Breast Cancer

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 two thirds of postmenopausal patients with cancer 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 called HER2/neu or ErbB2); its presence correlates with a poorer prognosis at any given stage of cancer. In about 20% of patients with breast cancer, HER2 receptors are overexpressed. Drugs that block these receptors are part of standard treatment for these patients.

BRCA1 and BRCA2 gene mutations increase the risk of developing breast cancer to 70% (1 Pathophysiology references Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more ). Prophylactic bilateral mastectomy reduces the risk of breast cancer by 90% and should be offered to women with a BRCA mutation. Other genetic mutations that increase the risk of developing breast cancer include mutations in CHEK2, PALB2, ATM, RAD51C, RAD51D, BARD1, and TP53, which are usually included in panel genetic testing (2 Pathophysiology references Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more ).

In mammography, low-dose x-rays of both breasts are taken in 2 views (oblique and craniocaudal).

Mammography is more accurate in women over 50, partly because with aging, fibroglandular tissue in breasts tends to be replaced with fatty tissue, which can be more easily distinguished from abnormal tissue. Mammography is less sensitive in women with dense breast tissue, and some states mandate informing patients that they have dense breast tissue when it is detected by screening mammography. Women with dense breast tissue may require additional imaging tests (eg, breast tomosynthesis [3-dimensional mammography], MRI).

Screening mammography guidelines for women with average risk of breast cancer vary, but generally, screening starts at age 40, 45, or 50 and is repeated every year or two until age 75 or life expectancy is < 10 years (see table Recommendations for Breast Cancer Screening Mammography in Women With Average Risk Recommendations for Breast Cancer Screening Mammography in Women With Average Risk ). Clinicians should make sure that patients understand what their individual risk of breast cancer is and ask patients what their preference for testing is.

The Breast Cancer Risk Assessment Tool (BCRAT), or Gail model, can be used to calculate a woman's 5-year and lifetime risk of developing breast cancer. A woman is considered at average risk if her lifetime risk of breast cancer is < 15%.

Concerns about when and how often to do screening mammography include

Only about 10 to 15% of abnormalities detected on screening mammography result from cancer—an 85 to 90% false-positive rate. False-negative results may exceed 15% (3 Screening references Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more ). Many of the false-positives are caused by benign lesions (eg, cysts, fibroadenomas), but there are concerns about detecting lesions that meet histologic definitions of cancer but do not develop into invasive cancer during a patient's lifetime.

Breast tomosynthesis (3-dimensional mammography), done with digital mammography, increases the rate of cancer detection slightly and decreases the rate of recall imaging (4 Screening references Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more ); this test is helpful for women with dense breast tissue. However, the test exposes women to almost twice as much radiation as traditional mammography.

Although mammography uses low doses of radiation, radiation exposure Risks of Medical Radiation Ionizing radiation (see also Radiation Exposure and Contamination) includes High-energy electromagnetic waves (x-rays, gamma rays) Particles (alpha particles, beta particles, neutrons) Ionizing... read more has cumulative effects on cancer risk. When radiologic screening is started at a young age, risk of cancer is increased.

Clinical breast examination (CBE) is usually part of routine annual care for women > 40 (1 Screening references Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more ). In the US, CBE augments rather than replaces screening mammography. The American Cancer Society and the US Preventive Services Task Force recommend against screening with clinical breast examination (CBE); the American College of Obstetricians and Gynecologists recommends counseling patients about its diagnostic limitations (1 Screening references Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more , 2 Screening references Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more ). However, in some countries where mammography is considered too expensive, CBE is the sole screen; reports on its effectiveness in this role vary.

Breast self-examination (BSE) alone as a screening method has not shown a benefit and may result in higher rates of unnecessary breast biopsy. The major professional organizations do not recommend it as part of routine screening. However, women should be counseled about breast self-awareness, and if they notice changes in how their breasts appear or feel (eg, masses, thickening, enlargement), they should be encouraged to have a medical evaluation.

MRI is used for screening women with a high (eg, > 20%) risk of breast cancer, such as those with a BRCA gene mutation. For these women, screening should include MRI as well as mammography and CBE. MRI has higher sensitivity but may be less specific. MRI may be recommended for women with dense breast tissue as part of overall assessment that includes evaluation of risk.

Percutaneous core needle biopsy is preferred to surgical biopsy. Core biopsy can be done guided by imaging or palpation (freehand). Routinely, stereotactic biopsy (needle biopsy guided by mammography done in 2 planes and analyzed by computer to produce a 3-dimensional image) or ultrasound-guided biopsy is being used to improve accuracy. Clips are placed at the biopsy site to identify it.

If core biopsy is not possible (eg, the lesion is too posterior), surgical biopsy can be done; a guidewire is inserted, using imaging for guidance, to help identify the biopsy site.

