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Breast cancer most often involves glandular breast cells in the ducts or lobules. Most patients present with an asymptomatic lump discovered during examination or screening mammography. Diagnosis is confirmed by biopsy. Treatment usually includes surgical excision, often with radiation therapy, with or without adjuvant chemotherapy, hormonal therapy, or both.

About 213,000 new cases were identified in 2006. It is the 2nd leading cause of cancer death in women (after lung cancer), with about 41,000 deaths in 2006. Male breast cancer accounts for < 1% of total cases; manifestations, diagnosis, and management are the same, although men tend to present later.

Risk Factors

In the US, cumulative risk of developing breast cancer is 12% (1 in 8) by age 95, and risk of dying of it is about 4%. Much of the risk is incurred after age 60 (see Table 2: Breast Disorders: Breast Cancer Risks). These statistics can be misleading because most people die before age 95, and cumulative risk of developing the cancer in any 20-yr period is considerably lower.

Table 2
Breast Cancer Risks Age (yr) Risk of Developing (or Dying of*) Breast Cancer (%) In 10 yr In 20 yr In 30 yr 30 0.4 (0.1) 2.0 (0.6) 4.3 (1.2) 40 1.6 (0.5) 3.9 (1.1) 7.1 (2.0) 50 2.4 (0.7) 5.7 (1.6) 9.0 (2.6) 60 3.6 (1.0) 7.1 (2.0) 9.1 (2.6) 70 4.1 (1.2) 6.5 (1.9) 7.1 (2.0) *Percentage for dying of breast cancer equals that for developing it divided by 3.5. Based on Feuer EJ, Wun LM, Boring CC, et al: The lifetime risk of developing breast cancer. Journal of the National Cancer Institute 85(11): 892–897, 1993.

Factors that may affect breast cancer risk include the following:

• Family history: Having a 1st-degree relative (mother, sister, daughter) with breast cancer doubles or triples risk of developing the cancer, but breast cancer in more distant relatives increases risk only slightly. When ≥ 2 1st-degree relatives have breast cancer, risk may be 5 to 6 times higher.
• Breast cancer gene: About 5% of women with breast cancer carry a mutation in one of the 2 known breast cancer genes, BRCA1 or BRCA2. If relatives of such a woman also carry the gene, they have a 50 to 85% lifetime risk of developing breast cancer. Women with BRCA1 mutations also have a 20 to 40% lifetime risk of developing ovarian cancer; risk among women with BRCA2 mutations is increased less. Women without a family history of breast cancer in at least 2 1st-degree relatives are unlikely to carry this gene and thus do not require screening for BRCA1 and BRCA2 mutations. Men who carry a BRCA2 mutation also have an increased risk of developing breast cancer. The genes are more common among Ashkenazi Jews. Women with BRCA1 or BRCA2 mutations may require closer surveillance or preventive measures, such as taking tamoxifen Some Trade Names
  NOLVADEX
  Click for Drug Monograph
  or raloxifene Some Trade Names
  EVISTA
  Click for Drug Monograph
  or undergoing double mastectomy.
• Personal history: Having had in situ or invasive breast cancer increases risk. Risk of developing cancer in the contralateral breast after mastectomy is about 0.5 to 1%/yr of follow-up.
• Gynecologic history: Early menarche, late menopause, or late first pregnancy increases risk. Women who have a first pregnancy after age 30 are at higher risk than those who are nulliparous.
• Breast changes: History of fibrocystic changes that require biopsy for diagnosis increases risk slightly. Women with multiple breast lumps but no histologic confirmation of a high-risk pattern should not be considered at high risk. Benign lesions that may slightly increase risk of developing invasive breast cancer include complex fibroadenoma, moderate or florid hyperplasia (with or without atypia), sclerosing adenosis, and papilloma. Risk is about 4 or 5 times higher than average in patients with atypical ductal or lobular hyperplasia and about 10 times higher if they also have a family history of invasive breast cancer in a 1st-degree relative. Increased breast density seen on screening mammography is associated with an increased risk of breast cancer
• Use of oral contraceptives: Oral contraceptive use increases risk very slightly (by about 5 more cases per 100,000 women). Risk increases primarily during the years of contraceptive use and tapers off during the 10 yr after stopping. Risk is highest in women who began to use contraceptives before age 20 (although absolute risk is still very low).
• Hormonal therapy: Postmenopausal hormone (estrogen plus a progestin) therapy appears to increase risk modestly after only 3 yr of use (see also Menopause: Hormone therapy). After 5 yr of use, the increased risk is about 7 or 8 more cases per 10,000 women for each year of use (about a 24% increase in relative risk). Use of estrogen alone does not appear to increase risk of breast cancer. Selective estrogen-receptor modulators (eg, raloxifene Some Trade Names
  EVISTA
  Click for Drug Monograph
  ) reduce the risk of developing breast cancer.
• Radiation therapy: Exposure to radiation therapy before age 30 increases risk. Mantle-field radiation therapy for Hodgkin lymphoma about quadruples risk of breast cancer over the next 20 to 30 yr.
• Diet: Diet may contribute to development or growth of breast cancers, but conclusive evidence about the effect of a particular diet (eg, one high in fats) is lacking. Obese postmenopausal women are at increased risk, but there is no evidence that dietary modification reduces risk. For obese women who are menstruating later than normal, risk may be decreased.

