVinorelbineGemcitabineAlbumin-bound paclitaxel

Fluorouracil-doxorubicin-cyclophosphamide/cyclophosphamide-doxorubicin-fluorouracil

Fluorouracil-epirubicin-cyclophosphamideDoxorubicin-cyclophosphamideEpirubicin-cyclophosphamideDoxorubicin-docetaxelCyclophosphamide-methotrexate-fluorouracilDocetaxel and capecitabineGemcitabine-paclitaxelPaclitaxel-carboplatin-trastuzumabDocetaxel-trastuzumabVinorelbine-trastuzumabLapatinib-capecitabine

CisplatinCarboplatinEtoposide (oral)VinblastineFluorouracil (continuous infusion)IxabepiloneIxabepilone and capecitabine


Capecitabine Capecitabine is an oral fluorouracil prodrug that undergoes enzymatic activation by thymidine phosphorylase to fluorouracil in tumor tissue. This agent was approved in 1998 as a single-agent therapy in patients whose disease has progressed on anthracycline and taxane therapy. Response rates range from 20% to 37% in patients with MBC. Toxicities commonly associated with capecitabine use include diarrhea, palmar-plantar erythrodysesthesia (hand-foot syndrome), nausea, and fatigue. Approved dosing is 1250 mg/m2 twice daily on days 114 of a 21-day cycle; however, because of toxicities, many patients are initiated on a lower starting dose of 1000 mg/m2. Because of the ease of oral administration, many combination chemotherapy studies use capecitabine. In a trial of docetaxel plus capecitabine versus docetaxel alone, patients receiving the combined therapy exhibited a superior time to progression and overall survival. More overall toxicity was identified in the combination arm, including gastrointestinal toxicities and hand-foot syndrome, whereas those receiving single-agent docetaxel experienced more myalgias, arthralgias, and neutropenia. This trial is the first combination study to exhibit increases in overall survival in this patient population compared with single-agent therapy. Study participants receiving only docetaxel were allowed to switch to capecitabine if their disease progressed (27% of patients), so a true understanding of the effect of capecitabine on overall survival cannot be determined.

Vinorelbine, Gemcitabine, and Platinum Analogs Other commonly used chemotherapeutic agents in MBC include vinorelbine, gemcitabine, and platinum analogs. Vinorelbine is a vinca alkaloid that blocks polymerization of microtubules and impairs mitotic spindle formation, leading to cell death. Common toxicities associated with this agent include neutropenia, neuropathy, constipation, anemia, and thrombocytopenia. As a single agent, vinorelbine has demonstrated response rates from 40% to 50% as a first-line treatment of MBC and between 25% and 40% as second-line therapy. Doses range from 25 mg/m2 to 35 mg/m2 with weekly intravenous administration. The overall efficacy of this agent has led to many combination regimens including those with gemcitabine and trastuzumab (discussed in the section on biologic therapy). No increase in survival was identified with the combination of gemcitabine and vinorelbine. In summary, vinorelbine is considered a second- or third-line option for MBC. Gemcitabine is a pyrimidine nucleoside antimetabolite that inhibits DNA polymerization activity, ultimately interrupting DNA replication. By itself, gemcitabine as a first-line treatment demonstrates responses in 14% to 37% of patients and up to 30% as a second-line treatment. Doses range from 800 mg/m2 to 1250 mg/m2 with weekly intravenous administration. Schedules include days 1 and 8 of a 21-day cycle, and days 1, 8, and 15 of a 28-day cycle. Common toxicities include myelosuppression, fatigue, and flu-like symptoms. Single-agent therapy is commonly administered, and gemcitabine is included in combination therapy with trastuzumab. Paclitaxel plus gemcitabine is an approved regimen for MBC; this is based on a 2004 study in which paclitaxel 175 mg/m2 was administered every

3 weeks and gemcitabine 1250 mg/m2 was given on days 1 and 8 in patients who did not respond to anthracycline adjuvant therapy unless an anthracycline was clinically contraindicated. The combination significantly improved overall survival compared with paclitaxel alone; however, greater toxicity was experienced in the combination arm of the trial. Gemcitabine can be considered first-line treatment in combination with paclitaxel or second- or third-line treatment as a single agent. Platinum analogs (cisplatin and carboplatin) originally were not commonly used in the treatment of breast cancer. However, after data demonstrated synergy when cisplatin was used in combination with trastuzumab, research interest in this area grew. The desire to develop a nonanthracycline-containing regimen also helped boost interest in these agents. Both drugs form platinum adducts that intercalate DNA, leading to the inhibition of DNA synthesis. Common toxicities associated with these agents include myelosuppression, nausea, nephrotoxicity, neurotoxicity, and electrolyte (potassium and magnesium) wasting. Both agents have been studied in weekly and every-3-week regimens in both the adjuvant and metastatic setting and in combination with trastuzumab, paclitaxel, and docetaxel. Cisplatin plus paclitaxel in previously treated patients and as a first-line treatment of MBC demonstrated response rates of 38% to 45% and 48% to 90%, respectively. Positive results were also identified with the combination of docetaxel and cisplatin. Data for several different doses and administration schedules are available, and cisplatin is now used more readily for MBC in clinical practice. Carboplatin has also demonstrated benefit in this patient population. With paclitaxel plus carboplatin as a first-line treatment of MBC, response rates of about 50% were reported. Responses of up to 60% were identified with the use of carboplatin plus docetaxel. These data include various doses and administration schedules. Carboplatin causes more thrombocytopenia and less nephrotoxicity than cisplatin. Both agents are being incorporated into adjuvant treatment of breast cancer. As a class, they can be offered as a first-line treatment of MBC, as well as later treatment (see Table 2-4).