Any skin taken with the biopsy specimen should be examined because it may show cancer cells in dermal lymphatic vessels.

The excised specimen should be x-rayed, and the x-ray should be compared with the prebiopsy mammogram to determine whether all of the lesion has been removed. If the original lesion contained microcalcifications, mammography is repeated when the breast is no longer tender, usually 6 to 12 weeks after biopsy, to check for residual microcalcifications. If radiation therapy is planned, mammography should be done before radiation therapy begins.

After cancer is diagnosed, a multidisciplinary evaluation is usually done to plan further testing and treatment. The core multidisciplinary team typically includes a breast surgical oncologist, medical oncologist, and radiation oncologist.

A positive biopsy specimen should be analyzed for estrogen and progesterone receptors and for HER2 protein.

Cells from blood or saliva should be tested for inherited gene mutations that predispose to breast cancer when

Some experts have recommended that genetic testing be offered to all patients with breast cancer (1 Diagnosis reference Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more ).

For these tests, the best approach is to refer patients to a genetic counselor, who can document a detailed family history, choose the most appropriate tests, and help interpret the results.

Chest x-ray, a complete blood count (CBC), liver tests, and measurement of serum calcium levels should be done to check for metastatic disease.

An oncologist should determine whether to measure serum carcinoembryonic antigen (CEA), cancer antigen (CA) 15-3, or CA 27-29 and whether bone scanning should be done.

For bone scanning, common indications include the following:

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

Chest CT is done if patients have either of the following:

MRI is often used by surgeons for preoperative planning; it can accurately determine tumor size, chest wall involvement, and number of tumors.

Grading is based on histologic examination of the tissue taken during biopsy. Tumor grade describes how abnormal tumor cells and tissue look under a microscope.

Staging follows the TNM (tumor, node, metastasis) classification (see table Anatomic Staging of Breast Cancer Anatomic Staging of Breast Cancer* ). Because clinical examination and imaging have poor sensitivity for nodal involvement, staging is refined during surgery, when regional lymph nodes can be evaluated. However, if patients have palpably abnormal axillary nodes, preoperative ultrasonography-guided fine needle aspiration or core biopsy may be done:

Staging classification follows these models:

Patients with breast cancer should not become pregnant while being treated for breast cancer. However, all patients who wish to preserve fertility should be referred to a reproductive endocrinologist to discuss fertility preservation before systemic therapy is initiated.

Options for fertility preservation include

Type of breast cancer, anticipated treatment, and patient preferences affect the type of fertility preservation that can be used. Ovarian suppression (eg, with leuprolide) has been used to minimize the destruction of ova by chemotherapy, but its efficacy is unproven.

Surgery involves mastectomy or breast-conserving surgery plus radiation therapy.

Mastectomy is removal of the entire breast and includes the following types:

Radical mastectomy is rarely done unless the cancer has invaded the pectoral muscles.

Breast-conserving surgery involves determining the size of the tumor and the required margins (based on the tumor's size relative to the volume of the breast), then surgically removing the tumor with its margins. Various terms (eg, lumpectomy, wide excision, quadrantectomy) are used to describe how much breast tissue is removed.

For patients with invasive cancer, survival and recurrence rates with mastectomy do not differ significantly from those with breast-conserving surgery plus radiation therapy as long as the entire tumor can be removed.

Thus, patient preference can guide choice of treatment within limits. The main advantage of breast-conserving surgery plus radiation therapy is less extensive surgery and opportunity to keep the breasts. The need for total removal of the tumor with a tumor-free margin overrides any cosmetic considerations. Consulting a plastic surgeon about oncoplastic surgery may help if patients have ptotic (sagging) breasts, while also achieving good resection margins.

Some physicians use neoadjuvant 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.

During both mastectomy and breast-conserving surgery, axillary lymph nodes are typically evaluated. Methods include

ALND is a fairly extensive procedure that involves removal of as many axillary nodes as possible; adverse effects, particularly lymphedema, are common. Risk of lymphedema is increased for patients with a high preoperative body mass index (BMI ≥ 30) and for those with significant weight gain during and after breast cancer treatment (1 Treatment references Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more ).

Most clinicians now first do SLNB unless biopsy of clinically suspect nodes detected cancer; risk of lymphedema is less with SLNB. Routine use of ALND is not justified because the main value of lymph node removal is diagnostic, not therapeutic, and SLNB has ≥ 95% sensitivity for axillary node involvement.

For SLNB, blue dye and/or radioactive colloid is injected around the breast, and a gamma probe (and when dye is used, direct inspection) is used to locate the nodes the tracer drains into. Because these nodes are the first to receive the tracers, they are considered the most likely to receive any metastatic cells and are thus called sentinel nodes.