Pathology

Most breast cancers are epithelial tumors that develop from cells lining ducts or lobules; less common are nonepithelial cancers of the supporting stroma (eg, angiosarcoma, primary stromal sarcomas, phyllodes tumor). Cancers are divided into carcinoma in situ and invasive cancer.

Carcinoma in situ is proliferation of cancer cells within ducts or lobules and without invasion of stromal tissue. Usually, ductal carcinoma in situ (DCIS) is detected only by mammography and is localized to one area; it may become invasive. Lobular carcinoma in situ (LCIS) is a nonpalpable lesion usually discovered via biopsy; it is rarely visualized with mammography. LCIS is often multifocal and bilateral. It is not malignant, but its presence indicates increased risk of subsequent invasive carcinoma in either breast; about 1 to 2% of patients with LCIS develop cancer annually.

Invasive carcinoma is primarily adenocarcinoma. About 80% is the infiltrating ductal type; most of the remainder is infiltrating lobular. Rare forms include medullary, mucinous, and tubular carcinomas.

Paget's disease of the nipple (not to be confused with the metabolic bone disease also called Paget's disease) is a form of ductal carcinoma in situ that extends into the overlying skin of the nipple and areola, manifesting with an inflammatory skin lesion (see Cancers of the Skin: Paget's Disease of the Nipple). Characteristic malignant cells called Paget cells are present in the epidermis. The cancer may become invasive.

Pathophysiology

Breast cancer invades locally and spreads initially through the regional lymph nodes, bloodstream, or both. Metastatic breast cancer may affect almost any organ in the body—most commonly, lungs, liver, bone, brain, and skin.

Most skin metastases occur near the site of breast surgery; scalp metastases also are common. Metastatic breast cancer frequently appears years or decades after initial diagnosis and treatment.

Estrogen and progesterone receptors, present in some breast cancers, are nuclear hormone receptors that promote DNA replication and cell division when the appropriate hormones bind to them. Thus, drugs that block these receptors may be useful in treating tumors with the receptors. About 2/3 of postmenopausal patients have an estrogen-receptor positive (ER+) tumor. Incidence of ER+ tumors is lower among premenopausal patients.

Another cellular receptor is human epidermal growth factor receptor 2 (HER2; also, HER2/neu or ErbB2); its presence correlates with a poorer prognosis at any given stage of cancer.

Symptoms and Signs

Most breast cancers are discovered as a lump by the patient or during routine physical examination or mammography. Less commonly, the presenting symptom is breast pain or enlargement or a nondescript thickening in the breast. Paget's disease of the nipple presents with skin changes, including erythema, crusting, scaling, and discharge; these usually appear so benign that the patient ignores them, delaying diagnosis for a year or more. About 50% of patients with Paget's disease of the nipple have a palpable mass at presentation. A few patients with breast cancer present with signs of metastatic disease (eg, pathologic fracture, pulmonary dysfunction).

A common finding during physical examination is a dominant mass—a lump distinctly different from the surrounding breast tissue. Diffuse fibrotic changes in a quadrant of the breast, usually the upper outer quadrant, are more characteristic of benign disorders; a slightly firmer thickening in one breast but not the other may be a sign of cancer. More advanced breast cancers are characterized by fixation of the lump to the chest wall or to overlying skin, by satellite nodules or ulcers in the skin, or by exaggeration of the usual skin markings resulting from lymphedema (so-called peau d'orange). Matted or fixed axillary lymph nodes suggest tumor spread, as does supraclavicular or infraclavicular lymphadenopathy. Inflammatory breast cancer is characterized by diffuse inflammation and enlargement of the breast, often without a lump, and has a particularly aggressive course.