Drug Selection Identifying which chemotherapy to use for MBC largely depends on the chemotherapy and hormonal therapy used in the adjuvant setting. Most individuals treated today will have received an anthracycline and a taxane as part of their adjuvant therapy. If the disease recurs quickly after this treatment, the disease can be considered resistant to these agents. There are data to support a lack of cross-resistance among taxanes. If a woman receives paclitaxel in the adjuvant setting, she may still benefit from docetaxel in the metastatic setting. In addition, the more agents a patient is exposed to, the less likely her disease is to respond to additional agents. If, at any time, the patient is eligible for a clinical trial and has a good performance status, this should also be an option for the patient. In conclusion, current therapeutic options for MBC include capecitabine, paclitaxel/docetaxel/nanoparticle albuminbound paclitaxel (depending on which agent the patient has used previously), vinorelbine, gemcitabine, cisplatin, carboplatin, and an anthracycline such as liposomal


doxorubicin (depending on the disease-free interval from the anthracycline used in the adjuvant setting). Rarely, etoposide or vinblastine may also be used as last-line options. There is no standardized approach when deciding which agent to use first. As discussed previously, a full review of the patients previous therapy, toxicity, and performance status is crucial in the decision-making. If the patient is HER2 positive, incorporating trastuzumab is an important consideration. If the patient has bone metastases, bisphosphonate therapy should be considered. Eligible patients should also be offered participation in clinical trials.

Biologic Therapy Biologic therapy revolutionized the treatment of breast cancer with the advent of trastuzumab and newer agents such as bevacizumab and lapatinib, each with its own specific mechanisms and toxicities.

Trastuzumab Trastuzumab is a humanized monoclonal antibody with numerous proposed mechanisms of action, including binding to the extracellular domain of the HER2 receptor and exerting antigen-dependent cellular cytotoxicity. To determine if a patient is a candidate for trastuzumab therapy, testing with immunohistochemistry (which detects protein expression of HER2 on the cell surface) or fluorescence in situ hybridization (which detects gene amplification [number of gene copies] of HER2) is needed to establish if the patient is positive for HER2. Interpretation of immunohistochemistry relies on a qualitative scoring system. On a scale of 0 to 3+, a patient may score a 0 (negative), 1+ (negative), 2+ (borderline), or 3+ (positive) based on the pathologists interpretation of staining intensity. With fluorescence in situ hybridization, the results are quantitative instead of qualitative. Results are interpreted as negative or positive by calculating the HER2 gene copy number. These results are determined by the ratio of the number of HER2 signals to the number of chromosome signals. A normal specimen results in a ratio of less than 2.0, whereas a specimen with an amplification of HER2 has a ratio of 2.0 or greater, which is considered HER2 positive. In the previously discussed cisplatin and trastuzumab trial, improved response rates were identified with this combination compared with treatment using each agent alone. In 2001, a pivotal trial was published with trastuzumab and chemotherapy as a first-line treatment of MBC. Overall survival was better with the trastuzumab arm, which led to the approval of trastuzumab for the treatment of MBC. The study was also the first to identify cardiotoxicity as a consequence of trastuzumab, which led to cardiac monitoring in all trastuzumab trials. Numerous agents have been combined with trastuzumab, including cisplatin, vinorelbine, capecitabine, gemcitabine, carboplatin plus paclitaxel or docetaxel, cisplatin plus docetaxel, and anastrozole. Any of these combinations are good choices for the patient with HER2-positive metastatic disease who does not have cardiac dysfunction (which prohibits the patient from receiving trastuzumab).

Trastuzumab alone has demonstrated response rates of up to 20% as salvage therapy and 25% to 28% as first-line therapy. Depending on the patients performance status, single-agent therapy with trastuzumab may be an option because of its relatively few adverse effects. Common toxicities include fever, chills, infusion-related reactions, and diarrhea, together with the well-known cardiac toxicity. If cardiac toxicity is identified, trastuzumab therapy should be discontinued until the patients cardiac function improves. Therapy can be reinitiated if the patient is maintained on appropriate cardiac therapy. It is unknown if a patient whose disease progresses on a regimen of trastuzumab and chemotherapy should be continued on trastuzumab when the chemotherapy agent is changed. Current practice is to continue trastuzumab regardless of the switch in chemotherapy. There is also a question of whether the patient might develop resistance to trastuzumab and whether drugs such as lapatinib would play a role in these circumstances in the future. Combination therapies including trastuzumab and other biologic therapies are currently being studied.

