Gerald Higa
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. List factors associated with an increased risk of breast cancer in the United States.
2. Assess patients for signs and symptoms related to breast cancer in early and late stages of the disease.
3. List all modalities that are appropriate screening tools for breast cancer and determine how they should best be used in the public domain.
4. Discuss available options for breast cancer prevention.
5. Critique available prognostic variables for clinical utility.
6. Determine which patient populations may benefit from systemic adjuvant therapy for breast cancer.
7. Determine the treatment goals for early stage, locally advanced and metastatic breast cancer.
8. Determine appropriate indications for endocrine therapy, chemotherapy and biologic therapy for patients with metastatic breast cancer.
9. Evaluate available chemotherapy options for patients with metastatic breast cancer based on pertinent patient and disease state characteristics.
10. Discuss the role of trastuzumab in the management of early and advanced stage breast cancer.
KEY CONCEPTS
Nearly 75% of breast cancers are diagnosed in women older than 50 years. Regular use of screening in this age group decreases the mortality from breast cancer by 20 to 40%.
Breast cancer is diagnosed most commonly in early stages, when it is highly curable.
Local therapy of early-stage breast cancer consists of modified radical mastectomy or lumpectomy plus external-beam radiation therapy. The surgical approach to the ipsilateral axilla may consist of a full level I/II axillary lymph node dissection or a lymph node mapping procedure with sentinel lymph node biopsy.
Adjuvant endocrine therapy reduces the rates of relapse and death in patients with hormone receptor-positive early breast cancer. Adjuvant chemotherapy reduces the rates of relapse and death in all patients with early-stage disease.
The choice of chemotherapy regimen, dose, schedule, and duration of therapy, as well as endocrine therapy, are controversial and changing as results from ongoing clinical trials are reported.
Neoadjuvant chemotherapy is appropriate for patients with locally advanced or inflammatory breast cancer, followed by local therapy and further systemic adjuvant therapy.
The goal of adjuvant chemotherapy is cure, whereas the goal of chemotherapy in the metastatic setting is improving or preserving quality of life.
Initial therapy of metastatic breast cancer in women with hormone receptor-positive tumors usually consists of hormonal therapy.
Women with metastatic breast cancer who have hormone receptor-positive tumors and respond to initial hormonal manipulation usually will respond to a second-hormonal therapy.
Approximately 50% to 60% of women who have not received prior chemotherapy for metastatic disease will respond to chemotherapy regimens; anthracycline- and taxane-containing regimens are the most active.
Although the incidence of breast cancer has been increasing in the United States, the mortality rate has been decreasing over the past two decades. This trend reflects the success of early detection and the development of effective treatment regimens. Treatment for most breast cancer patients includes a combination of pharmacologic and nonpharmacologic therapy.
EPIDEMIOLOGY AND ETIOLOGY
Breast cancer is the most common type of cancer and is second only to lung cancer as a cause of cancer death in American women. It is estimated that 194,280 new cases of breast cancer were diagnosed and that 40,610 women died of breast cancer in 2009.1 Whites account for the largest portion of estimated cases (82%) and deaths (80%). In addition to invasive breast cancers, it is estimated that 62,000 cases of in situ cancer were diagnosed among women in the United States in 2007. The median age for the diagnosis of breast cancer is between the ages of 60 and 65 years.2
Most breast cancers diagnosed are small tumors (less than or equal to 2 cm), and disease is localized in all racial and ethnic groups. However, blacks and other minority women have proportionally more cases of disease diagnosed at more advanced stages compared with white women. This is thought to reflect access to and use of screening mammography and timely treatment. The etiology of breast cancer is unknown, but a number of factors that increase a woman’s chances of developing the disease have been identified. These risk factors, as well as information regarding the biology of the disease, suggest that a complex interplay between hormones, genetic factors, and environmental and lifestyle influences contributes to the etiology of this disease.
The two variables most strongly associated with the occurrence of breast cancer are gender and age. Although one commonly thinks of breast cancer as a disease confined to women, about 2,000 cases of male breast cancer were diagnosed in the United States in 2006.1 When stage and other known prognostic factors are controlled for, men do not fare any differently from their female counterparts and receive similar treatment regimens.
The incidence of breast cancer increases with advancing age. Perhaps the most frequently quoted breast cancer statistic is that one in seven women will develop breast cancer during their lifetime. It should be emphasized that this is a cumulative lifetime risk of developing the disease from birth to age 110 and that the estimates are weighted by the probability of surviving through each decade of life.3 The one in seven women figure is often misinterpreted by women who assume that it translates into one in seven women being diagnosed with breast cancer each year. Feuer and colleagues developed a more useful method of presenting the risk data based on age intervals.3 As Table 89–1demonstrates, the risk of a woman developing breast cancer before the age of 40 years is about 1 in 250. It is apparent from this table that although the cumulative probability of developing breast cancer increases with increasing age, more than half the risk occurs after the age of 60.
Table 89–1 Risk of Developing Breast Cancer: SEER Areas, Women, All Races, 1998 to 2000
As many as 85% of American women have “lumpy breasts” and may have a clinical diagnosis of fibrocystic breast disease or benign breast disease. Data suggest that benign breast disease or fibrocystic disease is most often not associated with proliferation and that these women are not at an increased risk for developing breast cancer.4 However, it must be noted that “lumpy breasts” may lead to a delay in diagnosis of breast cancer because of an inability of the patient or physician to detect a true malignant lesion.
Endocrine Factors
A number of endocrine factors have been linked to the incidence of breast cancer.5,6 Many of these relate to the total duration of menstrual life. Early menarche (prior to age 12) and late menopause (after age 55) increase a women’s breast cancer risk. Similarly, investigators have reported that bilateral oophorectomy prior to age 35 reduces the relative risk of developing breast cancer. Nulliparity and a late age at first birth (greater than or equal to 30 years) have been reported to increase the lifetime risk of developing breast cancer twofold.
Long-term use of hormone-replacement therapy and concurrent use of progestins appear to contribute to breast cancer risk.7 The use of postmenopausal estrogen-replacement therapy in women with a history of breast cancer generally is considered contraindicated. However, most experts believe that the safety and benefits of low-dose oral contraceptives currently outweigh the potential risks and that changes in the prescribing practice for the use of oral contraceptives are not warranted. Oral contraceptives are known to reduce the risk of ovarian cancer by about 40% and the risk of endometrial cancer by about 60%.
Genetic Factors
Both personal and family histories influence a woman’s risk of developing breast cancer. A past medical history for breast cancer is associated with about a fivefold increased risk of contralateral breast cancer. Cancer of the uterus and ovary also has been associated with an increased risk of the development of breast cancer.
It has been recognized for some time that a family history of breast cancer is associated rather strongly with a woman’s own risk for developing the disease. The percentage of all breast cancers in the population that can be attributed to family history range between 6% and 12%.8 Empirical estimates of the risks associated with particular patterns of family history of breast cancer indicate the following:8
1. Having any first-degree relative with breast cancer increases a woman’s risk of breast cancer 1.5- to 3-fold, depending on age.
2. The higher relative risk is associated with breast cancer with onset younger than age 45 years in one or more first-degree relatives.
3. Having multiple first-degree relatives affected has been inconsistently associated with elevated risks.
4. Having a second-degree relative affected increases a woman’s risk of developing breast cancer by approximately 50% (relative risk [RR] 1.5).
5. Affected family members on the maternal side and the paternal side contribute similarly to the risk.
In the early 1990s, the BRCA1 gene on the long arm of chromosome 17 (17q21) was identified as abnormal in a large percentage of hereditary breast and ovarian cancer patients.9,10 A second breast cancer gene, called BRCA2,has been mapped to chromosome 13. Both genes are tumor suppressors. A woman with a strong family history of breast or ovarian cancer, or both, who carries a germ-line mutation of BRCA1 faces roughly an 85% lifetime risk of breast cancer and a 60% risk of ovarian cancer.11 Carriers of the BRCA2 mutation have similar risks for breast cancer but much lower risks for ovarian cancer. Jewish people of Eastern European decent (Ashkenazi Jews) have an unusually high (2.5%) carrier rate of germ-line mutations in BRCA1 and BRCA2 compared with the rest of the U.S. population.
There is a commercially available test for screening that should be done under the guidance of a genetic counselor. Oophorectomy at completion of childbearing is recommended for carriers of BRCA1 and BRCA2 from high-risk families. Bilateral total mastectomy does reduce the risk of breast cancer occurrence; however, both breast and ovarian cancer have been reported in patients who have had prophylactic removal of these organs. In BRCA carriers who do not opt for surgical prophylaxis, mammography every 6 months is recommended and tamoxifen therapy can be considered.
Environmental and Lifestyle Factors
Experimental and epidemiologic evidence suggests an association between breast cancer and the Western diet (high in calories, fat, and cooked meats). Obesity in postmenopausal women and distribution of body fat around the abdominal region also appear to increase the risk of breast cancer. A recent meta-analysis12 indicates both a modest positive association between alcohol ingestion and breast cancer and a dose-response relationship. Cigarette smoking and augmentation mammoplasty do not appear to increase the risk of breast cancer. Exercise may provide a modest protection against breast cancer.