Diagnosis

• Screening by mammography, breast examination, or sometimes MRI
• Biopsy, including analysis for estrogen and progesterone receptors and for HER2 protein

Testing is required to differentiate benign lesions from cancer. Because early detection and treatment of breast cancer improves prognosis, this differentiation must be conclusive before evaluation is terminated.

If advanced cancer is suspected based on physical examination, biopsy should be done first; otherwise, the approach is as for breast lumps (see Breast Disorders: Evaluation). A prebiopsy bilateral mammogram may help delineate other areas that should be biopsied and provides a baseline for future reference. However, mammogram results should not alter the decision to do a biopsy, based on physical findings. Biopsy can be needle or incisional biopsy or, if the tumor is small, excisional biopsy. Any skin with the biopsy specimen should be examined because it may show cancer cells in dermal lymphatic vessels. Routinely, stereotactic biopsy (needle biopsy during mammography) or ultrasound-guided biopsy is being used to improve accuracy.

Evaluation after cancer diagnosis: Part of a positive biopsy specimen should be analyzed for estrogen and progesterone receptors and for HER2 protein.

WBCs should be tested for BRCA1 and BRCA2 genes when

• Family history includes multiple cases of early-onset breast cancer.
• Ovarian cancer develops in patients with a family history of breast or ovarian cancer.
• Breast and ovarian cancers occur in the same patient.
• Patients have an Ashkenazi Jewish heritage.
• Family history includes a single case of male breast cancer.

Chest x-ray, CBC, and liver function tests and serum Ca should be done to check for metastatic disease. Generally, measuring serum carcinoembryonic antigen (CEA), cancer antigen (CA) 15-3, or CA 27-29 is not recommended because results have no effect on treatment or outcome.

Bone scanning should be done if patients have any of the following:

• Tumors > 2 cm
  Bone pain
  Lymph node involvement
  Elevated serum alkaline phosphatase or Ca levels

Abdominal CT is done if patients have any of the following:

• Abnormal liver function results
• Hepatomegaly
• Locally advanced cancer with or without axillary lymph node involvement

MRI is often used to evaluate breast cancer after it is diagnosed because MRI can accurately determine tumor size, chest wall involvement, and presence of multiple tumors. Use of MRI to identify axillary node involvement is under study.

Grading is based on histologic examination of the tissue taken during biopsy.

Staging follows the TNM (tumor, node, metastasis) classification. Staging is refined during surgery, when regional lymph nodes can be evaluated.

Screening: Screening includes mammography, clinical breast examination (CBE) by health care practitioners, MRI (for high-risk patients), and monthly breast self-examination (BSE).

Mammography, done annually, is recommended for women ≥ 50; it reduces mortality rate by 25 to 35% in this age group. Mammography is more accurate in older women, partly because with aging, fibroglandular tissue in breasts tends to be replaced with fatty tissue, which can be more easily distinguished from abnormal tissue. However, there is considerable disagreement about screening for women 40 to 50 yr; recommendations include annual mammography (American Cancer Society), mammography every 1 to 2 yr (National Cancer Institute), and no periodic mammography (American College of Physicians). Concerns about screening too soon or too often include increased radiation exposure and overdiagnosis of tumors (eg, DCIS) that may not develop into invasive cancer during the patient's lifetime. Young age at the time of radiation exposure increases the risk of cancer.

Only about 10% of abnormalities detected on screening mammography result from cancer, and false-negative results may exceed 15%. Accuracy depends partly on the techniques used and experience of the mammographer. Some centers use computer analysis of digitized mammography images (full-field digital mammography) to help in diagnosis. Such systems may be slightly more sensitive for invasive cancers in women age < 50 when results are interpreted by radiologists, but probably not when interpreted primarily via computer detection.

CBE is usually part of routine annual care for women > 35; it can detect 7 to 10% of cancers that cannot be seen on a mammogram. In the US, CBE augments rather than replaces screening mammography. However, in some countries where mammography is considered too expensive, CBE is the sole screen; reports on its effectiveness in this role vary.

MRI is thought to be better than CBE or mammography for screening women with a high (eg, > 15%) risk of breast cancer, such as those with a BRCA gene mutation. MRI has higher sensitivity but may be less specific. Because specificity is lower, MRI is not considered appropriate for screening women with average or slightly increased risk.

BSE alone has not been shown to reduce mortality rate, but evidence of its usefulness is mixed, and it is widely practiced. Because a negative BSE may tempt some women to forego mammography or CBE, the need for these procedures should be reinforced when BSE is taught. Patients should be instructed to do BSE on the same day each month. For menstruating women, 2 or 3 days after menses ends is recommended because breasts are less likely to be tender and swollen.

