Definition

Breast cancers are adenocarcinomas that originate from the epithelial component of breast tissue. The most common types of invasive breast cancer are infiltrating ductal carcinoma and infiltrating lobular carcinoma. Less common breast cancer histologies include tubular, mucinous, medullary and metaplastic carcinomas. Malignant tumors in the breast that are not carcinomas, such as lymphomas or sarcomas, are managed differently and in accordance with their specific tumor type.

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Prevalence

Excluding skin cancer, breast cancer is the most common cancer in American women, affecting over 200,000 individuals annually in the United States. A woman’s lifetime risk of breast cancer is estimated to be about 1 in 12.¹ Approximately 1% of breast cancers occur in men. Risk factors for breast cancer include increasing age, family history of breast cancer, prior therapeutic radiation to the chest, as well as hormonal factors including early menarche, late menopause, nulliparity and use of combination estrogen/progesterone menopausal hormone therapy. Mammographic breast density is a recently recognized risk factor for breast cancer. Certain benign breast biopsy findings, including atypical hyperplasia and lobular carcinoma in situ, are also associated with an increased risk of future breast cancer development. Individuals with inherited deleterious mutations in BRCA1 and BRCA2 genes have a particularly high risk of breast cancer which often occurs at a younger age than nonhereditary breast cancer and such mutations are associated with risk for other cancer types as well.

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Pathophysiology

Estrogen and progesterone are important regulators of normal breast growth and development as well as breast involution and play important roles in the pathogenesis of breast cancer.² A variety of factors, both genetic and environmental, may disrupt normal growth regulatory pathways resulting in the development of cancer. Endogenous as well as exogenous hormone exposure, ionizing radiation exposure, and genetic mutations in DNA repair genes are among the more well-known factors contributing to breast cancer development.

That natural history of breast cancer is extremely variable ranging from indolent cancers that may never become clinically apparent to aggressive cancers that invade and metastasize early in their course with fatal consequences. The majority of breast cancers present with early stage disease; however, occult metastases are common necessitating both local therapy and systemic therapy for optimal management.

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Signs and Symptoms

Breast cancer may present as a mass in the breast. Less commonly, skin changes such as dimpling, erythema, edema, or ulceration may indicate an underlying cancer. Frequently, breast cancer occurs without symptoms and is identified through screening mammography which may demonstrate a mass, suspicious calcifications or other abnormality to suggest an underlying concern. Uncommonly, an individual will present with signs or symptoms related to metastatic spread of their cancer. Such symptoms may include an enlarged lymph node mass, bone pain, gastrointestinal, respiratory or even neurological symptoms, depending on the sites of involvement.

Not all breast masses are cancer. Benign breast masses include cysts, papillomas and fibroadenomas. These lesions may have characteristic features on diagnostic imaging such as ultrasound; however, a biopsy may be necessary to confirm a benign finding.

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Diagnosis

When an individual presents with a breast lump, a mammographic abnormality, or other findings suspicious for cancer, additional diagnostic evaluation is pursued. Physical examination includes examination of both breasts and regional lymph nodes. Diagnostic breast imaging often includes mammogram magnification views and ultrasound evaluation. A mass that is easily palpable on physical examination or a suspicious finding visualized on mammogram and/or ultrasound is generally amenable to biopsy. Often, a core needle biopsy is done as the initial test to diagnose the breast cancer, although fine needle aspiration biopsy or excisional biopsy may also be appropriate.

The initial biopsy provides a diagnosis that is important for treatment planning. Testing for estrogen receptors, progesterone receptors and HER2neu can be done, providing important information regarding systemic treatment options. Staging evaluation may be done before or after surgery and includes laboratory evaluation including a complete blood count and liver enzymes with alkaline phosphatase. Bone scans, computerized tomography scans of chest, abdomen and pelvis and/or positron emission tomography scans may be performed when symptoms are present, initial laboratory evaluation is abnormal, or when risk for metastatic disease is felt to be relatively high such as when the primary tumor is large or when axillary lymph nodes are involved.