Patient Encounter, Part 1
BB is a 65-year-old woman who presents with a history of a small, hard lump in the upper outer quadrant of her right breast. This lump has been there for at least 3 months. She reports having mammograms in the past that were normal, but she has not had one in about 3 years. The lump in her breast is not painful. She has no nipple discharge or drainage from that breast and the skin appears normal. The left breast is normal. She has a history of hypertension and has been postmenopausal for approximately 10 years. She does not smoke and drinks an occasional glass of wine. She has no family history of breast cancer, but does have a sister with ovarian cancer at age 58 and her father had prostate cancer at age 85. She began menses at age 10, had two pregnancies (first at age 25) with two healthy daughters, and has taken Prempro since menopause at age 55 (for 10 years).
What risk factors for breast cancer does this patient have?
Radiation is associated with an increased risk of breast cancer in survivors of the atomic bomb, in patients given radiation for postpartum mastitis, in women receiving multiple fluoroscopic examinations during therapy for tuberculosis, and in patients who receive mediastinal radiation for malignancies. Interestingly, this risk appears to be confined to exposure to radiation prior to age 40, which suggests that a “window of initiation” for breast cancer occurs at a relatively early age. Exposure to diagnostic x-rays, including annual screening mammography, does not impart a sufficient dose of radiation for clinical concern.
It should be emphasized that more than 60% of women with breast cancer have no identifiable major risk factor, indicating that the search for the etiology of this disease is largely incomplete.
A number of calculators are available on the Internet to estimate a patient’s risk of developing breast cancer. The National Cancer Institute (NCI) has an online version of the Breast Cancer Risk Assessment Tool that is considered to be the most authoritative and accurate standard (www.cancer.gov/bcrisk-tool). The Breast Cancer Risk Assessment Tool was designed for health professionals to project a women’s individualized risk for invasive breast cancer over a 5-year period and over her lifetime.
PATHOPHYSIOLOGY
The pathologic evaluation of breast lesions serves to establish the histologic diagnosis and to confirm the presence or absence of other factors believed to influence prognosis. These prognostic factors include the presence of necrosis, lymphatic or vascular invasion, nuclear grade, hormonereceptor status, proliferative index, amount of aneuploidy, and HER-2/neu expression.
Invasive Carcinoma
Invasive breast cancers are a histologically heterogeneous group of lesions. Most breast carcinomas are adenocarcinomas and are classified on the basis of their microscopic appearance as either ductal or lobular, corresponding to the ducts and lobules of the normal breast. The various histologic types of breast cancer have different prognoses, but it is unknown whether their response to therapy differs because patients in therapeutic trials typically are not stratified according to histologic type. Infiltrating lobular carcinoma commonly metastasizes to meningeal and serosal surfaces and other unusual sites, whereas other types usually metas-tasize to the bone, brain, or liver.
Noninvasive Carcinoma
As with invasive carcinoma, the noninvasive lesions may be divided broadly into ductal and lobular categories. The widespread use of screening mammography and subsequent biopsy, coupled with recognition of noninvasive breast carcinoma by pathologists, has resulted in a significant increase in the diagnosis of in situ breast cancer during the past decade. A detailed discussion of the biology and appropriate management of noninvasive breast cancer is beyond the scope of this chapter, but some of the more salient characteristics of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) are described below, and the reader is referred to a number of excellent reviews for a more comprehensive discussion.13,14
DCIS is seen more frequently than LCIS. It is important to note that carcinoma in situ is treated as cancer. Simple or total mastectomy (without lymph node dissection) has been the standard treatment of DCIS for several decades. Breast conservation, i.e., wide local excision followed by irradiation of breast tissue, may be an effective alternative to mastectomy. Although radiation following lumpectomy does not appear to change the survival of patients with DCIS, it significantly reduces the incidence of local recurrences and enhances the breast preservation rate in these women. Axillary dissection generally is not indicated because there is only a 1% incidence of axillary node involvement. There is currently no proven benefit for the use of cytotoxic chemotherapy in patients who receive local therapy for DCIS. However, there are subgroups of patients with DCIS, such as hormone receptor-positive patients, who may benefit from the addition of tamoxifen to lumpectomy plus radiation.15
Clinical Presentation and Diagnosis of Breast Cancer
Common early symptoms include:
• Painless lump (90% of cases) that is:
• Solitary
• Unilateral
• Solid
• Hard
• Irregular
• Nontender
• Stabbing or aching pain (10% of cases) as the first symptom
Uncommon early symptoms include:
• Nipple discharge (3% of women and 20% of men), retraction, or dimpling
• Eczema appearance of the nipple (Paget’s carcinoma)
• Prominent skin edema, redness, warmth, and induration of the underlying tissue (inflammatory carcinoma)
Metastatic symptoms—tissues most commonly involved with metastases are lymph nodes (other than axillary or internal mammary), skin, bone, liver, lungs, and brain. The following symptoms of metastases will be present in about 10% of patients when they first seek treatment:
• Bone pain
• Difficulty breathing
• Abdominal enlargement
• Jaundice
• Mental status changes
CLINICAL PRESENTATION AND DIAGNOSIS
Prevention and Early Detection
Current efforts at breast cancer prevention are directed toward the identification and removal of risk factors. Unfortunately, a number of risk factors associated with the development of breast cancer, such as family history of breast cancer or personal history of breast or other gynecologic malignancies, cannot be modified. Isolation and cloning of breast cancer susceptibility genes now allows screening of women with histories suggestive of “breast cancer families” and identification of appropriate candidates for prophylactic bilateral mastectomy. There are currently no absolute indications for prophylactic bilateral mastectomy. This surgery is considered for women at very high risk for the development of breast cancer, particularly if the women’s breasts are difficult to evaluate by both physical examination and mammography, and the women have persistent disabling fears that they will be diagnosed with the disease.
The idea that prevention could also be achieved pharmacologically was based on results from clinical trials of tamoxifen, an antiestrogen used as adjuvant therapy for early breast cancer. Not only was the development of contralateral breast cancer lower, but a survival advantage was also clearly demonstrated in women who received tamoxifen for 2 to 5 years following mastectomy.16–18 Provided with an appropriate scientific rationale, several clinical trials were conducted with tamoxifen, which provided proof of principle that breast cancer risk reduction could be achieved through chemoprevention.19–21 A recent meta-analysis of these trials indicates a consistent benefit in reducing the risk of developing estrogen receptor (ER)-positive breast cancers in premenopausal and postmenopausal women.22
However, results of the prevention trials also confirmed the increased incidence of tamoxifen-induced endometrial cancer. That this concern could have a direct impact on patient acceptance of chemoprevention, a search was begun for an agent with a better safety profile. A compound related to tamoxifen known as raloxifene was found to reduce the incidence of spinal fractures in postmenopausal women at high-risk for osteoporosis.23 Because raloxifene was also an antiestrogen, the effects on breast and endometrium were also closely monitored. After 3 years of raloxifene therapy, investigators found a significant decrease in the incidence of breast cancer without the carcinogenic effect on the endometrium.24
The Study of Tamoxifen and Raloxifene (STAR) trial compared the two agents in postmenopausal women who were considered to be at increased risk (as determined by the Gail model)25 for developing invasive breast cancer.26Although there was a similar reduction in the incidence of breast cancer, raloxifene had a superior safety profile with regards to uterine cancer and thromboembolic events. Thus, raloxifene is the chemopreventive agent of choice for postmenopausal women at high-risk for breast cancer. Since premenopausal women were not included in the STAR trial, tamoxifen is the only agent approved for reducing the risk of breast cancer in younger patients.
The impressive data of the aromatase inhibitors in the adjuvant setting have provided the rationale and impetus for studying their potential as breast cancer chemoprevention agents also. Clinical trials have begun to investigate the use of third-generation aromatase inhibitors.27
The rationale for early detection of breast cancer is based on the clear relationship between stage of breast cancer at diagnosis and the probability of cure. Thus, if all breast cancers could be detected at a very early stage of the disease (i.e., small primary tumor and negative lymph nodes), then more patients with the disease could be cured. Screening guidelines for early detection of breast cancer have been put forward by the American Cancer Society, the United States Preventive Services Task Force, and the National Cancer Institute28–30 (Table 89–2). These all include recommendations for women at average risk, with some general statements regarding screening for high-risk women as well. 
Nearly 75% of all breast cancer occurs in women 50 years of age or older, and regular use of screening mammography can reduce mortality from breast cancer by 20% to 40% in this age group. Controversy regarding the use of screening mammography is largely confined to women younger than 50 years of age. After many years of debate, the three available guidelines discussed here recommend mammograms in this age group of women every 1 to 2 years.28–30
Diagnosis
Initial workup for a woman presenting with a lesion or symptoms suggestive of breast cancer should include a careful history, physical examination of the breast, three-dimensional mammography, and possibly other breast imaging techniques such as ultrasound. Most (80–85%) breast cancers can be visualized on a mammogram as a mass, a cluster of calcifications, or a combination of both. Breast biopsy is indicated for a mammographic abnormality that suggests malignancy or for a palpable mass on physical examination.
Clinical Staging
Stage (anatomic extent of disease) is defined on the basis of the primary tumor size (T1–4), presence and extent of lymph node involvement (N1–3 or pN1–3 if pathologic examination of lymph nodes is conducted), and presence or absence of distant metastases (M0–1) (Table 89–3). For a more complete description of the staging system, the reader is referred to the guidelines.31 Although many possible combinations of T and N are possible within a given stage, simplistically, stage 0 represents carcinoma in situ (Tis) or disease that has not invaded the basement membrane. Stage I represents small primary tumor without lymph node involvement, and the majority of stage II disease involves regional lymph nodes. Stages I and II are often referred to as early breast cancer. It is in these early stages that the disease is curable. Stage III, also referred to as locally advanced disease, usually represents a large tumor with extensive nodal involvement in which either node or tumor is fixed to the chest wall. Stage IV disease is characterized by the presence of metastases to organs distant from the primary tumor and is often referred to as advanced or metastatic disease, as described earlier. Most cancer today presents in early stages, where the prognosis is favorable (Table 89–4).