Prognosis

Long-term prognosis depends on tumor stage (see Table 3: Breast Disorders: Staging and Survival of Breast Cancer). Nodal status (including number and location of nodes) correlates with disease-free and overall survival better than any other prognostic factor.

Table 3
Staging and Survival of Breast Cancer Stage Tumor Regional Lymph Node/Distant Metastasis 10-yr Disease-Free Survival (%)* No Treatment Optimal Treatment 0 Tis N0/M0 94 98 I T1† N0/M0 92 96 IIA T0 N1/M0 80 90   T1† N1/M0 75 87   T2 N0/M0 83 90 IIB T2 N1/M0 60 80   T3 N0/M0 50 75 IIIA T0 N2/M0 50 75   TI† N2/M0 60 80   T2 N2/M0 55 75   T3 N1/M0 45 70   T3 N2/M0 30 65 IIIB T4 N0/M0 25 40   T4 N1/M0 10 30   T4 N2/M0 5 10 IIIC Any T N3/M0 5 10 IV Any T Any N/M1 5 10 *Data are for 60-yr-old women who have estrogen-receptor positive, intermediate nuclear grade, HER2-negative cancer and who are in otherwise good health. †T1 includes T1mic. Tis = carcinoma in situ or Paget's disease of the nipple with no tumor (Paget's disease with a tumor is classified by tumor size); T1 = tumor < 2 cm; T1mic = microinvasion ≤ 0.1 cm; T2 = tumor > 2 but < 5 cm; T3 = tumor > 5 cm; T4 = any size with extension to chest wall or skin or inflammatory cancer. Larger tumors are more likely to be node-positive, but they also confer a worse prognosis independent of nodal status. NX = Nearby nodes cannot be assessed (for example, removed previously). N0 = no spread to nearby nodes; N1 = spread to 1–3 axillary nodes, tiny amounts of cancer in internal mammary lymph nodes (near the sternum) detected during sentinel lymph node biopsy, or both; N2 = spread to 4–9 axillary nodes or enlargement of the internal mammary nodes; N3 = any of the following: Spread to ≥ 10 axillary nodes Spread to infraclavicular nodes Spread to supraclavicular nodes Spread to axillary nodes plus enlargement of internal mammary nodes Spread to ≥ 4 axillary nodes plus tiny amounts of cancer in internal mammary nodes detected during sentinel node biopsy M0 = none; M1 = present. Adapted from the American Joint Committee on Cancer, AJCC Cancer Staging Manual, Sixth Edition. New York, Springer-Verlag, 2002 and Thor A: A revised staging system for breast cancer. The Breast Journal 10 (S1): S15–S18 2004.

Poor prognosis is associated with the following other factors:

• Young age: Prognosis appears worse for patients diagnosed with breast cancer during their 20s and 30s than for patients diagnosed during middle age.
• Larger primary tumor: Larger tumors are more likely to be node-positive, but they also confer a worse prognosis independent of nodal status.
• High grade tumor: Patients with poorly differentiated tumors have a worse prognosis.
• Absence of estrogen and progesterone receptors: Patients with ER+ tumors have a somewhat better prognosis and are more likely to benefit from hormone therapy. Patients with progesterone receptors on a tumor may also have a better prognosis. Patients with both estrogen and progesterone receptors on a tumor may have a better prognosis than those who have only one of these receptors, but this is not clear.
• Presence of HER2 protein: When the HER2 gene (HER2/neu [erb-b2]) is amplified, HER2 is overexpressed, increasing cell growth and reproduction and often resulting in more aggressive tumor cells. Overexpression of HER2 is an independent risk factor for a poor prognosis; it also may be associated with high histologic grade, ER– tumors, greater proliferation, and larger tumor size, all poor prognostic factors.
• Presence of BRCA genes: For any given stage, patients with the BRCA1 gene appear to have a worse prognosis than those with sporadic tumors, perhaps because they have a higher proportion of high-grade, hormone receptor-negative cancers. Patients with the BRCA2 gene probably have the same prognosis as those without the genes if the tumors have similar characteristics. With either gene, risk of a 2nd cancer in remaining breast tissue is increased (to perhaps as high as 40%)

Treatment

• Surgery
• Usually radiation therapy
• Sometimes hormone therapy, chemotherapy or both

For most patients, primary treatment is surgery, often with radiation therapy. Chemotherapy, hormone therapy, or both may also be used, depending on tumor and patient characteristics (see Table 4: Breast Disorders: Treatment by Cancer Type).