Bevacizumab Bevacizumab is a recombinant, humanized, monoclonal antibody that inhibits vascular endothelial growth factor and ultimately inhibits angiogenesis. The dosing regimen approved was 10 mg/kg intravenously every 14 days. Toxicities associated with this agent include hypertension, proteinuria, venous and arterial thromboembolism, hemorrhage, wound healing complications, and gastrointestinal perforation. Single-agent trials produced modest benefit in previously treated patients. Preclinical data supported the theory of synergy with chemotherapy, and numerous clinical trials of combination therapies are under way. In one trial comparing capecitabine alone or in combination with bevacizumab in patients who were anthracycline and taxane resistant, the addition of bevacizumab did not prolong progression-free survival and did not improve overall survival. Researchers believed that the lack of response was because of the extent of prior therapies the patients had received. This theory was put to the test in another trial that evaluated the combination of paclitaxel and bevacizumab versus paclitaxel alone as first-line treatment of MBC. The investigators randomized patients to receive weekly treatments with paclitaxel 90 mg/m2 and bevacizumab 10 mg/kg on days 1 and 15 of a 28-day cycle. The primary end point of the study was progression-free survival, which was significantly improved with combination (11.8 months) versus single-agent (5.9 months) therapy. Overall survival, a secondary end point, did not show statistically significant improvement. Greater toxicity (including hypertension, neuropathy, and infection) was identified in the combination arm. Although overall survival was not significantly improved, bevacizumab labeling was granted accelerated approval by the FDA for MBC in February 2008. Many proponents question the use of this combination because of the lack of improvement in overall survival; however, this combination therapy has been added to the National Comprehensive Cancer Network guidelines as an option for first-line treatment of MBC.


Other Targeted Therapies Another targeted therapy approved for use in patients with MBC is lapatinib. Lapatinib is a small molecule that inhibits the tyrosine kinase activity of the oncogenes HER2 and epidermal growth factor receptor (also known as EGFR). In prior studies, this agent did not show cross-resistance with trastuzumab; in fact, it exhibited benefits when combined with capecitabine and trastuzumab. In a combination trial evaluating lapatinib and capecitabine in patients who received anthracyclines, taxanes, and trastuzumab, patients were randomized to receive one of two regimens. One group received capecitabine alone at 2500 mg/m2 orally in two divided doses on days 114 of a 21-day cycle. The second group receive lapatinib 1250 mg/day orally plus capecitabine 2000 mg/m2 in two divided doses on days 114 of a 21-day cycle. A 51% reduction in the risk of disease progression was identified with the combination therapy, resulting in early reporting of the data. Because lapatinib is an inhibitor of human EGFR similar to trastuzumab, cardiac toxicity was a concern. Left ventricular ejection fraction was monitored by echocardiography or multigated acquisition scan at the same time as efficacy assessments. At the time of data reporting, only four patients in the combination arm experienced asymptomatic cardiac events compared with one patient in the single-agent arm. No symptomatic cardiac events occurred and no patient discontinued lapatinib therapy because of a decrease in left ventricular ejection fraction. The most common toxicities of lapatinib included diarrhea, hand-foot syndrome, rash, nausea/vomiting, and fatigue. Questions must still be answered to fully understand the place of lapatinib in the treatment of MBC. Should lapatinib be compared with trastuzumab? Should these agents be combined? Answers to these and other questions will help clinicians better understand the usefulness of small molecules such as lapatinib in the treatment of MBC. Drug combinations currently being studied include taxanes, liposomal doxorubicin, trastuzumab, and lapatinib, as well as other classes of agents (Table 2-5). Another concern with lapatinib and other oral antineoplastic drugs currently available is drug-drug interactions. Lapatinib is a cytochrome P450 3A4 and 2C8 inhibitor. Drug-drug interactions can be expected with several agents including verapamil, rifampin, phenytoin, and St. Johns wort. Pharmacists should conduct a thorough review of all the patients drugs and over-the-counter supplements to ensure that the patient will not experience any adverse events or require drug dosage alteration.

Bisphosphonates Bisphosphonates are used in the treatment and prevention of skeletal events (e.g., pathologic fractures, spinal cord compression, surgery to bone, radiation therapy to bone) associated with bone metastases in breast, lung, and prostate cancer and in lytic lesions associated with multiple myeloma. Bisphosphonates reduce hypercalcemia, stabilize bony involvement, and help prevent fractures. Agents on the market used for this purpose include zoledronic acid (4 mg infused for 15 minutes) and pamidronate (90 mg infused for 2 hours). Both agents are administered once

monthly. In head-to-head evaluations, both were effective in treating bone metastases and were beneficial in treating or preventing skeletal events; however, there was a longer time to the first event with zoledronic acid (310 days) compared with pamidronate (174 days). Overall, zoledronic acid helped reduce skeletal morbidity more effectively than pamidronate. The first reports of osteonecrosis of the jaw were published in 2003. For a patient to be classified as having bisphosphonate-induced osteonecrosis, the American Association of Oral and Maxillofacial Surgeons set forth the following criteria: the patient must have received bisphosphonates in the past, have exposed and necrotic bone in the maxillofacial region for longer than 8 weeks, and have no history of radiation therapy to the jaw. Although not defined, risk factors associated with the development of osteonecrosis of the jaw include bisphosphonate therapy, dental surgery (extractions), radiation therapy, concomitant oral disease (periodontal and dental abscesses), poor oral hygiene, corticosteroid use, and dental trauma. The mechanism by which bisphosphonates induce osteonecrosis of the jaw is not understood. The best prevention modality is for patients to undergo a thorough dental examination and, if needed, consultation with an oral maxillofacial surgeon before bisphosphonate therapy. The best course of action is to do dental extractions or other oral surgery before initiating biphosphonate therapy. If possible, extractions should be avoided after bisphosphonates are started. When numerous tooth extractions are needed, the American Dental Association Council on Scientific Affairs recommends treating one tooth at a time with a 2-month window between extractions to ensure appropriate healing. These recommendations also include patients who require oral bisphosphonate therapy. If the patient taking intravenous bisphosphonates develops osteonecrosis of the jaw, treatment guidelines have been formulated to help the clinician make appropriate recommendations. First, however, the patient should be referred to an oral/maxillofacial surgeon so that further care can be coordinated by the surgeon and the patients medical oncologist.