Table 89–2 Guidelines for Early Detection of Breast Cancer
Table 89–3 TNM Stage Grouping for Breast Cancer
Prognostic Factors
A number of potential prognostic factors have been identified for breast cancer. Prognostic factors are measurements available at diagnosis or time of surgery that in the absence of adjuvant therapy are associated with recurrence rate, death rate, or other clinical outcome.
Table 89–4 Estimated Stage at Presentation and 5-Year Disease-Free Survival (DFS): Breast Cancer
• Patient age. Patients diagnosed at age younger than 35 years have a worse prognosis.
• Tumor size. In general, patients with a larger tumor have a worse prognosis.
• Nuclear grade describes the size and shape of the nucleus in tumor cells and the percentage of tumor cells that are dividing. A high nuclear grade signifies that a tumor is growing quickly and indicates a worse prognosis.
• Lymph node involvement. Patients with node-positive disease have a worse prognosis.
• Hormone-receptor status. Patients with negative-ER and negative-progesterone-receptor (PR) tumors have a worse prognosis.
• HER-2/neu protein expression. Patients with HER-2/neu overexpression have a worse prognosis.
EARLY BREAST CANCER
TREATMENT
Desired Outcome
Most patients presenting with breast cancer today have either an in situ tumor, a small tumor with negative lymph nodes (stage I), or a small stage II cancer. The goal of therapy in early breast cancer is curative. Surgery alone can cure most, if not all, patients with in situ cancers and approximately half of all patients with stage II cancers.
Nonpharmacologic Local-Regional Therapy
The choice of surgical procedures has changed drastically over the past 50 years. Current surgical management options for early invasive breast cancer include the modified radical mastectomy (also termed total mastectomy with ipsilateral axillary lymph node dissection) and breast conservation. In the modified radical mastectomy, the pectoralis minor muscle may be excised, divided, or left intact, and more important, there may be variation in the extent of axillary lymph node dissection, ranging from sampling to full dissection. It is important to note that in the elderly, patients with comorbid conditions, patients with particularly favorable tumors, or patients whose adjuvant therapy likely would not be affected by node status, axillary dissection can be considered optional. Breast conservation consists of lumpectomy, also referred to as segmental mastectomy, or partial mastectomy, and is defined as excision of the primary tumor and adjacent breast tissue, followed by radiation therapy to reduce the risk of local recurrence. Removal of level I/II axillary lymph nodes is recommended for completeness of staging and prognostic information. The National Institutes of Health (NIH) Consensus Conference on the Treatment of Early-Stage Breast Cancer addressed the roles of modified radical mastectomy versus breast conservation and concluded that primary therapy for breast cancer stages I and II should be breast conservation.32 The reason given for favoring breast conservation therapy is that it achieved similar results to more extensive surgical procedures and had superior results cosmetically.
Patient Encounter, Part 2: Medical History and Physical Exam
PMH: Hypertension for 15 years, currently controlled.
Endocrine History: Menarche age 10; menopause age 55 (natural); first child age 25; G2P2A0. Last Pap smear 10 years ago. HRT with Prempro since age 55 (10 years). No other exogenous hormone exposure
Meds: Valsartan 160 mg by mouth daily; prempro one tablet by mouth daily.
ROS: (+) lump in right breast; otherwise (-).
PE:
Gen: Obese 65-year-old Caucasian woman who appears her stated age, in NAD
VS: BP 135/76, P 78, RR 18, T 38.1 °C (100.6°F); ht 5’4”, wt 100 kg (220 lbs).
Breast: Right: Hard 2.4? 3 cm mass in upper outer quadrant without associated erythema, dimpling or skin changes, not fixed to skin, no ulceration. No palpable lymph nodes in axilla. Left: Without masses or lymphadenopathy
Labs: All within normal limits
CXR: Lungs are clear
What information is suggestive of breast cancer?
What other tests do you need to make a diagnosis and develop a treatment plan?
In most instances, external-beam radiation therapy used in conjunction with breast-conserving procedures involves 4 to 6 weeks of radiation therapy directed to the breast tissue to eradicate residual disease. Complications associated with radiation therapy to the breast are minor and include reddening and erythema of the breast tissue and subsequent shrinkage of total breast mass beyond that predicted on the basis of breast tissue removal. Some clinical situations also require postmastectomy radiation therapy as well (see section on locally advanced breast cancer).
There are several contraindications to breast conservation that must be considered when selecting patients:
• Multiple sites of cancer within the breast
• Pregnancy (patient cannot receive radiation)
• Inability to attain negative pathologic margins on the excised breast specimen
• Pre-existing collagen-vascular diseases (e.g., scleroderma and systemic lupus erythematosus)
• Diffuse malignant-appearing microcalcifications on mammogram
• Prior radiation treatment to the breast or chest wall
• Large tumor volume in a woman with small breasts (better cosmetic results often can be obtained with mastectomy and reconstruction).
The importance of stage I/II axillary dissection is being challenged. Although highly accurate, its morbidity is significant, with an acute complication rate as high as 20% to 30% and rates of chronic lymphedema also on the order of 20% to 30%.33,34 A new procedure involving lymphatic mapping and sentinel lymph node biopsy is becoming more acceptable at many academic centers across the United States.35 The sentinel lymph node is the first lymph node that drains a cancer. Injection of a dye around the primary breast tumor results in identification of the sentinel lymph node in the majority of patients, and the status of this lymph node may predict the status of the remaining nodes in the nodal basin. A sentinel lymph node can be identified in 90% of patients and can accurately predict the status of the remaining axillary nodes in 95% of patients.36
Pharmacologic Systemic Adjuvant Therapy
Unfortunately, breast cancer cells often spread by contiguity, lymph channels, and through the blood to distant sites. This often occurs early in the breast cancer growth, and deposits of tumor cells form in distant sites that cannot be detected with current diagnostic methods and equipment (micrometastases). Systemic adjuvant therapy is defined as the administration of systemic therapy following definitive local therapy (i.e., surgery, radiation, or a combination of these) when there is no evidence of metastatic disease but a high likelihood of disease recurrence. 
Most published results confirm that chemotherapy (in all patients), hormonal therapy (in patients with hormone-receptor-positive disease), or both result in improved DFS and/or overall survival (OS) for patients with early-stage breast cancer.
A standard approach was formalized at the National Institute of Health’s 2000 Consensus Development Conference on adjuvant therapy for breast cancer.32 The conference panel recommended consideration of adjuvant hormonal therapy for women whose tumors contain hormone-receptor protein regardless of age, menopausal status, involvement of axillary lymph nodes, or tumor size. They also recommended that adjuvant chemotherapy be given for essentially all patients with lymph node metastases or breast tumors 1 cm or larger in size.32
Another group, the St. Gallen expert panel, is convened every 2 years to review new information and establish evidence-based recommendations regarding the treatment of early breast cancer.37 In 2007, the panel endorsed the concept and definition of “endocrine-responsive” tumors, as well as the classification of patients into three risk groups, which were established in 2005. Briefly, tumors were categorized as endocrine responsive (10% or greater number of ER-positive tumor cells), endocrine nonresponsive (0% ER-positive tumor cells), and endocrine responsive uncertain (1–9% ER-positive tumor cells). Risk classification was based on a number of tumor and patient characteristics with the regional lymph node status being the major criterion. The most prominent new recommendation in 2007 was the addition of adjuvant trastuzumab for all patients with HER-2/neu overexpressing tumors. A summary of the risk classification and therapy recommendations is provided in Table 89–5.
The National Comprehensive Cancer Network (NCCN) also has developed practice guidelines for the treatment of early breast cancer.38 Whereas the 2008 guidelines already included the use of trastuzumab, the 2009 version added further recommendations related to HER-2/neu overexpressing tumors. First, although the prognosis of patients with tumors 1 cm or smaller and negative or micro tumor-involved nodes is generally good, the decision to use trastuzumab must consider the relative clinical benefits and drug-associated toxicities. Second, adjuvant trastuzumab should be given for at least 1 year in the absence of treatment-limiting toxicity. Third, the use of preoperative (neoadjuvant) systemic therapy is gaining favor in both early-stage and locally advanced breast cancers. When used prior to surgery, treatments incorporating trastuzumab should be given for at least 9 weeks before the operation is performed.
Although neoadjuvant therapy most often consists of cytotoxic chemotherapy, hormonal agents may be preferable in patients with significant comorbidities. Nonetheless, this strategy can be used to determine tumor response in vivo (an important prognostic indicator) as well as minimize the amount of breast tissue resected. While this approach to therapy generally is reserved for patients with inoperable tumors (locally advanced), early-stage breast cancer patients who meet the criteria for breast-conserving therapy except for the size of the tumor may be considered for preoperative systemic therapy.
Adjuvant Chemotherapy
Cytotoxic drugs that have been used alone and in combination as adjuvant therapy in breast cancer include doxorubicin, epirubicin, cyclophosphamide, methotrexate, fluorouracil, paclitaxel, docetaxel, melphalan, prednisone, vinorelbine, and vincristine. The most common combination chemotherapy regimens employed in the adjuvant and metastatic setting are listed in Table 89–6. The dose-limiting toxicities and other significant toxicities are listed for each chemotherapeutic agent in Table 89–7.