Table 4
Treatment by Cancer Type Type Possible Treatments DCIS Mastectomy Wide excision with or without* radiation therapy LCIS Observation with regular examinations and mammograms Tamoxifen Some Trade Names NOLVADEX Click for Drug Monograph or, for some postmenopausal women, raloxifene Some Trade Names EVISTA Click for Drug Monograph to reduce risk of invasive cancer Bilateral prophylactic mastectomy (rarely) Stages I and II (early stage) cancer Breast-conserving surgery to remove the tumor and some surrounding tissue, followed by radiation therapy Sometimes mastectomy with breast reconstruction Postoperative chemotherapy, hormonal therapy, trastuzumab Some Trade Names HERCEPTIN Click for Drug Monograph , or a combination, except in some postmenopausal women with tumors < 1 cm Preoperative chemotherapy if tumor is > 5 cm Stage III (locally advanced) cancer Preoperative systemic therapy, usually chemotherapy Breast-conserving surgery or mastectomy if tumor is resectable after preoperative therapy Mastectomy for inflammatory breast cancer Usually, postoperative radiation therapy Sometimes postoperative chemotherapy, hormonal therapy, or both Stage IV (metastatic) cancer If cancer is symptomatic and multifocal, hormone therapy, ovarian ablation therapy, or chemotherapy If HER2 is overexpressed, trastuzumab Some Trade Names HERCEPTIN Click for Drug Monograph For brain metastases, local skin recurrences, or isolated, symptomatic bone metastases, radiation therapy For bone metastases, IV bisphosphonates to reduce bone loss and bone pain Paget's disease of the nipple Usually, the same as for other types Occasionally, local excision only Locally recurrent breast cancer Mastectomy, sometimes preceded by chemotherapy or hormone therapy Phyllodes tumors if cancerous Wide excision Mastectomy if the mass is large or histology suggests cancer *Wide excision may be used alone, especially if the lesion is < 2.5 cm and histologic characteristics are favorable, or with radiation therapy if size and histologic characteristics are less favorable. DCIS = ductal carcinoma in situ; LCIS = lobular carcinoma in situ.

Surgery: For patients with invasive cancer, survival rates do not differ significantly whether modified radical mastectomy (simple mastectomy plus lymph node dissection) or breast-conserving surgery plus radiation therapy is used. Breast-conserving surgery includes lumpectomy, wide excision or quadrantectomy. Thus, patient preference can guide choice of treatment within limits. The main advantage of breast-conserving surgery plus radiation therapy is cosmetic. In 15% of patients thus treated, cosmetic results are excellent. However, the need for total removal of the tumor with a tumor-free margin overrides cosmetic considerations. With both types of surgery, lymph node dissection or node sampling should be done. Routine use of extensive procedures is not justified because the main value of lymph node removal is diagnostic, not therapeutic. However, results of frozen section analysis may change the extent of surgery needed. Some surgeons get prior agreement for more invasive surgery in case nodes are positive; others wake the patient and do a 2nd procedure if needed.

Some physicians use preoperative chemotherapy to shrink the tumor before removing it and applying radiation therapy; thus some patients who might otherwise have required mastectomy can have breast-conserving surgery. Early data suggest that this approach does not affect survival.

Radiation therapy after mastectomy significantly reduces incidence of local recurrence on the chest wall and in regional lymph nodes and may improve overall survival in patients with primary tumors > 5 cm or with involvement of ≥ 4 axillary nodes. Adverse effects of radiation therapy (eg, fatigue, skin changes) are usually transient and mild. Late adverse effects (eg, lymphedema, brachial plexopathy, radiation pneumonitis, rib damage, secondary cancers, cardiac toxicity) are less common.

After axillary dissection (or radiation therapy), lymphatic drainage of the ipsilateral arm can be impaired, sometimes resulting in substantial swelling due to lymphedema; magnitude of the effect is roughly proportional to the number of nodes removed.

If lymphedema develops, venipuncture, BP measurement, and IV infusions are usually avoided on the affected side. A specially trained therapist must treat lymphedema. Special massage techniques once or twice daily may help drain fluid from congested areas toward functioning lymph basins; low-stretch bandaging is applied immediately after manual drainage, and patients should exercise daily as prescribed. After the lymphedema resolves, typically in 1 to 4 wk, patients continue daily exercise and overnight bandaging of the affected limb indefinitely.