Table 2-5. Emerging Targeted Therapies for Breast CancerClass AgentEpidermal growth factor receptor inhibitors Gefitinib

ErlotinibDual epidermal growth factor receptor/HER2

tyrosine kinase inhibitorsLapatinib

Multitargeted kinase inhibitors SunitinibFarnesyltransferase inhibitors Tipifarnib

LonafarnibRapamycin inhibitors Sirolimus

TemsirolimusHeat shock proteins 17-AAG

KOS-953HER2 = human epidermal growth factor receptor 2.


Brain Metastases About 15% to 20% of patients with MBC eventually receive a diagnosis of brain metastasis. Patients typically present with symptoms such as headache, mental status changes, diplopia, gait disturbances, seizures, and speech problems. If brain metastasis is suspected, an MRI should be ordered to evaluate for possible lesions. Treatment with corticosteroids helps decrease inflammation around the tumors and can lead to symptomatic improvement. Survival is poor and can range from 3 months to 6 months, with up to 20% of patients alive at 1 year. Different modalities are available for treatment, including radiation, surgery, and systemic therapy. Choice of therapy varies based on the number and size of the lesions as well as their location. The number of patients receiving a diagnosis of brain metastasis has increased as the number of patients living longer with MBC increases. Traditionally, clinicians believed that chemotherapy could not cross the blood-brain barrier; however, there is evidence that demonstrates disruption of the barrier by the brain metastases themselves. This theory could lend itself to successful treatment of brain metastases with smaller, lipid-soluble molecules or small molecules with targeted activity (i.e., inhibitors of EGFR). In a trial evaluating capecitabine versus capecitabine and lapatinib, fewer patients with central nervous system progression were observed in the combination arm. Studies should be conducted to evaluate the incorporation of these types of agents to see if survival is improved.

Conclusion The treatment of MBC has slowly evolved; however, overall survival has only slightly improved. When selecting a treatment plan, the goal of palliation should be kept in mind. The patients site of disease and performance status must be considered when planning care. If a patient has ER/PR-positive breast cancer, hormonal therapy is an option. If the patient has extensive disease or numerous symptoms, chemotherapy is appropriate. Chemotherapy can be used regardless of the patients ER/PR status, and a decision about which agent or regimen to use is dependent on the treatment administered previously in the adjuvant setting. Single-agent therapy is preferred to combination therapy because combination therapy has demonstrated little additional survival benefit. There are no clear guidelines for a stepwise approach when choosing an agent. If a patient is HER2 positive, treatment with trastuzumab is warranted as long as the patient does not have underlying cardiac dysfunction. Together with trastuzumab, bevacizumab and lapatinib are being explored for the treatment of HER2-positive MBC. Newer agents and combination therapies are also being evaluated. As we learn more about tumor biology and the signaling pathways involved in breast cancer progression, we may someday be able to better target therapy and improve overall survival in this patient population.

Annotated Bibliography 1. Greenberg PA, Hortobagyi GN, Smith TL, Ziegler LD,

Frye DK, Buzdar AU. Long-term follow-up of patients with complete remission after combination chemotherapy for metastatic breast cancer. J Clin Oncol 1996;14:2197205.

This article is included as a historic reference. The authors conducted a retrospective review of 1581 patients who received front-line chemotherapy regimens of doxorubicin and an alkylating agent for MBC from 1973 to 1982. Of the patients able to achieve a complete response with their initial chemotherapy regimen, 18% were still disease free at 5 years, and more than 10% remained disease free for 10 years. Many factors helped identify patients likely to achieve a complete response. They included younger patients (median age of 50), lower number of different metastatic sites, and better performance status. It is understood that most patients with metastatic disease are not curable. However, a few patients, as demonstrated in this review, maintain long-term remission with standard chemotherapy that includes an anthracycline.

2. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med 2003;348:243142.

This paper is a review of AIs in the treatment of breast cancer. The authors review the development and classification of each AI, including the clinical development of this class and how each AI compares with the others. The authors then describe the clinical role of AIs as first- and second-line treatment of breast cancer in the neoadjuvant, adjuvant, and metastatic setting. A thorough review of the toxicities is also included.

3. Bonneterre J, Buzdar A, Nabholtz JM, Robertson JF, Thurlimann B, von Euler M, et al. Anastrozole is superior to tamoxifen as first line therapy in hormone receptor positive advanced breast carcinoma. Cancer 2001;92:224758.

This article reveals the results of two randomized trials designed for combined analysis. One of the studies was conducted in the United States and Canada, and the other was conducted in Europe, Australia, New Zealand, South America, and South Africa. These two trials were run concurrently. Initial results identified anastrozole as at least equivalent to tamoxifen in median time to progression. However, with a subgroup analysis, anastrozole was superior to tamoxifen when evaluating only patients with ER- or PR-positive breast cancer. On further review, it was identified that patients outside North America were allowed to enter the study even if their ER/PR status was unknown. In the North American trial, 90% of patients were known to be ER/PR positive; in the other trial, only 45% of patients were known to be ER/PR positive. These findings highlighted the disparity in clinical practice around the world in 2001. This trial concluded that patients with ER/PR-positive disease fared better in time to progression and clinical benefit (complete response plus partial response plus stabilization of 24 weeks or more). In addition, anastrozole resulted in significantly fewer venous thromboembolic events and less vaginal bleeding than tamoxifen, and anastrozole was well tolerated. With the results of these two trials, anastrozole was approved as a first-line treatment option for women with MBC.