The basic principle of adjuvant therapy for any cancer type is that the regimen with the highest response rate in advanced disease should be the optimal regimen for use in the adjuvant setting. Early administration of effective combination chemotherapy at a time when the tumor burden is low should increase the likelihood of cure and minimize the emergence of drug-resistant tumor cell clones. Anthracyclines (e.g., doxorubicin and epirubicin) historically have been referred to as the most active class of chemotherapy agents in the treatment of metastatic breast cancer. This has led to the assumption that anthracycline-containing regimens are associated with a higher cure rate than nonanthracycline-containing regimens when used in the adjuvant setting.
Table 89–5 St. Gallen Risk Classification and Therapy Recommendations, 2007
Table 89–6 Common Chemotherapy Regimens for Breast Cancer
Table 89–7 Toxicities of Common Chemotherapies Used for Breast Cancer
The taxanes (e.g., paclitaxel and docetaxel) are a newer class of agents that rival the anthracyclines in their activity in metastatic breast cancer, becoming (arguably) the most active class of chemotherapy for this disease.
Although the optimal duration of adjuvant chemotherapy administration is unknown, it appears to be on the order of 12 to 24 weeks and may depend on the regimen being used. Chemotherapy is usually initiated within 3 weeks of surgical removal of the primary tumor. Dose intensity and dose density appear to be critical factors in achieving optimal outcomes in adjuvant breast cancer therapy. Dose intensity is defined as the amount of drug administered per unit of time and typically is reported in milligrams per square meter of body surface area per week (mg/m2/weak). Increasing dose, decreasing time, or both can increase dose intensity. Dose density is equivalent to the concept of increasing dose intensity but not by increasing the amount of drug given, as occurs with dose esca lation, but instead by decreasing the time between treatment cycles. Reducing the dose for standard treatment regimens should be avoided unless necessitated by severe toxicity. On the other hand, increasing doses beyond those contained in standard treatment regimens does not appear to add benefit because there is a threshold for dosing adjuvant chemotherapy above which only additional toxicity is seen without any improvement in patient outcomes.
The short-term toxic effects of chemotherapy used in the adjuvant setting generally are well tolerated. Although a number of investigators have demonstrated a reduction in quality of life, most patients are able to maintain a reasonable level of function and emotional and social well-being during treatment.39 In general, supportive therapy of the patient receiving systemic adjuvant chemotherapy has improved in the past decade. Increased attention to the impact of symptoms on quality of life may account for some of this improvement. In addition, antiemetics that block serotonin and substance P have become available to assist in managing chemotherapy-induced nausea and vomiting, and colony-stimulating factors often are helpful in preventing febrile neutropenia, particularly in elderly patients or patients receiving high-dose and dose-dense chemotherapy regimens. A number of side effects are common with the regimens employed, and patients should be counseled appropriately regarding the likelihood of alopecia, weight gain, and fatigue. Patients who are menstruating usually experience a cessation of menses that may or may not return. Along with cessation of menses are accompanying signs and symptoms of menopause. Deep vein thrombosis has been reported in women receiving combination chemotherapy regimens.40 A recent study estimated that 1 to 10 of 10,000 patients treated for 6 months with cyclophosphamide-based regimens might be expected to have leukemia within 10 years of diagnosis of breast cancer.41 Cardiomyopathy induced by doxorubicin occurs less than 1% of the time in women whose total dose of doxorubicin is less than 320 mg/m2.42 It should be noted that epirubicin in the adjuvant setting is given at a dose of 100 to 120 mg/m2.43 At this dose, epirubicin has an equal chance of causing cardiomyopathy as standard doxorubicin doses when both agents are given as bolus or short infusions. Taxanes often are associated with hypersensitivity reactions, peripheral neuropathy, and/or myalgias and arthralgias for a few days following the infusion.
It is important to note that the magnitude of survival benefit for chemotherapy appears to be small, with an absolute reduction in mortality of only 5% at 10 years for patients with negative axillary lymph nodes and 10% for patients with positive axillary lymph nodes. Regardless, it has been reported that most patients with early breast cancer would accept drug-related toxicities in order to achieve the modest overall benefits.44,45 Because the risks are not insignificant, investigators have been searching for ways to identify patients who could avoid chemotherapy without altering the disease prognosis. Recently, three gene expression assays (e.g., Oncotype DX, MammaPrint, and H/I) with the potential to do this have become commercially available. Of the three, Oncotype DX provides the strongest evidence that a subset of patients, especially those with ER-positive, lymph node-negative tumors derive little or no benefit from adjuvant chemotherapy when compared to the use of hormonal therapy alone.46 Some newer data also suggest this is true for patients with lymph node-positive disease.47 In essence, genomic analyses may play an important role in improving risk stratification and determining chemotherapy benefit.48
Adjuvant Biologic Therapy
Trastuzumab is a monoclonal antibody directed against the HER-2/neu receptor. HER-2/neu is a member of the erbB (or HER) growth factor receptor family and is expressed at low levels in the epithelial cells of normal breast tissue. The overexpression of HER-2/neu is associated with increased transmission of growth signals that control aspects of cell growth and division. Most experts would agree that women whose tumors overexpress HER-2/neu appear to be relatively resistant to alkylating agent-based adjuvant therapy, and they might derive greater benefit from an anthracycline-based adjuvant therapy regimen.49-51
While HER-2/neu positively (but not absolutely) predicts response to trastuzumab therapy, receptor over expression is also considered a negative prognostic factor. Currently, the use of trastuzumab is indicated for treatment of adjuvant and metastatic breast cancer in patients who have tumors that overexpress HER-2/neu.38 It is important to note that trastuzumab therapy should not be given concurrently with the anthracyclines because of an increased risk of cardiotoxicity (see section on metastatic breast cancer). Doses and common toxicities for trastuzumab are listed in Table 89–8.
Adjuvant Endocrine Therapy
Hormonal therapies that have been studied in the treatment of primary or early breast cancer include antiestrogens, oophorectomy, ovarian irradiation, luteinizing hormone-releasing hormone (LHRH) agonists, and aromatase inhibitors.
Hormone receptors are used clinically as indicators of prognosis and to predict response to hormone therapy. Hormone receptors are cytoplasmic proteins that transmit signals to the nucleus of the cell for growth and proliferation. The hormone receptors clinically useful in discussions of breast cancer include the ER and the PR. The presence of these proteins in the primary tumor (or less often in metastases) is measured routinely by enzyme-linked immunochemical assays and radio assays (enzyme-linked immunosorbent assay). About 50% to 70% of patients with primary or metastatic breast cancer have hormone-receptor-positive tumors. Hormone-receptor positivity is associated with a superior response to hormone therapy and a longer disease-free interval between primary and subsequent metastatic disease and overall a more favorable prognosis. Hormone-receptor-positive tumors are more common in postmenopausal patients than in premenopausal patients. Many experts suggest that breast cancer in postmenopausal women is substantively different from that occurring in premenopausal women.
Tamoxifen traditionally was the “gold standard” adjuvant hormonal therapy and has been used in the adjuvant setting for three decades. Tamoxifen is antiestrogenic in breast cancer cells, but it appears to have estrogenic properties in other tissues and organs.52,53 Newer information confirms that tamoxifen and other similar drugs have many estrogenic and antiestrogenic effects that depend on the tissue and the gene in question, and they are more appropriately called selective estrogen-receptor modulators (SERMs). Women receiving adjuvant tamoxifen therapy have a reduction in recurrence and mortality compared with women not receiving adjuvant tamoxifen therapy.54This observation, coupled with evidence of tamoxifen’s tolerability, including beneficial estrogenic effects on the lipid profile and bone density, led to tamoxifen being the hormonal agent of choice.
Adjuvant tamoxifen therapy generally is initiated shortly after surgery or as soon as pathology results are known and the decision to administer tamoxifen as adjuvant therapy is made. The administration of tamoxifen should be limited to administration after completion of chemotherapy based on results from a study that randomized patients to receive chemotherapy for six cycles with concurrent tamoxifen, followed by continued tamoxifen for a total of 5 years, or chemotherapy with sequential tamoxifen for 5 years.55 After a median follow-up of 8.5 years, the administration of sequential tamoxifen resulted in an estimated DFS advantage of 18% (hazard ratio [HR] 1.18) compared with the concurrent use of tamoxifen with chemotherapy.55 It is believed the growth-inhibitory effect of tamoxifen therefore may diminish the cytotoxic effect of chemotherapy, resulting in subsequent recurrence of disease in women who received the two agents concurrently.
The optimal duration of tamoxifen therapy (20 mg/day) in the adjuvant setting is currently defined as 5 years. Studies examining prolonged administration (e.g., 10 years) have failed to demonstrate any advantage and may, in fact, be associated with a slightly worse survival.56 Owing to the potential serious side effects of tamoxifen, all patients must be counseled properly about warning signs of endometrial cancer (i.e., vaginal bleeding or groin pain/pressure) and thromboembolism (i.e., chest pain, trouble breathing, changes in vision, one-sided weakness, or pain/swelling in the legs).