Alternative node sampling methods include selective fine-needle aspiration of abnormalities identified at the time of breast biopsy (eg, by ultrasonography) and the commonly done sentinel node biopsy. Both result in less lymphedema than lymph node dissection. With sentinel node biopsy, sensitivity for axillary node involvement is ≥ 95%. However, the effect on mortality rate has not been established. For this biopsy, blue dye or radioactive colloid is injected around the breast, and a scanner is used to locate the first nodes the substance drains into (ie, sentinel nodes). If the sentinel node is cancerous, lymph node dissection is necessary.

Reconstructive procedures include

• Submuscular or subcutaneous (less common) placement of a silicone or saline implant
• Use of a tissue expander with delayed placement of the implant
• Muscle flap transfer using the latissimus dorsi or the lower rectus abdominis
• Creation of a free flap by anastomosing the gluteus maximus to the internal mammary vessels

Free flap transfer is being increasingly used for DCIS.

Fig. 2
Surgery for Breast Cancer Surgery for breast cancer consists of two main options: Breast-conserving surgery, which includes lumpectomy (removal of a small amount of surrounding normal tissue), wide excision or partial mastectomy (removal of a somewhat larger amount of the surrounding normal tissue), and quadrantectomy (removal of 1/4 of the breast) Mastectomy (removal of all breast tissue)

Adjuvant systemic therapy: Patients with LCIS are often treated with daily oral tamoxifen Some Trade Names
NOLVADEX
Click for Drug Monograph
. For postmenopausal women, raloxifene Some Trade Names
EVISTA
Click for Drug Monograph
is an alternative.

For patients with invasive cancer, chemotherapy or hormone therapy is usually begun soon after surgery and continued for months or years; these therapies delay or prevent recurrence in almost all patients and prolong survival in some. However, some experts believe that these therapies are not necessary for tumors < 1 cm with no lymph node involvement (particularly in postmenopausal patients) because the prognosis is already excellent. If tumors are > 5 cm, adjuvant systemic therapy may be started before surgery.

Relative reduction in risk of recurrence and death with chemotherapy or hormone therapy is the same regardless of the clinical-pathologic stage of the cancer. Thus, absolute benefit is greater for patients with a greater risk of recurrence or death (ie, a 20% relative risk reduction reduces a 10% recurrence rate to 8% but a 50% rate to 40%). Adjuvant chemotherapy reduces annual odds of death (relative risk) on average by 25 to 35% for premenopausal patients; for postmenopausal patients, the reduction is about ¹/₂ of that (9 to 19%), and the absolute benefit in 10-yr survival is much smaller.

Postmenopausal patients with ER– tumors benefit the most from adjuvant chemotherapy (see Table 5: Breast Disorders: Preferred Breast Cancer Adjuvant Systemic Therapy). However, predictive genomic testing of the primary breast cancer is being used increasingly to determine whether combination chemotherapy or hormone therapy alone is indicated.

Table 5
Preferred Breast Cancer Adjuvant Systemic Therapy Axillary Lymph Node Premenopausal Postmenopausal ER+ ER− ER+ ER− Negative* Tamoxifen Some Trade Names NOLVADEX Click for Drug Monograph with or without chemotherapy Chemotherapy An aromatase inhibitor or tamoxifen Some Trade Names NOLVADEX Click for Drug Monograph (or raloxifene Some Trade Names EVISTA Click for Drug Monograph ) with or without chemotherapy Chemotherapy Positive Chemotherapy (with or without a taxane) plus tamoxifen Some Trade Names NOLVADEX Click for Drug Monograph Chemotherapy (including a taxane) Chemotherapy (with or without a taxane) plus an aromatase inhibitor or tamoxifen Some Trade Names NOLVADEX Click for Drug Monograph (or raloxifene Some Trade Names EVISTA Click for Drug Monograph ) Chemotherapy (including a taxane) ER = estrogen receptor. *Treatment of node-negative tumors also depends on tumor size and grade. Note: For all protocols involving chemotherapy, enrollment in a clinical trial is often considered.