4. Howell A, Pippen J, Elledge RM, Mauriac L, Vergote I, Jones SE, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined analysis of two multicenter trials. Cancer 2005;104:2369.


This study is a combined survival analysis of two multicenter trials that were conducted concurrently, with one study in North America and the other in Europe, Australia, and South Africa. In overall survival, fulvestrant was considered at least as effective as anastrozole (27.4 months vs. 27.7 months, respectively) when used as second-line treatment of postmenopausal women with advanced breast cancer. Based on these trials, fulvestrant was approved for the treatment of hormone-positive MBC in postmenopausal women with disease progression after antiestrogen therapy.

5. Robertson JF. Fulvestrant (Faslodex): how to make a good drug better. Oncologist 2007;12:77484.

This article reviews the data available for fulvestrant in the treatment of MBC. The author discusses the role of fulvestrant in the treatment of tamoxifen-resistant breast cancer and as first-line treatment of advanced cancer. The author also reviews the data available on different dosing regimens (i.e., standard dose, loading dose, or high dose). As discussed in this chapter, a question posed by clinicians is, How can steady-state concentrations of fulvestrant be achieved more quickly, allowing the patient to have an earlier response? In addition, the author discusses upcoming combination trials using other therapies such as AIs and trastuzumab.

6. Michaud LB. Aromatase inhibitors in early and advanced disease. Agrawal A, Roberts JF, Cheung KL. Fulvestrant in metastatic disease. Espirito JL. Progestins and androgens. All in Buzdar AU, ed. Endocrine Therapies in Breast Cancer. New York: Oxford University Press, 2007.

These three chapters discuss AIs in early and advanced breast cancer, fulvestrant in metastatic disease, and progestins and estrogens in advanced disease. Together they form a concise summary of hormonal treatments for breast cancer, containing information on both early- and advanced-stage disease and offering guidance in selecting hormonal therapy for patients. Because this book is a pocket guide, concise summaries of the data are presented throughout. This guide offers a brief, helpful review of currently published data and of trials in progress.

7. Ingle JN. Sequencing of endocrine therapy in postmenopausal women with advanced breast cancer. Clin Cancer Res 2004;10:362S7S.

This article reviews the trials conducted in patients who have progressed while on hormonal therapy. The author groups patients into four categories: (1) hormonal therapy nave (patients who have not received hormonal therapy previously); (2) prior exposure to tamoxifen for more than 1 year; (3) prior exposure to tamoxifen within 1 year; and (4) prior anastrozole exposure. This patient classification helps the clinician decide how to proceed with therapy. The article also highlights how a patient may respond after completing previous hormonal therapy. If a patient responds to previous hormonal therapy with a long progression-free survival, the patient is more likely to respond to subsequent hormonal therapy. The author subsequently states that patients who are hormonal therapy nave are becoming increasingly rare whereas patients with prior anastrozole exposure are becoming more prevalent because of the use of anastrozole in the adjuvant setting.

8. Mayer EL, Burstein HJ. Chemotherapy for metastatic breast cancer. Hematol Oncol Clin North Am 2007;21:25772.

This article reviews chemotherapy in the treatment of MBC. The author walks the reader through the thought

process of when to initiate therapy, how long to treat, and when to discontinue therapy, and also reviews common chemotherapies used in MBC. In addition, the author addresses indications for single-agent versus combination therapy. Summary data are available regarding the different classes of drugs, the particular chemotherapeutic agents used, and the toxicities associated with those drugs. The author concludes with future directions for chemotherapy use in treatment of MBC.

9. Briest S, Stearns V. Chemotherapeutic strategies for advanced breast cancer. Oncology (Williston) 2007;21:132535.

This article reviews all aspects and treatment of MBC. The author discusses the roles of treatment and explains how treatment decisions should be based on a review of the prognostic and predictive factors and the appropriateness of hormonal therapy versus chemotherapy. An extensive review of data is presented, with information encompassing both single-agent treatment and combination therapy. Newer strategies for targeted therapies are discussed, as are future directions in MBC management.

10. Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, et al. Randomized Phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 2005;23:554251.

This article discusses the first trial to directly compare docetaxel with paclitaxel as single-agent therapy for MBC. The overall response duration (32% vs. 25%; p=0.10), time to progression (5.7 vs. 3.6 months; p


paclitaxel may become part of the treatment regimen for adjuvant breast cancer.

12. Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 2007;25:52107.

Ixabepilone is the first agent in the class of epothilones approved for the treatment of MBC. Epothilones work by stabilizing the microtubule complex leading to apoptosis. In this trial, progression-free survival was the primary end point, and ixabepilone exhibited a 25% reduction in risk of disease progression. Overall survival was a secondary end point; however, at the time of the studys publication, the planned number of events for analysis had not been reached. Of interest, patients had a 25% reduction in risk of progressive disease even after their anthracycline and taxane therapy had failed. This agent poses promise in MBC as well as the likelihood of being studied in the adjuvant setting.

13. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:273343.

Clinicians understand the role of HER2 in breast cancer, but they also understand the possibility of patients developing resistance to trastuzumab; therefore, alternatives are under evaluation. Lapatinib is a small-molecule tyrosine kinase inhibitor that targets HER2 and EGFR. This article discusses the combination of capecitabine and lapatinib versus capecitabine alone in patients who have already received anthracyclines, taxanes, and trastuzumab. In this trial, a 51% reduction in risk of progression was identified with the combination of lapatinib and capecitabine; as a result, lapatinib was approved for use in combination with capecitabine to treat patients with MBC who have progressed despite anthracyclines, taxanes, and trastuzumab. This is only one of numerous trials to evaluate the combination of a targeted therapy with traditional chemotherapy for the treatment of MBC.

14. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:78392.

This article, included for historic purposes, is the trial that led to the approval of trastuzumab for MBC. It dramatically changed the way patients with breast cancer were treated around the world. Patients were randomized to receive chemotherapy alone or in combination with trastuzumab. The trial arms included the following: doxorubicin and cyclophosphamide, either with or without trastuzumab, or paclitaxel either alone or in combination with trastuzumab. Cardiac toxicity was identified with the anthracycline and trastuzumab combination in 27% of patients, whereas only 8% of patients receiving doxorubicin plus cyclophosphamide experienced cardiac toxicity. In the paclitaxel combination group, compared with the single-agent therapy group, the risk of cardiac toxicity was 13% versus 1%, respectively. When this article was published, very few studies had demonstrated survival advantages in the metastatic setting. This is the first trial in which a monoclonal antibody exhibited survival advantages when added to traditional chemotherapy in the treatment of patients with MBC.

15. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357:266676.

This article one of the newest publications on the treatment of MBC evaluates the combination of paclitaxel and bevacizumab as first-line treatment in MBC versus single-agent treatment with paclitaxel. The primary end point of this trial was progression-free survival. Response rates were significantly better with the combination arm compared to the single agent arm (36.9% vs. 21.2%, respectively; p


metastatic breast cancer: evidence for receptor-enhanced chemosensitivity. Semin Oncol 1999;26(Suppl 12):8995.

In this Phase II trial, patients with MBC who were previously exposed to chemotherapy had a 24% response rate when treated with the combination of cisplatin and trastuzumab. This trial was the first to demonstrate an improved response to the combination of chemotherapy with trastuzumab. Based on these results, the authors suggested the idea of enhancing chemosensitivity with trastuzumab. This has led to numerous clinical trials incorporating combination chemotherapy with trastuzumab, which shows increased effectiveness compared with trastuzumab alone. This trial is also the basis for many of the ongoing trials incorporating trastuzumab for enhanced activity.


Questions 21 and 22 pertain to the following case.J.J., a 65-year-old African American woman, presented to the outpatient clinic after her first-ever mammogram and subsequent breast biopsy. Before her examination, the patient admitted to having had pain in her right breast for about 1 year but had not gone for an evaluation. In addition, J.J. complains of right abdominal pain for about 2 months, not relieved with around-the-clock hydrocodone therapy. This pain keeps her awake at night, and she is unable to complete activities of daily living. Breast biopsy revealed invasive ductal carcinoma that is estrogen receptor (ER) negative, progesterone receptor (PR) 2%, and human epidermal growth factor receptor 2 (HER2) negative. Her computed tomography (CT) scan of the abdomen revealed two liver lesions (0.7 cm and 1.1 cm) consistent with metastatic disease. J.J.s medical history is significant for obesity, hyperlipidemia, hypertension, and diabetes mellitus.

21. Which one of the following is the best treatment for J.J. at this time?A. Hormonal therapy.B. Single-agent chemotherapy.C. Combined chemotherapy and biologic therapy.D. Combination chemotherapy.

22. J.J. responds well to treatment and is able to perform activities of daily living. In the past 2 weeks, however, she has noticed increased pain in her left arm that never goes away; she does not remember falling or experiencing any trauma to the area. A radiograph reveals a suspicious lesion in her left arm. A bone scan demonstrates increased uptake in the left humerus and right femur consistent with metastatic disease. Which one of the following is the best therapeutic option for J.J. at this time?A. Zoledronic acid 4 mg intravenously monthly.B. Pamidronate 90 mg intravenously monthly.C. Alendronate 70 mg orally once daily.D. Risedronate 35 mg orally once weekly.

Questions 23 and 24 pertain to the following case.G.T., a 62-year-old white woman, was given a diagnosis of left breast cancer 15 years ago. At her initial diagnosis, her tumor characteristics included ER 70%; PR 65%; and HER2 negative. On physical examination, the tumor measured 2.1 cm, and the axillary lymph nodes were negative. G.T. was taken to the operating room, and a modified radical mastectomy was completed with a sentinel lymph node biopsy. Pathology revealed a 2.2-cm invasive ductal carcinoma with negative lymph nodes. In the adjuvant setting, G.T. received four courses of fluorouracil, doxorubicin, and cyclophosphamide and completed 5 years of tamoxifen therapy. G.T. has presented to the clinic with persistent bone pain during the past month. She does not recall any injuries to this area. A bone scan reveals metastatic breast cancer (MBC) in her left sixth rib.

23. In addition to bisphosphonate therapy, which one of the following is the best regimen at this time for G.T.?A. Anastrozole daily.B. Paclitaxel weekly.C. Tamoxifen daily.D. Capecitabine twice daily.

24. G.T. did well during the next year and presented to the clinic for a yearly follow-up examination. Follow-up bone and CT scans revealed new metastases in her left femur and another metastatic site in her ribs. In addition to bisphosphonate therapy, which one of the following is the best regimen for G.T. at this time?A. Fulvestrant.B. Exemestane.C. Tamoxifen.D. Letrozole.