Table 89–8 Breast Cancer Pharmacogenomics
One of the most intriguing observations associated with the adjuvant tamoxifen trials relates to the role of pharmacogenomics in terms of tailoring therapy to individual patients (Table 89–9). For example, compelling evidence from a number of studies indicate that women with germline variants of CYP2D6 is associated with substantially lower concentrations of the active tamoxifen metabolite endoxifen and significantly more disease recurrence and shorter DFS.57,58 Consistent with this finding are additional data that concomitant administration of drugs that inhibit CYP2D6 resulted in reduced plasma levels of endoxifen and was an independent predictor of breast cancer outcomes in patients receiving tamoxifen.59–61
Toremifene is a recently marketed antiestrogen whose primary advantage is a lower estrogenic: antiestrogenic ratio than tamoxifen (based on laboratory data).62 Toremifene (60 mg orally daily) has been found to have efficacy similar to that of tamoxifen in metastatic disease and a generally similar side-effect profile.63 Currently, toremifene is indicated as an alternative to tamoxifen in patients with metastatic breast cancer, but studies are ongoing that evaluate its safety and efficacy in the adjuvant setting.
In premenopausal women, the use of LHRH agonists or other means of ovarian ablation have been shown to provide benefit in the adjuvant setting.64 The use of goserelin (an LHRH agonist), alone or with tamoxifen, has been compared with standard chemotherapy (CMF) for six cycles. As a single agent, goserelin appears to provide similar benefit to CMF for six cycles for node-positive, ER-positive premenopausal breast cancer patients.65 In another trial, the combination of goserelin and tamoxifen was compared with CMF for six cycles.66 After a median follow-up of 6 years, this trial demonstrated a significant advantage of endocrine therapy in terms of DFS over chemotherapy alone. Retrospective reviews have found that premenopausal women who cease to menstruate with chemotherapy may have a better survival than women who continue to menstruate.67 Therefore, the role of an LHRH agonist after chemotherapy in women who continue to menstruate is being investigated.
In postmenopausal women, recently reported evidence supporting the use of aromatase inhibitors in the adjuvant setting is intriguing and may usurp the role of tamoxifen. Three different approaches to therapy have been undertaken with these new agents: (a) direct comparison with tamoxifen for adjuvant hormonal therapy; (b) sequential use after 5 years of adjuvant tamoxifen therapy; and (c) sequential use after 2 to 3 years of adjuvant tamoxifen. Based on results of several studies, it has been concluded that therapy for postmenopausal women with ER-positive breast cancer should include an aromatase inhibitor.37,68 It is still unclear if the aromatase inhibitor should be used instead of tamoxifen or sequentially after receiving tamoxifen for 2 to 5 years.37 Nonetheless, the 2009 NCCN Practice Guidelines recommend “bone mineral density determination at initiation of aromatase inhibitor therapy and periodically thereafter.”38 Other concerns related to changes in blood lipids and cardiovascular disease require further study. Successful coadministration of bisphosphonates with the aromatase inhibitors has been accomplished in many patients in the metastatic setting. The three available aromatase inhibitors are exemestane, anastrozole, and letrozole.
Table 89–9 Endocrine Therapies Used for Metastatic Breast Cancer
LOCALLY ADVANCED BREAST CANCER (STAGE III)
TREATMENT
Desired Outcome
Locally advanced breast cancer generally refers to breast carcinomas with significant primary tumor and nodal disease but in which distant metastases cannot be documented. A wide variety of clinical scenarios can be seen within this group of patients, including neglected tumors that have spread locally and inflammatory breast cancers that are a unique clinical entity. Many locally advanced breast cancers are diagnosed in patients who have had symptoms for months to years and have neglected to seek medical attention. Patients with inflammatory breast cancer often are treated inappropriately for cellulitis with antibiotics for several weeks to months.
Treatment of stage III breast cancer generally consists of a combination of surgery, radiation, and chemotherapy administered in an aggressive approach. The natural history of locally advanced breast cancer suggested that even when local-regional control was accomplished, systemic relapse and death from breast cancer occurred eventually in most patients.69 This led to interest in the use of neoadjuvant or primary chemotherapy in locally advanced breast cancer, as discussed previously. This approach to therapy renders inoperable tumors resectable and can increase rates of breast-conserving therapy. Theoretical advantages also include potential benefits related to early initiation of systemic therapy, delivery of drugs through an intact vasculature, in vivo assessment of response to therapy, and the opportunity to study the biologic effects of the systemic treatment. However, this approach to therapy also results in a loss of standard, well-validated pathologic prognostic markers, such as initial tumor size and the number of axillary lymph nodes involved. Also, as discussed earlier, OS with adjuvant compared with neoadjuvant chemotherapy is similar, making either approach reasonable for a patient with operable breast cancer.
Pharmacologic Therapy
For patients with inoperable breast cancer, including inflammatory breast cancer, the initial approach to therapy should be chemotherapy with the goal of achieving resectability. After neoadjuvant chemotherapy, most tumors respond with more than a 50% decrease in tumor size; about 70% of patients experience downstaging. Chemotherapy regimens used in this setting are similar to those used in the adjuvant setting. Supporting evidence for each individual regimen differs, but most of the available data support the use of anthracycline-containing regimens, incorporation of the taxanes in some manner, and other approaches to improve dose density or dose intensity. For more details regarding the specific regimens, the reader is referred to a recently published review.69 Neoadjuvant endocrine therapy may be an option for patients who have unresectable hormone-receptor-positive tumors who are unable to receive chemotherapy (e.g., multiple comorbid conditions). In terms of local therapy, this usually follows chemotherapy, and the extent of surgery will be determined by response to chemotherapy, the wishes of the patient, and the cosmetic results likely to be achieved. Many patients may be able to have breast-conserving surgery if an acceptable response to chemotherapy is achieved. Adjuvant radiation therapy should be administered to all locally advanced breast cancer patients to minimize local recurrences regardless of the type of surgery used for that individual patient (e.g., mastectomy or segmental mastectomy). Inoperable tumors that are unresponsive to systemic chemotherapy may require radiation therapy for local management and may or may not be eligible for surgical resection after that radiation. Such patients are not seen commonly, but they have a very poor prognosis. For most patients in this category, cure is still the primary goal of therapy and can be achieved in a large number of patients when all treatment modalities are employed.
METASTATIC BREAST CANCER (STAGE IV)
TREATMENT
Desired Outcome
The goal of therapy with early and locally advanced breast cancer is to cure the disease. Breast cancer is currently incurable after it has advanced beyond local-regional disease. The goal of treatment of metastatic breast cancer is to improve symptoms, maintain quality of life, and extend survival. Thus, it is important to choose therapy with good activity while minimizing toxicities. Treatment of metastatic breast cancer with either cytotoxic or endocrine therapy often results in regression of disease and improvements in quality of life.
General Approach to Treatment
The choice of therapy for metastatic disease is based on the site of disease involvement and presence or absence of certain characteristics (i.e., hormone and HER-2 receptor status of the primary tumor). For example, patients who experience a long DFS following local-regional therapy or have disease that is located primarily in the bone or soft tissue likely will respond to endocrine therapy. Patients with asymptomatic visceral involvement (e.g., liver or lung) may be candidates for hormonal therapy depending on the clinical circumstance (generally, hormones work more slowly than chemotherapy). Patients who are hormone-receptor-positive generally will receive initial endocrine therapy followed by combination chemotherapy when endocrine therapy fails. 
Patients who respond to initial endocrine therapy often respond to a second (or even third) hormonal manipulation. Response rate is lower and duration of response is shorter with second (and third) hormonal manipulations. Patients are treated sequentially with endocrine therapy until their tumors cease to respond, at which time cytotoxic chemotherapy can be given. Between 50% and 60% of ER-positive patients and 75% and 80% of ER-and PR-positive patients will respond to hormonal therapy, whereas those with ER- and PR-negative tumors have a less than 10% response rate. Thus, the largest factor determining choice of endocrine versus cytotoxic chemotherapy is the presence of hormone receptors in the primary breast tumor.
Patients who are hormone-receptor-negative with rapidly progressive or symptomatic disease involving the liver, lung, or CNS or those having progressed on initial endocrine therapy usually are treated with cytotoxic chemotherapy initially. Chemotherapy will result in an objective response in about 50% to 60% of patients previously unexposed to chemotherapy. Most patients have partial response, and complete disappearance of disease occurs in fewer than 20% of patients treated. Median duration of response is 5 to 12 months, although some patients will have an excellent response to an initial course of chemotherapy and may live 5 to 10 years without evidence of disease. In general, survival of patients after treatment with commonly used drug combinations for metastatic breast cancer is a median of 14 to 33 months. The response rate to second- and third-line combination chemotherapy varies from 20% to 40% depending on the previous chemotherapy regimens the patient has received. Combinations of different hormonal therapies or chemotherapy plus hormones are not employed in the setting of metastatic breast cancer owing to the lack of increased efficacy and evidence of increased toxicity. Patients with tumors that have HER-2/neu overexpression should be considered for treatment with trastuzumab, alone or with chemotherapy.
Pharmacologic Systemic Therapy
Endocrine Therapy
The pharmacologic goals of endocrine therapy for breast cancer are either to decrease circulating levels of estrogen and/or to prevent the effects of estrogen on the breast cancer cell (targeted therapy) through blocking the hormone receptors or downregulating the presence of those receptors. Achievement of the first goal depends on the menopausal status of the patient, but achievement of the second goal is independent of menopausal status. Many endocrine therapies are available to target either goal of therapy, and combination studies also have been conducted in an attempt to combine differing mechanisms of action and improve outcomes. Unfortunately, combinations have not demonstrated any efficacy benefits but have increased toxicity. Therefore, combinations of endocrine agents for breast cancer are not recommended outside the context of a clinical trial. Patients often are treated with a series of endocrine agents, frequently over several years, before chemotherapy is considered.