Combination chemotherapy regimens (eg, cyclophosphamide Some Trade Names
CYTOXAN
Click for Drug Monograph
, methotrexate Some Trade Names
RHEUMATREX
Click for Drug Monograph
, plus 5- fluorouracil Some Trade Names
ADRUCIL
Click for Drug Monograph
; doxorubicin Some Trade Names
ADRIAMYCIN
Click for Drug Monograph
plus cyclophosphamide Some Trade Names
CYTOXAN
Click for Drug Monograph
; docetaxel Some Trade Names
TAXOTERE
Click for Drug Monograph
plus cyclophosphamide Some Trade Names
CYTOXAN
Click for Drug Monograph
) are more effective than a single drug. Regimens given for 4 to 6 mo are preferred; they are as effective as regimens given for 6 to 24 mo. Acute adverse effects depend on the regimen but usually include nausea, vomiting, mucositis, fatigue, alopecia, myelosuppression, and thrombocytopenia. Growth factors that stimulate the bone marrow (eg, filgrastim Some Trade Names
NEUPOGEN
Click for Drug Monograph
, pegfilgrastim Some Trade Names
NEULASTA
Click for Drug Monograph
) are commonly used to reduce risk of fever and infection due to chemotherapy. Long-term adverse effects are infrequent with most regimens; death due to infection or bleeding is rare (< 0.2%).

High-dose chemotherapy plus bone marrow or stem cell transplantation offers no therapeutic advantage over standard therapy and should not be used.

If tumors overexpress HER2 (HER2+), adding the humanized monoclonal antibody trastuzumab Some Trade Names
HERCEPTIN
Click for Drug Monograph
to chemotherapy provides substantial benefit. Trastuzumab Some Trade Names
HERCEPTIN
Click for Drug Monograph
is usually continued for a year, although the optimal duration of therapy is unknown. A serious potential side effect is decreased cardiac ejection fraction.

With hormone therapy (eg, tamoxifen Some Trade Names
NOLVADEX
Click for Drug Monograph
, raloxifene Some Trade Names
EVISTA
Click for Drug Monograph
, aromatase inhibitors), benefit is greatest when tumors have estrogen and progesterone receptors, nearly as great when they have only estrogen receptors, minimal when they have only progesterone receptors, and absent when they have neither receptor. In patients with ER? tumors, particularly low-risk tumors, hormone therapy may be used instead of chemotherapy.

• Tamoxifen: This drug competitively binds with estrogen receptors. Adjuvant tamoxifen Some Trade Names
  NOLVADEX
  Click for Drug Monograph
  for 5 yr reduces annual odds of death by about 25% in premenopausal and postmenopausal women regardless of axillary lymph node involvement; treatment for 2 yr is not as effective, but treatment for > 5 yr has no advantage and may increase the likelihood that any recurrent cancer is tamoxifen Some Trade Names
  NOLVADEX
  Click for Drug Monograph
  -resistant. Tamoxifen Some Trade Names
  NOLVADEX
  Click for Drug Monograph
  can induce or exacerbate menopausal symptoms but reduces incidence of contralateral breast cancer and lowers serum cholesterol. Tamoxifen Some Trade Names
  NOLVADEX
  Click for Drug Monograph
  increases bone density in postmenopausal women and may reduce risk of fractures and ischemic heart disease. However, it significantly increases risk of developing endometrial cancer; reported incidence is 1% in postmenopausal women after 5 yr of use. Thus, if such women have spotting or bleeding, they must be evaluated for endometrial cancer (see Gynecologic Tumors: Endometrial Cancer). Nonetheless, the improved survival for women with breast cancer far outweighs increased risk of death due to endometrial cancer. Risk of thromboembolism is also increased. Raloxifene Some Trade Names
  EVISTA
  Click for Drug Monograph
  , although indicated for prevention, is not indicated for treatment.
• Aromatase inhibitors: These drugs ( anastrozole Some Trade Names
  ARIMIDEX
  Click for Drug Monograph
  , exemestane Some Trade Names
  AROMASIN
  Click for Drug Monograph
  , letrozole Some Trade Names
  FEMARA
  Click for Drug Monograph
  ) block peripheral production of estrogen in postmenopausal women. More effective than tamoxifen Some Trade Names
  NOLVADEX
  Click for Drug Monograph
  , these drugs are becoming the preferred treatment for early-stage receptor-positive cancer in postmenopausal patients. Letrozole Some Trade Names
  FEMARA
  Click for Drug Monograph
  may be used in postmenopausal women who have completed 5 yr of daily tamoxifen Some Trade Names
  NOLVADEX
  Click for Drug Monograph
  . Optimal duration of aromatase inhibitor therapy is uncertain.

Metastatic disease: Any indication of metastases should prompt immediate evaluation. Treatment of metastases increases median survival by 6 mo or longer. These treatments (eg, chemotherapy), although relatively toxic, may palliate symptoms and improve quality of life. Thus, the decision to be treated may be highly personal.