If any of the sentinel nodes contain cancer cells, ALND may be necessary, based on numerous factors such as

Some surgeons do frozen section analysis during mastectomy with SLNB and get prior agreement for ALND in case nodes are positive; others await standard pathology results and do ALND as a 2nd procedure if needed. Frozen section analysis is not routinely done with lumpectomy.

Impaired lymphatic drainage of the ipsilateral arm often occurs after axillary node removal (ALND or SLNB) or radiation therapy, sometimes resulting in substantial swelling due to lymphedema. Magnitude of the effect is roughly proportional to the number of nodes removed; thus, SLNB causes less lymphedema than ALND. The lifetime risk of lymphedema after ALND is about 25%. However, even with SLNB, there is a 6% lifetime risk of lymphedema. To reduce risk of lymphedema, practitioners usually avoid giving IV infusions on the affected side. Wearing compression garments and preventing infection in the affected limbs (eg, by wearing gloves during yard work) are important. Avoiding ipsilateral blood pressure measurement and venipuncture is sometimes also recommended, even though supporting evidence is minimal (3 Treatment references Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more ).

If lymphedema develops, a specially trained therapist must treat it. Special massage techniques used once or twice a day 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 lessens, typically in 1 to 4 weeks, patients continue daily exercise and overnight bandaging of the affected limb indefinitely.

Reconstructive procedures include the following:

Breast reconstruction can be done during the initial mastectomy or breast-conserving surgery or later as a separate procedure. Timing of surgery depends on patient preference as well as the need for adjuvant therapy such as radiation therapy. However, doing radiation therapy first limits the types of reconstructive surgery that can be done. Thus, consulting a plastic surgeon early during treatment planning is recommended.

Advantages of breast reconstruction include improved mental health in patients who have a mastectomy. Disadvantages include surgical complications and possible long-term adverse effects of implants.

Early consultation with a plastic surgeon should also be considered when lumpectomy (especially lower breast or upper inner quadrant lumpectomy) is being done. The best candidates for oncoplastic surgery (which combines cancer removal with reconstruction of the breast) are patients with ptotic (sagging) breasts. Contralateral mastopexy may improve symmetry.

Contralateral prophylactic mastectomy is an option for some women with breast cancer (eg, those with a genetic mutation conferring a high risk of breast cancer).

In women with lobular carcinoma in situ in one breast, invasive cancer is equally likely to develop in either breast. Thus, the only way to eliminate the risk of breast cancer for these women is bilateral mastectomy. Some women, particularly those who are at high risk of developing invasive breast cancer, choose this option.

Advantages of contralateral prophylactic mastectomy include

Disadvantages of contralateral prophylactic mastectomy include

Contralateral prophylactic mastectomy is not mandatory for patients with the highest risk of developing cancer in the contralateral breast. Close surveillance is a reasonable alternative.

Radiation therapy after breast-conserving surgery significantly reduces incidence of local recurrence in the breast and in regional lymph nodes and may improve overall survival. However, if patients are > 70 and have early ER+ breast cancer, adding radiation therapy to lumpectomy plus tamoxifen may not be necessary; adding radiation therapy does not significantly decrease the rate of mastectomy for local recurrence or the occurrence of distant metastases nor increase the survival rate (4 Treatment references Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more ).

Radiation therapy is indicated after mastectomy if any of the following is present:

In such cases, radiation therapy after mastectomy significantly reduces incidence of local recurrence on the chest wall and in regional lymph nodes and improves overall survival.

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.

To improve radiation therapy, researchers are studying several new procedures. Many of these procedures aim to target radiation to the cancer more precisely and spare the rest of the breast from the effects of radiation.

(See also NCCN Clinical Practice Guideline: Breast Cancer.)

Chemotherapy or endocrine therapy delay or prevent recurrence in almost all patients and prolong survival in some. However, studies have shown that chemotherapy is not necessary for many small (< 0.5 to 1 cm) tumors with no lymph node involvement (particularly in postmenopausal patients) because the prognosis is already excellent.

Usual indications for chemotherapy are one or more of the following:

Relative reduction in risk of recurrence and death with chemotherapy or endocrine 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 half of that (9 to 19%), and the absolute benefit in 10-year survival is much smaller.

Postmenopausal patients with ER– tumors benefit the most from adjuvant chemotherapy (see table Preferred Breast Cancer Adjuvant Systemic Therapy Preferred Breast Cancer Adjuvant Systemic Therapy* ). For ER+ breast cancer, predictive genomic testing of the primary breast cancer is being used increasingly to stratify risk in patients and to determine whether combination chemotherapy or endocrine therapy alone is indicated. Common prognostic tests include

In the US, most women with breast cancer have ER+/PR+/HER- breast cancer with negative axillary nodes. In these women, a low or intermediate score on the 21-gene recurrence score assay predicts similar survival rates with chemotherapy plus endocrine therapy and with endocrine therapy alone. Therefore, in this subset of women with breast cancer, chemotherapy may not be necessary.