Until recently, there was little evidence that the response or survival benefit from one endocrine therapy was clearly superior to that achieved with other therapies. Given this equality in efficacy, the choice of a particular endocrine therapy was based primarily on toxicity (Table 89–9). Based on these criteria, tamoxifen has been the preferred initial agent when metastases are present. An exception to this occurs when the patient is receiving adjuvant tamoxifen at the time or within 1 year of occurrence of metastatic disease.
Over the past decade, new information has been published regarding the use of a new generation of aromatase inhibitors. These data have changed the way we treat metastatic breast cancer, as well as early-stage breast cancer (as noted previously). In postmenopausal and castrated women, the main source of estrogen is derived from the peripheral conversion of androstenedione, produced by the adrenal gland, to estrone and estradiol. This conversion requires the enzyme aromatase. Aromatase also catalyzes the conversion of androgens to estrogens in the ovary in premenopausal women and in extraglandular tissue, including the breast itself, in postmenopausal women. Therefore, aromatase inhibitors (e.g., anastrozole, letrozole, and exemestane) effectively reduce the level of circulating estrogens, as well as estrogens in the target organ. Their toxicity profile consists mainly of nausea, hot flashes, arthralgias/myalgias, and mild fatigue. Anastrozole and letrozole are nonsteroidal compounds that exhibit reversible, competitive inhibition of aromatase. Exemestane is a steroidal compound that binds irreversibly to aromatase, forming a covalent bond. There is no clinical evidence that exemestane produces superior results over the other agents in this class.
Aromatase inhibitors are used for first-line therapy for advanced breast cancer in postmenopausal women. Large trials have compared these agents with tamoxifen and have found similar response rates and a longer median time to progression for patients receiving the selective aromatase inhibitor.49 A consistent finding in these trials was a lower incidence of thromboembolic events and vaginal bleeding in patients who received selective aromatase inhibitors, which, together with the advantage in terms of time to progression, led to the conclusion that the new aromatase inhibitors are superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women. Use of a steroidal aromatase inhibitor (exemestane) after a patient progresses on a nonsteroidal inhibitor (anastrozole or letrozole) may provide some benefit and is a common practice based on small clinical trials investigating this sequential approach to therapy.70 The opposite sequence also has shown some benefit. Therefore, patients may receive two aromatase inhibitors (first and second line sequentially), especially patients who progress while on adjuvant tamoxifen therapy.
As mentioned several times so far, the aromatase inhibitors are only used appropriately in women who are postmenopausal. Premenopausal or perimenopausal women, whose ovaries are functioning, are not appropriate candidates for these therapies, at least based on the available evidence. Use of the aromatase inhibitors in addition to ovarian ablation (e.g., oophorectomy or LHRH agonists) is currently being investigated. Also, the use of aromatase inhibitors in men with advanced breast cancer should be avoided. Available evidence suggests that use of these agents in men increases circulating levels of testosterone, which may negate the therapeutic effects of the drug.71
Antiestrogens bind to estrogen receptors, preventing receptor-mediated gene transcription, and therefore are used to block the effect of estrogen on the end target. This class of agents now is subdivided into two pharmacologic categories, SERMs and pure antiestrogens. SERMs include tamoxifen and toremifene and demonstrate tissue-specific activity, both estrogenic and antiestrogenic, as described previously. The agonistic activity is thought to be responsible for many of the adverse reactions seen with these agents, including the increased risk of endometrial cancer. Research into how to minimize this agonistic activity has led to the production of pure estrogen-receptor antagonists that lack estrogen agonist activity. Pure antiestrogens are a new class of agents that are also referred to as selective estrogen-receptor downregulators (SERDs). These molecules bind to the ER, inhibiting estrogen binding, and cause a degradation of the drug-ER complex, decreasing the amount of ER on the tumor cell surface. There is currently only one pure antiestrogen available commercially in the United States, namely, fulvestrant.
Tamoxifen can be used in both premenopausal and postmenopausal women with metastatic breast cancer who have tumors that are hormone-receptor-positive. The toxicities of tamoxifen are described in the section on adjuvant endocrine therapy. The only additional toxicity that one might expect to find in the setting of metastatic breast cancer (specifically bone metastases) is a tumor flare or hypercalcemia, which occurs in approximately 5% of patients following the initiation of any SERM therapy and is not an indication to discontinue SERM therapy. It is generally accepted that this is a positive indication that the patient will respond to endocrine therapy.
Toremifene is another commercially available SERM for the treatment of breast cancer. It exhibits similar efficacy and tolerability to tamoxifen in the metastatic setting. Cross-resistance to toremifene has been demonstrated in patients with tamoxifen-refractory disease.72 Therefore, toremifene appears to be an alternative to tamoxifen in postmenopausal patients with positive or unknown hormone-receptor status with metastatic breast cancer.
Fulvestrant is a new agent approved for the second-line therapy of postmenopausal metastatic breast cancer patients who have tumors that are hormone-receptor-positive. Studies examining the role of fulvestrant in the treatment of metastatic breast cancer have compared this agent with anastrozole. Given anastrozole’s mechanism of action, only postmenopausal women were eligible for these trials. There is no biologic reason why fulvestrant should not produce similar outcomes in premenopausal women, but no data exist to confirm the safety or efficacy in premenopausal women. In the comparative trials with fulvestrant and anastrozole, similar efficacy and safety were demonstrated with both agents when given after patients progressed on tamoxifen therapy.73,74 Adverse events related to fulvestrant include injection-site reactions, hot flashes, asthenia, and headaches. This agent is a good option for patients who are unable to take an oral medication because it is given as an intramuscular injection over 28 days.
Another goal of antitumor treatment is to reduce estrogen production in premenopausal women with surgery, irradiation, or medication. No difference has been found in two randomized trials of the overall response rate between tamoxifen and oophorectomy in premenopausal women. However, the secondary response rate to oophorectomy after tamoxifen treatment was somewhat higher than the response to tamoxifen after primary oophorectomy (33% versus 11%).75 Some experts interpret this as suggesting that tamoxifen does not completely antagonize available estrogen, particularly in premenopausal women. Ovarian ablation (surgically or chemically) is still used commonly in some parts of the United States and is considered by many specialists to be the endocrine therapy of choice in premenopausal women. The mortality rate with surgical oophorectomy is low, usually less than 2% to 3% in appropriately selected patients. Irradiation of the ovaries was a means of castration many years ago but was associated with multiple complications and is no longer performed for these purposes. Medical castration with LHRH analogs is used increasingly in lieu of oophorectomy in premenopausal women.
Medical castration with LHRH analogs has been used in premenopausal metastatic breast cancer patients and induces remission in about one-third of unselected patients. The mechanism of action of LHRH analogs in breast cancer is thought to result from down-regulation of LHRH receptors in the pituitary. Decreased levels of luteinizing hormone (LH) subsequently lead to a decrease in estrogen to castrated levels. The three agents available in the United States are leuprolide, goserelin, and triptorelin, but only goserelin is approved for the treatment of metastatic breast cancer. These agents are administered as an injection and are associated with minimal side effects, including amenorrhea, hot flashes, and occasionally nausea. A recent metaanalysis was reported on combined tamoxifen and LHRH agonists versus LHRH agonists alone in premenopausal patients with metastatic breast cancer.76 With a median follow-up of 6.8 years, there was a significant survival benefit and progression-free survival (PFS) benefit in favor of the combined treatment. The overall response rate was significantly higher on combined endocrine treatment. However, this analysis did not compare tamoxifen alone against the combination of an LHRH agonist with tamoxifen. LHRH agonists also may produce a flare response owing to an initial surge in LH and estrogen production for the first 2 to 4 weeks. This flare response is similar to that seen with tamoxifen, and patients should be monitored for increasing pain and/or hypercalcemia during the initiation period.
Progestins such as megestrol acetate and medroxy-progesterone acetate have been compared with tamoxifen in randomized trials and have been found to yield equal response rates. Although there were no direct comparisons of these two forms of progestational therapy, they appear to be equally effective. Medroxyprogesterone acetate is used more frequently in Europe, and megestrol acetate is used more frequently in the United States. Based on efficacy and tolerability, these agents generally are reserved as third-line therapy after patients have received an aromatase inhibitor and a SERM (i.e., tamoxifen or toremifene). The most common side effect is weight gain, occurring in 20% to 50% of patients. Patients experiencing weight gain may have fluid retention, but fluid retention is not totally responsible for the weight gain. In cachectic cancer patients, the weight gain may be desirable, but this is not uniformly true of all patients with metastatic breast cancer. Additional side effects associated with progestins include vaginal bleeding in 5% to 10% of patients, either while patients are taking the progestational agent or when it is discontinued, and somewhat less than a 10% incidence of hot flashes. Thromboembolic complications are also significant with these agents.
High-dose estrogens and androgens are used rarely today because these agents are more toxic than the other hormonal agents discussed thus far. About one-third of patients placed on high-dose estrogens will discontinue them because of side effects, the most important of which are thromboembolic events, vomiting, and fluid retention. Given the recent availability of the aromatase inhibitors, use of androgens and estrogens has become rare.