Choice of therapy depends on the following:

• Hormone-receptor status of the tumor
• Length of the disease-free interval (from remission to manifestation of metastases)
• Number of metastatic sites and organs affected
• Patient's menopausal status

Systemic hormone therapy or chemotherapy is usually used to treat symptomatic metastatic disease. Initially, patients with multiple metastatic sites outside the CNS should be given systemic therapy. If metastases are asymptomatic, there is no proof that treatment substantially increases survival, and it may reduce quality of life.

Hormone therapy is preferred over chemotherapy for patients with ER+ tumors, a disease-free interval of > 2 yr, or disease that is not immediately life threatening. In premenopausal women, tamoxifen Some Trade Names
NOLVADEX
Click for Drug Monograph
is often used first. Reasonable alternatives include ovarian ablation by surgery, radiation therapy, and use of a luteinizing-releasing hormone agonist (eg, buserelin, goserelin Some Trade Names
ZOLADEX
Click for Drug Monograph
, leuprolide Some Trade Names
LUPRON
Click for Drug Monograph
). Some experts combine ovarian ablation with tamoxifen Some Trade Names
NOLVADEX
Click for Drug Monograph
or an aromatase inhibitor. In postmenopausal women, aromatase inhibitors are being increasingly used as primary hormone therapy. If the cancer initially responds to hormone therapy but progresses months or years later, additional forms of hormone therapy (eg, progestins, the antiestrogen fulvestrant) may be used sequentially until no further response occurs.

The most effective chemotherapy drugs are capecitabine Some Trade Names
XELODA
Click for Drug Monograph
, doxorubicin Some Trade Names
ADRIAMYCIN
Click for Drug Monograph
(including its liposomal formulation), gemcitabine Some Trade Names
GEMZAR
Click for Drug Monograph
, the taxanes paclitaxel Some Trade Names
TAXOL
Click for Drug Monograph
and docetaxel Some Trade Names
TAXOTERE
Click for Drug Monograph
, and vinorelbine Some Trade Names
NAVELBINE
Click for Drug Monograph
. Response rate to a combination of drugs is higher than that to a single drug, but survival is not improved and toxicity is increased. Thus, some oncologists use single drugs sequentially.

For tumors that overexpress HER2, trastuzumab Some Trade Names
HERCEPTIN
Click for Drug Monograph
is effective in treating and controlling visceral metastatic sites. It is used alone or with hormone therapy or chemotherapy. Lapatinib is being used increasingly. Its role is evolving.

Radiation therapy alone may be used to treat isolated, symptomatic bone lesions or local skin recurrences not amenable to surgical resection. Radiation therapy is the most effective treatment for brain metastases, occasionally providing long-term control.

IV bisphosphonates (eg, pamidronate Some Trade Names
AREDIA
Click for Drug Monograph
, zoledronate) decrease bone pain and bone loss and prevent or delay skeletal complications due to bone metastases. About 10% of patients with bone metastases eventually develop hypercalcemia, which can also be treated with IV bisphosphonates.

Prevention

Chemoprevention with tamoxifen Some Trade Names
NOLVADEX
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or raloxifene Some Trade Names
EVISTA
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is indicated for the following groups of women:

• Age > 60
• Age > 35 and previous LCIS
• Presence of BRCA1 or BRCA2 mutations
• 5-yr risk of developing breast cancer > 1.66% based on the multivariable Gail model, which includes the women's current age, age at menarche, age at first live childbirth, number of 1st-degree relatives with breast cancer, and results of prior breast biopsies

A computer program to calculate breast cancer risk by the Gail model is available from the NCI at 1-800-4CANCER and online at http://www.cancer.gov/bcrisktool/. U. S. Preventive Services Task Force (USPSTF) recommendations Preventive Medication: Breast Cancer are available at http://www.ahrq.gov/clinic/uspstf/uspsbrpv.htm.www.ahrq.gov/clinic/uspstf/uspsbrpv.htm.

Patients should be informed of risks before beginning chemoprevention. Risks of tamoxifen Some Trade Names
NOLVADEX
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include uterine cancer, thromboembolic complications, cataracts, and possibly stroke. Risks are higher for older women. Raloxifene Some Trade Names
EVISTA
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appears to be about as effective as tamoxifen Some Trade Names
NOLVADEX
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in postmenopausal women and to have a lower risk of thromboembolic complications and cataracts. Raloxifene Some Trade Names
EVISTA
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, like tamoxifen Some Trade Names
NOLVADEX
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, may also increase bone density. Raloxifene Some Trade Names
EVISTA
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should be considered as an alternative to tamoxifen Some Trade Names
NOLVADEX
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for chemoprevention in postmenopausal women.

Last full review/revision November 2008 by Victor G. Vogel, MD

Content last modified November 2008