Breast cancer staging uses the “TNM” system where T refers to the primary tumor in the breast, N refers to regional lymph nodes and M refers to distant metastatic sites (Figure 1).³ Increasing stage is associated with a less favorable prognosis. In general, stage 0, I and II as well as most stage III breast cancers are considered operable and approached with curative intent. Some locally advanced cancers, particularly stage IIIB cancers, may require downstaging with systemic treatment in order to be rendered operable. Individuals with distant metastases, or stage IV disease, are primarily treated with systemic treatment with surgery being a secondary consideration.

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Treatment

Local Therapy

Since most breast cancer presents as early stage (operable) disease, surgery is frequently the initial treatment. A partial mastectomy, also referred to as a lumpectomy, involves removal of the tumor with a surrounding rim of normal tissue preserving the remaining breast. A mastectomy or total mastectomy involves removal of the entire breast and is the preferred option for tumors that are multifocal or large in size compared with the breast size. For invasive cancers, surgical staging includes axillary lymph node sampling which may be done with an axillary dissection or a sentinel lymph node biopsy. Sentinel lymph node biopsy involves the injection of a blue dye and/or radioactive tracer into the breast and removal of the first lymph node(s) to pick up the dye or radioactive tracer. The absence of tumor involvement in the sentinel lymph node(s) predicts for a high probability that there is no further lymph node involvement⁴ and allows for omission of a full axillary dissection and its associated morbidity.

Radiation treatment to the breast or chest wall is administered to improve local control of breast cancer and may also improve survival. Common indications for adjuvant radiation treatment include breast conserving surgery (partial mastectomy), large tumors (such as greater than 5 cm), axillary lymph node involvement (particularly when four or more lymph nodes are involved), skin or muscle involvement, and the presence of tumor cells at the surgical resection margin. The use of radiotherapy after breast conserving surgery has been associated with an approximately 48% reduction in the risk of breast cancer recurrence, predominantly through the reduction in risk of local recurrence and is also associated with an approximately 8% reduction in overall mortality.⁵

Adjuvant Systemic Therapy

Adjuvant systemic treatment, aimed at eradicating any micrometastatic disease, is administered following breast surgery to improve on the cure rates achieved with local therapy alone. Adjuvant endocrine therapy is an effective adjuvant systemic treatment for tumors that are estrogen receptor and/or progesterone receptor positive. A 5-year course of tamoxifen, an oral selective estrogen receptor modulator (SERM), reduces recurrence risk approximately in one-half and reduces mortality by about one-third.⁶ Estrogen receptor positivity appears to be the strongest predictor of benefit to adjuvant tamoxifen. Tamoxifen is effective for both premenopausal and postmenopausal women and is administered for up to 10 years in the adjuvant setting.

For women who are known to be postmenopausal, aromatase inhibitors used as an alternative to tamoxifen or in sequence to tamoxifen can further reduce recurrence risk and have a somewhat more favorable toxicity profile.⁷ Aromatase inhibitors lower estrogen levels in postmenopausal women through preventing the conversion of adrenally produced androgens into estrogens in the tissues but these drugs do not prevent ovarian estrogen production and are, therefore, ineffective on their own in premenopausal women. In some situations, ovarian ablation will be combined with tamoxifen or an aromatase inhibitor as endocrine treatment in premenopausal women.

Adjuvant chemotherapy, both with and without the use of adjuvant endocrine therapy, has also been shown to improve breast cancer survival. Modern chemotherapy regimens are estimated to reduce breast cancer mortality rate by approximately 36% compared with no chemotherapy.⁸ Combination chemotherapy regimens including cyclophosphamide, anthracycline and taxane chemotherapy drugs appear to be most effective. Regimens that do not include an anthracycline are less likely to be associated with serious long-term toxicity and are often recommended for patients with lower risk disease or who may be at increased risk for toxicity due to age or other medical problems. For breast cancers that overexpress HER2neu, the use of the monoclonal antibody trastuzumab along with chemotherapy further improves survival.⁹

Neoadjuvant Therapy

Administration of systemic anticancer therapy prior to surgery is called neoadjuvant therapy. The regimens used in the neoadjuvant setting are generally the same as those used in the adjuvant setting and provide a similar survival advantage whether given preoperatively or postoperatively.¹⁰ Reasons for administering systemic therapy prior to surgery include downstaging of locally advanced disease to improve operability, shrinking a tumor to improve prospects for breast conservation, or to evaluate the efficacy of a chemotherapy regimen as in the setting of a clinical trial. Chemotherapy with or without HER2-directed therapy is most commonly used in the neoadjuvant setting, however, endocrine therapy can also be an effective neoadjuvant treatment.