Cytotoxic Chemotherapy
Cytotoxic chemotherapy is eventually required in most patients with metastatic breast cancer. Patients with hormone-receptor-negative tumors r-equire chemotherapy as initial therapy of symptomatic metastases. Patients who respond initially to hormonal manipulations eventually cease to respond and go on to require chemotherapy. The median duration of response is 5 to 12 months, but some patients will have an excellent response to an initial course of chemotherapy and may live 5 to 10 years or longer without evidence of disease. In general, median survival of patients after treatment with commonly used drug combinations for metastatic breast cancer is 14 to 33 months. The median time to response has ranged from 2 to 3 months in most studies, but this period depends in large part on the site of measurable disease. The median time to appearance of response is between 3 and 6 weeks in patients whose disease is primarily in the skin and lymph nodes, 6 to 9 weeks in patients with metastatic lung involvement, 15 weeks in patients with hepatic involvement, and nearly 18 weeks in patients with bone involvement. Thus it is often the case that an immediate response to therapy is not apparent, and in general, once a chemotherapy regimen has been initiated, it is continued until there is unequivocal evidence of progressive disease.
There are no well-defined clinical characteristics or established tests to identify patients likely to benefit from chemotherapy. Factors associated with an increased probability of response that have been identified include a good performance status, a limited number (one-two) of disease sites, and patients who respond to chemotherapy or hormonal therapy with a long disease-free interval. Patients who have progressive disease during chemotherapy have a lower probability of response to a different type of chemotherapy. However, this is not necessarily true for patients who are given chemotherapy after some interval during which they have received no chemotherapy. Patients who do not respond to endocrine therapy are as likely to respond to chemotherapy as patients who are treated with chemotherapy as their initial treatment modality. Age, menopausal status, and receptor status have not been associated with favorable or unfavorable response to chemotherapy.
A number of chemotherapeutic agents have demonstrated activity in the treatment of breast cancer, including doxorubicin, epirubicin, paclitaxel, nab-paclitaxel, docetaxel, capecitabine, fluorouracil, cyclophosphamide, methotrexate, vinblastine, vinorelbine, ixabepilone, gemcitabine, mito-xantrone, mitomycin-C, thiotepa, and melphalan. The most active classes of chemotherapy in metastatic breast cancer are the anthracyclines and the taxanes, producing response rates as high as 50% to 60% in patients who have not received prior chemotherapy for metastatic disease.77 Themost useful weekly dose of paclitaxel in the metastatic setting appears to be 80 mg/m2/weak with no breaks in therapy. With this approach, the toxicity profile of paclitaxel changes with less myelosuppression and delayed onset of peripheral neuropathy but slightly more fluid retention and skin and nail changes. Patients should be premedicated with a steroid (dexamethasone), H1 antagonist (diphenhydramine), and H2 antagonist (ranitidine or famotidine) prior to treatment to minimize hypersensitivity reactions. A randomized study comparing doses of 60, 75, and 100 mg/m2 docetaxel was published recently and demonstrates a dose-response relationship with regard to response rates only.78 Time to progression and os were similar among all three dose levels. Therefore, dose remains important for symptomatic patients who require a rapid response to therapy. In asymptomatic patients requiring docetaxel chemotherapy, lower doses may be appropriate. Results from a single randomized trial appear to indicate that docetaxel is associated with less neuropathy, myalgia, and hypersensitivity than paclitaxel given every 3 weeks, but febrile neutropenia, fluid retention, and skin reactions appear to occur more frequently with the newer taxane.79 The median cumulative docetaxel dose to the onset of fluid retention is 400 mg/m2 in nonpremedicated patients. Premedication with a steroid (dexamethasone) prior to beginning docetaxel and continued for 3 days helps to prevent hypersensitivity reactions and fluid retention.
Regardless of the minor controversy regarding whether a new formulation of an old drug can be considered a “new” drug, nanoparticle albumin-bound paclitaxel or nabpaclitaxel exhibits some distinct advantages over conventional paclitaxel. In a pivotal clinical study designed to compare the efficacy and safety of nab-paclitaxel with the older formulation, patients with metastatic breast cancer were enrolled into a randomized trial.80 Patients received either 260 mg/m2 nab-paclitaxel or 175 mg/m2 conventional paclitaxel. Because the albumin-bound drug does not require solvents, standard premedications to prevent acute drug reactions were not given to those randomized to the newly formulated product. Results of the trial indicated significantly better outcomes in patients treated with nab-paclitaxel compared to those receiving standard paclitaxel. The overall response rates of 33% and 19% favored patients in the nab-paclitaxel arm; P = 0.001; and median time to progression for the nab-paclitaxel group and conventional paclitaxel group was 23 weeks versus 16.9 weeks, respectively, P = 0.006. Despite the higher dosage, the incidence of severe neutropenia was significantly lower with nab-paclitaxel compared to conventional paclitaxel, 9% versus 22%, respectively; P < 0.001. In addition, even in the absence of premedication, no acute hypersensitivity reactions were observed with nab-paclitaxel administration. Nab-paclitaxel is currently indicated for patients with metastatic breast cancer resistant to conventional chemotherapy or progressing within 6 months of receiving an adjuvant anthracycline-containing chemotherapy regimen.
Ixabepilone is a member of a distinct class of microtubule-targeted agents known as the epothilones. In vitro studies show that the antitumor activity of ixabepilone, like the taxanes, occurs primarily by blocking disassembly, thus kinetically “stabilizing” the microtubule structure. The results of an international phase III clinical trial demonstrated that the combination of ixabepilone plus capecitabine significantly prolonged PFS by approximately 1.6 months compared to capecbine alone (median 5.8 months versus 4.2 months, respectively; P = 0.0003).81 This relatively modest improvement represented a 38% overall increase in PFS. The objective response rate (ORR) was more than twice as high with the combination compared to capecitabine alone, 35% versus 14%, respectively. Notably, the response rates were nearly identical to the ORRs (33% versus 14%) in patients who had disease which was intrinsically resistant to previous taxane therapy. The findings from this study support preclinical data that the antitumor activity between ixabepilone and capecitabine are at least additive, and may in fact, be synergistic.82
However, a much higher incidence of adverse effects involving the bone marrow and peripheral nervous system was apparent in those receiving ixabepilone plus capecitabine. Five infection-related deaths were associated with abnormal liver function at the time of enrollment. In addition, two-thirds of the patients developed variable grades of sensory neuropathy; 21% of the all patients discontinued treatment due to this adverse effect.
Ixabepilone is approved for use in combination with capecitabine for patients with advanced breast cancer resistant to or progressing on previous anthracycline and taxane therapy or for patients in whom anthracyclines are contraindicated. The use of single-agent ixabepilone is approved for use in patients with disease resistant capecitabine as well as any drugs in the two classes mentioned above.
Capecitabine is a novel oral agent approved in the mid-1990s with significant activity in metastatic breast cancer patients who have progressed on an anthracycline-containing regimen as well as a taxane regimen. This agent is a prodrug for fluorouracil with somewhat targeted activity toward malignant cells. The parent compound undergoes a three-step enzymatic conversion to become fluorouracil at the target cell (Table 89–9).83 The third and final step in this conversion is more likely to occur in malignant cells than normal cells owing to the presence of higher levels of the responsible enzyme in malignant tissues. Approximately 85% of fluorouracil is degraded by dihydropyrimidine dehydrogenase (Table 89–9). In patients who have been exposed to an anthracycline and a taxane, capecitabine produces response rates of about 25%, which is impressive compared with other tested chemotherapy agents.84
Vinorelbine, a microtubule interactive agent, also has shown impressive response rates in metastatic breast cancer.85 Vinorelbine was approved by the FDA in 1994 for the treatment of nonsmall cell lung cancer. It is not approved for breast cancer, but response rates to vinorelbine range from 30% to 50%, with an overall 5% complete response rate in phase I and phase II studies in patients with advanced breast cancer. Importantly, paclitaxel, docetaxel, and vinorelbine do not appear to be cross-resistant with anthracyclines, which are arguably considered first-line treatment of metastatic breast cancer.
Gemcitabine is another agent that is used quite frequently in patients who have received the aforementioned chemotherapy regimens, who still have a good performance status, and who may benefit from additional chemotherapy. This is a nucleotide analog that inhibits DNA synthesis. Response rates ranging from 13% to 42% have been reported in a number of phase II trials.85 In patients who have been exposed to an anthracycline and a taxane, gemcitabine appears to provide similar benefit to capecitabine. This agent appears to affect platelets more frequently than other chemotherapy previously mentioned, and close monitoring is required for patients receiving this agent.
Combination chemotherapy regimens are associated with higher response rates than are single-agent therapies in the treatment of metastatic breast cancer, but the higher response rates usually have not translated into significant differences in time to progression and OS. The use of sequential single-agent chemotherapies versus the combination regimens has been debated widely for metastatic breast cancer. Current consensus is that first-line chemotherapy includes sequential single agents or combination chemotherapy.38 In the palliative metastatic setting, using the least toxic approach is preferred when efficacy is considered equal. In clinical practice, patients who require a rapid response to chemotherapy (e.g., those with symptomatic bulky metastases) often receive combination therapy despite the added toxicity. This decision is complex and should be made on an individual patient basis.
Because most patients are given adjuvant chemotherapy, regimens chosen for first-line use in the metastatic setting often are different from those used in the adjuvant setting. If a patient’s cancer recurs within 1 year of finishing adjuvant chemotherapy, those chemotherapy agents are not considered effective for treatment of the metastatic disease. However, if the patient recurs more than 1 year after the end of her adjuvant chemotherapy, the same agents also may be helpful in the metastatic setting.