Questions 2527 pertain to the following case.M.D., a 64-year-old woman, received a diagnosis of left breast cancer in 2000. Her cancer history includes a left modified radical mastectomy that revealed an invasive lobular carcinoma (1.5 cm, ER 63%, PR 59%, and HER2 negative) by fluorescence in situ hybridization with 2 of 15 positive axillary lymph nodes. After surgery, she received four courses of doxorubicin and cyclophosphamide, followed by four courses of every-3-week paclitaxel. Her adjuvant hormonal therapy consisted of anastrozole for 5 years. In 2007, M.D. developed metastatic disease in her right humerus and was placed on exemestane and a bisphosphonate. She continues this regimen today. M.D. returns to the clinic for a follow-up examination and is noted to have tenderness in her abdomen and a lingering pain in her right hip. A CT scan demonstrates a small 1-cm liver lesion, and a bone scan reveals a lesion in her right sacrum as well as disease in her right humerus. Her laboratory values are all within normal limits except for a CA27.29 (a tumor marker for breast cancer), which is elevated at 65 U/mL.

25. In addition to a bisphosphonate, which one of the following is the best therapy for M.D.?A. Fluoxymesterone 10 mg orally twice daily.B. Ethinyl estradiol 3 mg/day orally.C. Fulvestrant 250 mg intramuscularly once monthly.D. Megestrol acetate 160 mg orally in divided doses

daily.

26. Which one of the following should be prescribed to help prevent toxicity associated with M.D.s bisphosphonate therapy? A. Monitoring of serum calcium and creatinine.B. Tooth extractions after thorough discussion with

her dentist and medical oncologist.

Self-Assessment Questions


C. Avoidance of endodontic and restorative dental procedures.

D. Prophylactic antibiotics.

27. As part of M.D.s follow-up, in addition to CT and bone scan, which of the following tests and laboratory values are best to monitor during her treatment course? A. CA27.29 and CA15.3.B. CA15.3 and circulating tumor cells.C. CA27.29 and brain magnetic resonance imaging

(MRI).D. CA15.3 and position emission tomography scan.

Questions 28 and 29 pertain to the following case.C.F., a 42-year-old premenopausal woman, recently received a diagnosis of breast cancer that had metastasized to the lungs. Two years ago, C.F. received a diagnosis of stage II invasive lobular, right breast cancer. Her tumor was ER/PR negative and HER2 negative. She completed neoadjuvant chemotherapy consisting of flurouracil, doxorubicin, and cyclophosphamide for four cycles, followed by weekly paclitaxel for 12 doses. C.F. was doing well until the past month when she started experiencing shortness of breath. This kept her from walking up and down the stairs in her home and from performing normal activities of daily living. A CT scan demonstrates new nodules in both lungs, consistent with metastatic disease.

28. Which one of the following is the best therapy for C.F. at this time?A. Docetaxel plus capecitabine.B. Goserelin plus anastrozole.C. Liposomal doxorubicin plus vinorelbine.D. Goserelin plus tamoxifen.

29. C.F. continued treatment for 8 months and tolerated therapy well. She has been monitored in the clinic monthly; today, she brings the results of repeat scans that show progression of her lung metastases. C.F. has been able to walk up and down the stairs at home with no problems. Which one of the following is the best therapy for C.F. at this time?A. Gemcitabine plus paclitaxel.B. Vinorelbine.C. Capecitabine plus lapatinib.D. Carboplatin.

Questions 30 and 31 pertain to the following case.N.W., a 64-year-old woman, received a diagnosis of breast cancer last year and underwent surgery and chemotherapy. She does not remember what chemotherapy she received but recalls that it was red. She moved recently and has been unable to obtain her records from her doctors office. She recently completed restaging because of increased abdominal pain. A CT scan of N.W.s chest and abdomen revealed a 1.5-cm liver lesion. A liver biopsy was performed. The tumor is ER/PR negative and HER2 positive by fluorescence in situ hybridization. Her medical history includes hypertension, hypothyroidism, and gout. Her laboratory values today are

as follows: CA27.29 = 75 U/mL and blood urea nitrogen and serum creatinine slightly elevated at 24 mg/dL and 1.2 mg/dL, respectively.

30. Based on the new information from this biopsy, which one of the following is the best first-line treatment for N.W.s MBC?A. Capecitabine plus lapatinib.B. Trastuzumab plus paclitaxel.C. Trastuzumab plus liposomal doxorubicin.D. Trastuzumab.

31. For 15 months, N.W. responded with stable disease. She returns to the clinic today with repeat staging consisting of CT and bone scans together with laboratory data. Her bone scan is negative; however, her CT scan shows new liver lesions. Which one of the following regimens is best for N.W. at this time?A. Capecitabine plus lapatinib.B. Trastuzumab.C. Liposomal doxorubicin.D. Gemcitabine plus paclitaxel.

32. B.A. is a 59-year-old woman who received a diagnosis of stage II breast cancer in 2003. She underwent a right modified radical mastectomy, followed by chemotherapy consisting of fluorouracil, doxorubicin, and cyclophosphamide for four cycles. She has remained disease free to this point. She returns today with results of restaging bone and CT scans and a liver biopsy. The bone scan was negative, as is the CT scan of the chest. However, the CT scan of her abdomen was positive for two metastatic lesions measuring 0.7 cm and 0.9 cm. A biopsy of the liver metastases reveals a disease status of ER/PR negative, HER2 negative. Which one of the following is the best therapy for B.A. at this time?A. Paclitaxel weekly.B. Paclitaxel every 3 weeks.C. Nanoparticle albuminbound paclitaxel every 3

weeks.D. Paclitaxel and bevacizumab.