Metastatic Disease

Metastatic breast cancer, whether occurring at first presentation or following initial treatment for earlier stage disease, is usually not a curable situation, although survival is often measured in years. Goals of therapy include prolongation of survival and minimizing symptoms related to the cancer while avoiding excessive side effects from treatment. For breast cancer that is estrogen receptor positive, hormonal treatments are the preferred initial approach and often can provide durable control of disease. As in early stage breast cancer, aromatase inhibitors, tamoxifen and ovarian ablation are all effective treatments for metastatic disease. Other endocrine therapies used, usually sequentially, in the treatment of advanced breast cancer include fulvestrant, megestrol acetate, androgens and even high-dose estrogens.

For metastatic breast cancer that is refractory to endocrine treatment or that is estrogen and/or progesterone receptor negative, chemotherapy is the mainstay of treatment. Because individuals with metastatic breast cancer will often be receiving treatment for prolonged periods of time, an effective strategy in this setting is to use single-agent chemotherapy drugs with manageable toxicity in sequence rather than combination chemotherapy regimens which may result in more toxicity.

Increasingly, chemotherapy and endocrine therapy treatments are being combined with biologic treatments with improved efficacy. Biologic treatments targeting HER2neu have been particularly successful. As in the adjuvant setting, the monoclonal antibody trastuzumab added to chemotherapy improves survival for individuals with metastatic breast cancer.¹¹ More recently pertuzumab, another HER2neu directed monoclonal antibody and trastuzumab-emtansine, a trastuzumab-chemotherapy conjugate, have demonstrated additional improvements in the outcome of HER2neu overexpressing metastatic breast cancer. In addition, lapatinib, an oral dual inhibitor of the epidermal growth factor receptor and HER2neu is active in combination with either chemotherapy or trastuzumab in HER2neu overexpressing metastatic breast cancer.

Treatment of metastatic breast cancer may include palliative radiotherapy for specific areas of concern such as brain metastases or painful bone metastases. The use of bisphosphonates such as zoledronic acid or the receptor activator of nuclear factor kappa-B ligand inhibiting monoclonal antibody denosumab improve pain scores and reduce risk for fracture and other skeletal events in patients with lytic bone metastases from breast cancer.¹² Other palliative treatments including effective pain management are important as well.

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Screening and Prevention

Breast cancer screening with mammography with or without clinical breast examination has been shown to reduce breast cancer mortality. While controversy exists over the optimal age of initiation and time interval for mammography screening of women at average risk for breast cancer, there is consensus that screening is clearly beneficial for women between the ages of 50 and 69. Every other year mammography beginning at age 50 has been recommended by the United States Preventive Services Task Force, although many groups continue to recommend annual mammography screening beginning at age 40.¹³ While breast self-examination and clinical breast examination remain unproven in their ability to reduce breast cancer mortality, these may identify cancers not detected on mammography. For individuals at very high risk for breast cancer, such as those with BRCA1 or BRCA2 mutations, screening with breast magnetic resonance imaging may be added.