Biologic Therapy
Trastuzumab is a humanized monoclonal antibody that binds with a specific epitope of the HER-2/neu protein. Single-agent treatment with trastuzumab has a response rate of 15% to 20% and a clinical benefit rate of nearly 40% in patients with HER-2/neu-overexpressing cancers.86 Trastuzumab has additive and perhaps synergistic activity with other chemotherapeutic agents.87 In the pivotal trial, patients who received the doxorubicin-trastuzumab combination had a very high incidence of cardiotoxicity (27%), leading to a black-box warning regarding this combination in the product information for trastuzumab. Many investigators are attempting to circumvent this toxicity while giving these two classes of agents together (e.g., liposomal doxorubicin or continuous-infusion doxorubicin). Until further information regarding the safety of these approaches becomes available, this combination should not be given outside the context of a clinical trial. Other chemotherapy agents that are being evaluated in combination with trastuzumab include docetaxel, vinorelbine, gemcitabine, capecitabine, and the platinum agents (e.g., cisplatin and carboplatin).88
Trastuzumab is reasonably well tolerated. The most common adverse effects are infusion-related, primarily fever and chills, and occur in about 40% of patients during the initial infusion. Acetaminophen and diphenhydramine may be given and/or the infusion rate reduced to help alleviate the symptoms related to these reactions. A more severe adverse effect consisting of severe hypersensitivity and/or pulmonary reactions has been reported but is rare. It is important to educate patients regarding the pulmonary reactions because these may occur up to 24 hours after the infusion and can be fatal if not treated promptly. Trastuzumab may increase the incidence of infection, diarrhea, and/or other adverse events when given with chemotherapy. As mentioned previously, when given with an anthracycline, the rates of heart failure are unacceptably high, but even when given as a single agent, there is about a 5% incidence of heart failure. Fortunately, the heart failure seen with trastuzumab is somewhat reversible with pharmacologic management, and some patients have continued therapy with trastuzumab after their left ventricular ejection fraction has returned to normal. Close monitoring for clinical signs and symptoms of heart failure is important in order to intervene with appropriate cardiac treatments.
It should be noted that only 20% to 30% of patients with metastatic breast cancer overexpress HER-2/neu, and commercially available immunohistochemistry (IHC) tests that are reported back as 2+ for HER-2/neu are often negative by the more sensitive and specific fluorescence in situ hybridization (FISH) technique. To date, there is no benefit associated with the administration of trastuzumab to the subset of patients who are HER-2/neu-negative and a very questionable benefit associated with administration of trastuzumab to women who are 2+ for HER-2/neu by IHC staining alone. The patients who benefit most from trastuzumab therapy include those whose tumors express HER-2 protein at the 3+ level and/or demonstrate gene amplification by FISH testing.89
Lapatinib is a dual inhibitor of HER-2/neu and the epidermal growth factor receptor (EGFR). In contrast to the extracellular recognition site of trastuzumab, the specific targets of lapatinib are the receptors’ intracellular kinase domain. A critical phase III trial was conducted to assess the efficacy and safety of lapatinib plus capecitabine versus capecitabine alone in patients with trastuzumab-refractory advanced breast cancer.90 Of note, the trial was terminated early when a preplanned interim analysis indicated a significant reduction in risk of disease progression (time to progression [TTP], P < 0.001) which favored the group receiving the combination to capecitabine alone. Efficacy data of the entire patient cohort were reanalyzed 4 months later. Based on an independent review, the median TTP was 27.1 weeks and 18.6 weeks (P = 0.00013, HR 0.57) and response rates were 23.7% and 13.9% for the lapatinib combination arm and capecitabine monotherapy arm, respectively. Interestingly, tumor cell expression of EGFR was not an eligibility criterion. This is especially notable because results from an earlier study of lapatinib suggested that clinical response may be higher in breast tumors that coexpressed EGFR and HER2.91Another relevant outcome was the significantly lower incidence of brain metastasis in the lapatinib-treated group compared to capecitabine alone, 2% versus 11%, respectively, P = 0.0445.92
Clinical trials of lapatinib have revealed a remarkably similar side-effect profile which included nontreatment-limiting diarrhea, rash, nausea and fatigue among the most frequently reported side effects. The incidence of diarrhea, dyspepsia, and rash was higher when lapatinib was combined with capecitabine.81 Cardiac events were also monitored because severe toxicity related to blockade of the HER-2/neusignaling pathway has been previously reported.93,94 Although addition of lapatinib was not associated with any cardiac event resulting in subject withdrawal, the answer related to this issue is not final as the possibility of selection bias and the relatively short observation period.
Based on these data, lapatinib in combination with capecitabine was approved in March 2007 for patients with HER-2/neu-overexpressing metastatic breast cancer progressing on prior anthracycline, taxane, and trastuzumab therapy.
Another monoclonal antibody, bevacizumab, was combined with paclitaxel in a clinical trial for first-line chemotherapy in women with metastastic breast cancer. The PFS was improved for the combination regimen over paclitaxel alone.38 Bevacizumab targets vascular endothelial growth factor (VEGF), thereby preventing angiogenesis, which is a necessary process to support tumor growth and metastasis. Bevacizumab was first approved by the FDA for the treatment of colorectal cancer and in February 2008, received FDA approval as first-line therapy in combination with paclitaxel for metastatic HER-2-negative breast cancer. Additional studies are being conducted to elucidate bevacizumab’s role in the treatment of breast cancer, including combination with trastuzumab.
Patient Encounter 1, Part 3: Creating a Care Plan
BB is diagnosed with stage IV metastatic, ER+ HER-2/neu+ breast cancer that is metastatic to the bone.
What are the goals of therapy?
What patient-specific therapeutic plan do you recommend?
How should the patient be monitored for efficacy and toxcity?
Bisphosphonates
For women whose breast cancer has metastasized to bone, bisphosphonates are recommended, in addition to chemotherapy or endocrine therapy, to reduce bone pain and fractures.38,95 Pamidronate (90 mg) and zoledronate (4 mg) can be given IV once each month. These bisphosphonates are given in combination with calcium and vitamin D.
Local-Regional Control
Radiation Therapy
Radiation is an important modality in the treatment of symptomatic metastatic disease. The most common indication for treatment with radiation therapy is painful bone metastases or other localized sites of disease refractory to systemic therapy. Radiation therapy gives significant pain relief to approximately 90% of patients who are treated for painful bone metastases. Radiation is also an important modality in the palliative treatment of metastatic brain lesions and spinal cord lesions, which respond poorly to systemic therapy, as well as eye or orbit lesions and other sites where significant accumulation of tumor cells occurs. Skin and/or lymph node metastases confined to the chest wall area also may be treated with radiation therapy for palliation (e.g., open wounds or painful lesions).
OUTCOME EVALUATION
Early breast cancer is resected completely with curative intent, and adjuvant chemotherapy and hormonal therapy are initiated to prevent recurrence. During adjuvant chemotherapy, laboratory values to monitor chemotherapy toxicity are obtained prior to each cycle of chemotherapy. After completion of adjuvant therapy, patients are monitored every 3 months for the first few years after diagnosis, with intervals between exams extended as time from diagnosis lengthens.
• Physical examination to detect breast cancer recurrence
• Annual mammography
• Symptom-directed workup
Locally advanced breast cancer often is treated with neoadjuvant therapy to make the tumor surgically resectable.
During neoadjuvant chemotherapy, laboratory values to monitor chemotherapy toxicity are obtained prior to each cycle of chemotherapy, and a physical and ultrasound examinations to detect size of tumor are performed after the cycles of neoadjuvant therapy are completed. After a complete surgical resection, monitoring proceeds as described earlier for early breast cancer.
Patient Care and Monitoring
1. Review the patient’s diagnostic information to determine the stage of disease, overall prognosis and goals of therapy.
2. Obtain a thorough history of prescription, nonprescription, and natural drug product use. Is the patient taking any medications that may contribute to breast cancer and require discontinuation?
3. Review the patient’s past medical history to determine the risks associated with any potential therapies and/or surgery and/or radiation therapy.
4. Educate the patient on the chemotherapy or endocrine therapy regimen chosen for the patient, focusing on what adverse events to expect, when to expect them, and how to manage them if they do occur. Also, include in the initial education an overall plan of care, including the duration of therapy, other treatment modalities that will follow (e.g., radiation therapy, surgery, endocrine therapy) and when they will receive them.
5. Develop a premedication and postmedication plan for the chemotherapy or endocrine therapy regimen chosen based on the patient’s risk factors for adverse events, chemotherapy/endocrine therapy drugs chosen, and dose, route, and timing of administration chosen.
6. Develop a plan to assess effectiveness of the overall treatment plan, focusing on educating the patient on ways to monitor and track adverse events and/or disease-related symptoms throughout therapy.
7. Determine success of the overall treatment plan by obtaining a thorough history of adverse events experienced with the previous chemotherapy/endocrine therapy treatment and objective measures of response to therapy. Assess effects on quality of life measures such as physical, psychological, and social function and well-being.
8. Address any adverse events the patient experienced and alter the premedication and postmedication plan for the next treatment accordingly.
9. Provide follow-up patient education regarding the new plan for side effect management.
10. Stress importance of reporting adverse events and adherence with the prescribed medication regimen. Attempt to develop a therapeutic regimen that is easy for the patient to accomplish.
Metastatic breast cancer is not curable, and therapy is intended to palliate symptoms. In most cases, hormonal therapy is the mainstay. While on therapy, patients are monitored monthly for signs of disease progression or metastasis to common sites, such as the bones, brain, or liver:
• Pain
• Mental status or other neurologic findings
• Laboratory tests
• Liver function tests
• CBC
• Calcium, electrolytes
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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