33. S.S. is a 45-year-old premenopausal woman seen in the clinic for recently diagnosed left breast cancer. A biopsy reveals ER/PR-positive and HER2-negative disease. On a routine staging work-up, a CT scan reveals three metastatic lesions in her liver, but her bone scan is negative. Her medical history is noncontributory. S.S. says she has not experienced any problems with pain or jaundice, maintaining that she is able to perform normal activities of daily living. Based on this information, which one of the following is the best drug regimen for S.S. at this time?A. Goserelin plus anastrozole.B. Goserelin plus tamoxifen.C. Paclitaxel plus bevacizumab.D. Doxorubicin plus cyclophosphamide.


Questions 3436 pertain to the following case.C.L. is a 68-year-old woman with MBC. Her stage II right breast cancer was diagnosed in 1997, and she received neoadjuvant chemotherapy consisting of four doses of doxorubicin and cyclophosphamide, followed by a right lumpectomy and radiation therapy. The pathology report at that time showed ER/PR positive, HER2 negative, and a 2.1-cm invasive ductal carcinoma; none of the 15 lymph nodes excised was positive. After therapy, C.L. received adjuvant tamoxifen for 5 years. In 2004, C.L. complained of left hip pain, and a bone scan detected metastatic disease. She has received several hormonal agents: anastrozole for 1 year; exemestane for 8 months; fulvestrant for 8 months; megestrol acetate for 6 months; and, finally, fluoxymesterone for 4 months. She also received a bisphosphonate. Her medical history is significant for hypertension, deep vein thrombosis, and coronary artery disease. A recent bone scan reveals new metastases in the rib cage and left sacrum; her CT scan reveals probable metastases in the lung. She is still able to perform activities of daily living.

34. Based on C.L.s past treatment of her MBC, which one of the following is the best treatment at this time for C.L.? A. Ethinyl estradiol.B. Paclitaxel.C. Letrozole.D. Vinorelbine.

35. C.L. tolerates her therapy well and returns to the clinic with new CT and bone scans. The CT scan shows progression of her disease in the lung and new bone metastases. Which one of the following is the next best option for C.L. at this time?A. Clinical trial.B. Best supportive care.C. Chemotherapy holiday.D. Hormonal therapy.

36. During the next 6 months, C.L. develops brain metastases. An MRI identifies three metastatic lesions of various sizes. She has completed whole-brain radiation therapy and comes to the clinic today to discuss systemic treatment of her brain metastases. Which one of the following treatments is best for C.L. at this time? A. Liposomal doxorubicin.B. Trastuzumab.C. Lapatinib.D. Sunitinib.

37. As part of a baseline work-up before starting chemotherapy, a patient had echocardiography that revealed an ejection fraction of 64%. After 3 months of trastuzumab therapy, repeat echocardiography reveals an ejection fraction of 49%. Which one of the following is the best course of action for this patient at this time?A. Continue trastuzumab and tell the patient to inform

the clinic of any symptoms of congestive heart failure.

B. Discontinue trastuzumab therapy and do not reinitiate therapy.

C. Discontinue trastuzumab therapy and initiate medical management.

D. Continue trastuzumab and initiate monthly echocardiography.

38. M.J. is a 55-year-old woman with MBC confined to the lungs. She is being seen in the clinic for a second opinion regarding her treatment options. Her previous physician recommended paclitaxel and bevacizumab. Her medical history is significant for hypercholesterolemia, hypertension, hypothyroidism, arthritis, and diabetes mellitus. Her vital signs today are as follows: blood pressure 175/100 mm Hg; pulse rate 65 beats/minute; respiratory rate 16 breaths/minute; height 164 cm; and weight 73 kg. She currently takes levothyroxine, simvastatin, metoprolol extended release, amlodipine, metformin, glyburide, and naproxen sodium. Which one of the following conditions would most likely eliminate M.J. as a candidate for bevacizumab therapy?A. Uncontrolled hypertension.B. Lack of approval for use in MBC.C. History of diabetes.D. Pulmonary metastases.

39. W.S. is a 53-year-old woman diagnosed with stage II, ER/PR-positive, HER2-positive breast cancer. In 2003 she underwent a left mastectomy (2.3-cm tumor with 2 of 12 lymph nodes positive), followed by adjuvant doxorubicin and cyclophosphamide every 3 weeks. This was followed by sequential weekly paclitaxel in addition to trastuzumab. A recent CT scan of her lungs revealed metastatic disease. Her current drugs include metoprolol, gabapentin, carbamazepine, Multivitamin Plus (purchased at a health food store; W.C. is not sure what is in it) and acetaminophen. Which one of the following drugs should be discussed with the physician regarding drug-drug interactions before dispensing lapatinib and capecitabine to the patient?A. Metoprolol.B. Gabapentin.C. Carbamazepine.D. Multivitamin Plus.

40. A patient in your outpatient clinic is receiving therapy today for treatment of her MBC. The attending physician has ordered nanoparticle albuminbound paclitaxel 260 mg/m2 = 510 mg intravenously for 30 minutes. The patient is to be premedicated with one dose each of dexamethasone 20 mg intravenously, diphenhydramine 50 mg intravenously, and ranitidine 150 mg intravenously, to be given 30 minutes before her chemotherapy is begun. Which one of the following statements is the best regarding the orders you received?A. An in-line filter should be used for administration.B. No premedication is required.C. Prepare in a DHEP-free solution container.D. The infusion rate should be 3 hours.

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