An observation that women taking adjuvant endocrine therapy for early stage breast cancer had a reduced incidence of contralateral new primary cancers led to the evaluation of these drugs for primary prevention of breast cancer. In a placebo-controlled randomized study of healthy women at risk for breast cancer, 5 years of tamoxifen was associated with a 49% reduction in the risk of developing breast cancer.¹⁴ Uncommon but serious side effects of tamoxifen include endometrial cancer and thromboembolic events, including stroke. Such concerns have limited the uptake of tamoxifen for breast cancer prevention, a setting in which a survival benefit to tamoxifen has not been demonstrated. Raloxifene, another SERM, has been compared with tamoxifen for breast cancer prevention in postmenopausal women and was associated with fewer serious side effects, although its effectiveness in breast cancer prevention was somewhat less.¹⁵ The aromatase inhibitor exemestane has also been shown to be effective at reducing the risk of breast cancer development with an acceptable side-effect profile.¹⁶

Surgical options for breast cancer prevention include bilateral mastectomy which appears to reduce breast cancer risk by at least 90%¹⁷ and bilateral oophorectomy which may cut breast cancer risk nearly in half.¹⁸ Surgical means of breast cancer prevention are usually reserved for those individuals at particularly high risk for the development of breast cancer, such as carriers of BRCA1 or BRCA2 mutations. In those individuals, oophorectomy also provides risk reduction for ovarian cancer.

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Considerations in Special Populations

Male Breast Cancer

Breast cancer in men is relatively uncommon. Treatment is similar to that of women with breast cancer with a few exceptions. There is little experience with breast conserving surgery in men with breast cancer, so most will undergo mastectomy. In addition, tamoxifen is the preferred first line endocrine therapy for men with estrogen receptor-positive breast cancer. Indications for radiation treatment, chemotherapy and biologic therapies are similar in men and women with breast cancer.

Pregnancy-Associated Breast Cancer

Women who are diagnosed with breast cancer during pregnancy present a particular challenge. The cancers tend to be of higher stage than other breast cancers due the younger age of the patients, difficulties in diagnosis due to expected changes in the breast during pregnancy, and due to the fact that this is not a population that is getting screening mammography which tends to find earlier stage cancer. It is possible to do breast surgery and even chemotherapy during pregnancy when necessary, although there are special considerations including issues related to anesthesia, chemotherapy choice and supportive medications. Gestational age also plays a role in the safety of various treatments and high-risk obstetrics care is an important aspect of management. Radiation treatment, endocrine therapies and certain chemotherapy drugs such as methotrexate are avoided during pregnancy.

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Conclusion

Breast cancer is a common malignancy with excellent prospects for long-term survival. Multimodality treatment may include surgery, radiation, chemotherapy, endocrine therapy and/or biologic therapy. Optimal treatment and prevention strategies are based on stage, individual patient risk, and biologic characteristics of the cancer itself.

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Summary

• Breast cancer risk is influenced by genetic and environmental factors, including both endogenous and exogenous hormonal exposures.
• Most breast cancers are detected as early stage disease and are operable.
• The use of radiation treatment and systemic treatment including adjuvant endocrine therapy and adjuvant chemotherapy improve on cure rates over surgery alone.
• Locally advanced and metastatic breast cancers are often initially treated with systemic therapy.
• Mammography screening reduces breast cancer mortality through the early detection of breast cancer.
• Pharmacologic and surgical options for breast cancer prevention are available for women at high risk of developing breast cancer.

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Suggested Readings

• Beslija S, Bonneterre J, Burstein HJ, et al; Central European Cooperative Oncology Group (CECOG). Third consensus on the medical treatment of metastatic breast cancer [published online ahead of print July 16, 2009]. Ann Oncol 2009; 20:1771–1785. doi:10.1093/annonc/mdp261
• Burstein HJ, Pestrud AA, Seidenfeld J, et al. American Society of Clinical Oncology clinical practice guidelines: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer [published online ahead of print July 12, 2010]. J Clin Oncol 2010; 28:3784–3796. doi:10.1200/JCO.2009.26.3756
• Early and locally advanced breast cancer: diagnosis and treatment. National Institute for Health and Clinical Excellence website. www.nice.org.uk/guidance/CG80. Published February 2009. Accessed June 23, 2014.
• Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002; 347:1233–1241.
• Visvanathan K, Chlebowski RT, Hurley P, et al. American Society of Clinical Oncology clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction [published online ahead of print May 26, 2009]. J Clin Oncol 2009; 27:3235–3258. doi:10.1200/JCO.2008.20.5179

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References