Chemotherapy is usually begun soon after surgery. If systemic chemotherapy is not required, endocrine therapy is usually begun soon after surgery and is continued for 5 to 10 years.

If tumors are > 5 cm, systemic therapy may be started before surgery.

Combination chemotherapy regimens are more effective than a single drug. Dose-dense regimens given for 4 to 6 months are preferred; in dose-dense regimens, the time between doses is shorter than that in standard-dose regimens. There are many regimens; a commonly used one is ACT (doxorubicin plus cyclophosphamide followed by paclitaxel). Acute adverse effects depend on the regimen but usually include nausea, vomiting, mucositis, fatigue, alopecia, myelosuppression, cardiotoxicity, and thrombocytopenia. Growth factors that stimulate bone marrow (eg, filgrastim, pegfilgrastim) 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%).

If tumors overexpress HER2 (HER2+), anti-HER2 drugs (trastuzumab, pertuzumab) may be used. Adding the humanized monoclonal antibody trastuzumab to chemotherapy provides substantial benefit. Trastuzumab is usually continued for a year, although the optimal duration of therapy is unknown. If lymph nodes are involved, adding pertuzumab to trastuzumab improves disease-free survival. A serious potential adverse effect of both these anti-HER2 drugs is a decreased cardiac ejection fraction.

With endocrine therapy (eg, tamoxifen, aromatase inhibitors), benefit depends on estrogen and progesterone receptor expression; benefit is

In patients with ER+ tumors, particularly low-risk tumors, endocrine therapy may be used instead of chemotherapy.

Patients with DCIS are often treated with daily oral tamoxifen. For postmenopausal women, an aromatase inhibitor is preferred.

Any indication of metastases should prompt immediate evaluation. Treatment of metastases increases median survival by 6 months 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:

Systemic endocrine therapy or chemotherapy is usually used to treat symptomatic metastatic disease. Initially, patients with multiple metastatic sites outside the central nervous system (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.

Endocrine therapy is preferred over chemotherapy for patients with any of the following:

In premenopausal women, tamoxifen is often used first. Reasonable alternatives include ovarian ablation by surgery, radiation therapy, and use of a luteinizing-releasing hormone agonist (eg, buserelin, goserelin, leuprolide). Some experts combine ovarian ablation with tamoxifen or an aromatase inhibitor. In postmenopausal women, aromatase inhibitors are being increasingly used as primary endocrine therapy. If the cancer initially responds to endocrine therapy but progresses months or years later, additional forms of endocrine therapy (eg, progestins, the antiestrogen fulvestrant) may be used sequentially until no further response occurs.

The most effective chemotherapy drugs are capecitabine, doxorubicin (including its liposomal formulation), gemcitabine, the taxanes paclitaxel and docetaxel, and vinorelbine. 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.

Anti-HER2 drugs (eg, trastuzumab, pertuzumab) are used to treat tumors that overexpress HER2. These drugs are effective in treating and controlling visceral metastatic sites. Trastuzumab is used alone or with endocrine therapy, chemotherapy, or pertuzumab. Trastuzumab plus chemotherapy plus pertuzumab slows the growth of HER2+ metastatic breast cancer and increases survival more than trastuzumab plus chemotherapy (5 Treatment references Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more ).

Tyrosine kinase inhibitors (eg, lapatinib, neratinib) are being increasingly used in women with HER2+ tumors.

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.

Palliative mastectomy is sometimes an option for patients with stable metastatic breast cancer.

IV bisphosphonates (eg, pamidronate, 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.

For patients with metastatic breast cancer, quality of life may deteriorate, and the chances that further treatment will prolong life may be small. Palliation may eventually become more important than prolongation of life.

Cancer pain Pain Physical, psychologic, emotional, and spiritual distress is common among patients living with fatal illness, and patients commonly fear protracted and unrelieved suffering. Health care providers... read more can be adequately controlled with appropriate drugs, including opioid analgesics Opioid Analgesics Nonopioid and opioid analgesics are the main drugs used to treat pain. Antidepressants, antiseizure drugs, and other central nervous system (CNS)–active drugs may also be used for chronic or... read more . Other symptoms (eg, constipation, difficulty breathing, nausea) should also be treated.

Psychologic and spiritual counseling should be offered.

Patients with metastatic breast cancer should be encouraged to prepare advance directives Advance Directives Advance directives are legal documents that extend a person's control over health care decisions in the event that the person becomes incapacitated. They are called advance directives because... read more , indicating the type of care they desire in case they are no longer able to make such decisions.