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Breast Cancer

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Breast Cancer
Author: Alison T Stopeck, MD; Chief Editor: Jules E Harris, MD more... Updated: Dec 23, 2013

Practice Essentials
Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and the leading cause of cancer death among women.

Essential update: FDA warns against nipple aspirate tests for breast cancer screens
The US Food and Drug Administration (FDA) recently issued a warning that nipple aspirate tests are not an effective screening tool for breast cancer or other breast diseases and should not be used in place of mammography, other imaging tests, or biopsy. The agency is concerned that the test, which involves analysis of fluid aspirated from a woman's breast with a pump device, could lead to false-positive or -negative results if fluid analysis alone is used as a screen.[1] A warning against the use of nipple aspiration for breast cancer screening is also found in the National Comprehensive Cancer Networks (NCCNs) 2013 guidelines, which, in addition, state that the test is currently being evaluated for clinical usefulness.

Signs and symptoms

Early breast cancers may be asymptomatic, and pain and discomfort are typically not present. If a lump is discovered, the following may indicate the possible presence of breast cancer: Change in breast size or shape Skin dimpling or skin changes Recent nipple inversion or skin change, or nipple abnormalities Single-duct discharge, particularly if blood-stained Axillary lump See Clinical Presentation for more detail.

Diagnosis
Breast cancer is often first detected as an abnormality on a mammogram before it is felt by the patient or health care provider. Evaluation of breast cancer includes the following: Clinical examination Imaging Needle biopsy
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Physical examination The following physical findings should raise concern: Lump or contour change Skin tethering Nipple inversion Dilated veins Ulceration Paget disease Edema or peau dorange If a palpable lump is found and possesses any of the following features, breast cancer may be present: Hardness Irregularity Focal nodularity Fixation to skin or muscle Screening Early detection remains the primary defense in preventing breast cancer. Screening modalities include the following: Breast self-examination Clinical breast examination Mammography Ultrasonography Magnetic resonance imaging Ultrasonography and MRI are more sensitive than mammography for invasive cancer in nonfatty breasts. Combined mammography, clinical examination, and MRI are more sensitive than any other individual test or combination of tests. Biopsy Core biopsy with image guidance is the recommended diagnostic approach for newly diagnosed breast cancers. This is a method for obtaining breast tissue without surgery and can eliminate the need for additional surgeries. Open excisional biopsy is the surgical removal of the entire lump. See Workup for more detail.

Management
Surgery Surgery is the primary treatment for breast cancer. Lumpectomy or total mastectomy may be indicated. Radiation therapy may follow surgery in an effort to eradicate residual disease while reducing recurrence rates. Adjuvant treatment for breast cancer involves radiation therapy and a variety of chemotherapeutic and biologic agents. There are 2 general approaches for delivering radiation therapy: External-beam radiotherapy (EBRT) Partial-breast irradiation (PBI) Surgical resection with or without radiation is the standard treatment for ductal carcinoma in situ. Pharmacologic agents Hormone therapy and chemotherapy are the 2 main interventions for treating metastatic breast cancer. Common chemotherapeutic regimens include the following:
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Docetaxel Cyclophosphamide Doxorubicin Carboplatin Methotrexate Trastuzumab Two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, are approved for reduction of breast cancer risk in high-risk women. In patients receiving adjuvant aromatase inhibitor therapy for breast cancer who are at high risk for fracture, the monoclonal antibody denosumab or either of the bisphosphonates zoledronic acid and pamidronate may be added to the treatment regimen to increase bone mass. These agents are given along with calcium and vitamin D supplementation. See Treatment and Medication for more detail.

Image library

Anatomy of breast.

Background
Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and the leading cause of cancer death in women.[2] In the United States, breast cancer accounts for 29% of all cancers in women and is second only to lung cancer as a cause of cancer deaths.[3] (For discussion of male breast cancer, see Breast Cancer in Men.) Many early breast carcinomas are asymptomatic; pain or discomfort is not usually a symptom of breast cancer. Breast cancer is often first detected as an abnormality on a mammogram before it is felt by the patient or healthcare provider. The general approach to evaluation of breast cancer has become formalized as triple assessment: clinical examination, imaging (usually mammography, ultrasonography, or both), and needle biopsy. (See Workup.) Increased public awareness and improved screening have led to earlier diagnosis, at stages amenable to complete surgical resection and curative therapies. Improvements in therapy and screening have led to improved survival rates for women diagnosed with breast cancer. Surgery and radiation therapy, along with adjuvant hormone or chemotherapy when indicated, are now considered primary treatment for breast cancer. For many patients with low-risk early-stage breast cancer, surgery with local radiation is curative. (See Treatment and Management.) Surgery is considered primary treatment for breast cancer. Many patients with early-stage breast cancer are cured with surgery alone. (See Treatment and Management.) Adjuvant breast cancer therapies are designed to treat micrometastatic disease or breast cancer cells that have
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escaped the breast and regional lymph nodes but do not yet have an established identifiable metastasis. Depending on the model of risk reduction, adjuvant therapy has been estimated to be responsible for 35-72% of the decrease in mortality. Over the past 3 decades, extensive and advocate-driven breast cancer research has led to extraordinary progress in the understanding of the disease. This has resulted in the development of more targeted and less toxic treatments. (See Treatmentand Medication.) For patient education information, see the Breast Cancer Health Center, as well as Breast Cancer, Mastectomy, Breast Lumps and Pain, Breast Self-Exam, and Mammogram.

Anatomy
The breasts of an adult woman are milk-producing glands on the front of the chest wall. They rest on the pectoralis major and are supported by and attached to the front of the chest wall on either side of the sternum by ligaments. Each breast contains 15-20 lobes arranged in a circular fashion. The fat that covers the lobes gives the breast its size and shape. Each lobe comprises many lobules, at the end of which are glands that produce milk in response to hormones (see the image below).

Anatomy of breast.

Pathophysiology
The current understanding of breast cancer etiopathogenesis is that invasive cancers arise through a series of molecular alterations at the cell level. These alterations result in breast epithelial cells with immortal features and uncontrolled growth. Genomic profiling has demonstrated the presence of discrete breast tumor subtypes with distinct natural histories and clinical behavior. The exact number of disease subtypes and molecular alterations from which these subtypes arise remains to be fully elucidated, but these generally align with the presence or absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). This view of breast cancer--not as a set of stochastic molecular events, but as a limited set of separable diseases of distinct molecular and cellular origins--has altered thinking about breast cancer etiology, type-specific risk factors, and prevention and has had a substantial impact on treatment strategies and breast cancer research. Evidence from The Cancer Genome Atlas Network (TCGA) confirms the following 4 main breast tumor subtypes, with distinct genetic and epigenetic aberrations [4] (see the image below): Luminal A Luminal B Basal-like HER2-positive

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Intrinsic subtypes of breast cancer.

It is noteworthy that the basal-like breast tumor subgroup shares a number of molecular characteristics common to serous ovarian tumors, including the types and frequencies of genomic mutations. These data support the evidence that some breast cancers share etiologic factors with ovarian cancer. Most compelling are the data showing that patients with basal-type breast cancers show treatment responsiveness similar to that of ovarian cancer patients.[5] The various types of breast cancers are listed below by percentage of cases: Infiltrating ductal carcinoma is the most commonly diagnosed breast tumor and has a tendency to metastasize via lymphatics; this lesion accounts for 75% of breast cancers Over the past 25 years, the incidence of lobular carcinoma in situ (LCIS) has doubled, reaching a current level of 2.8 per 100,000 women; the peak incidence is in women aged 40-50 years Infiltrating lobular carcinoma accounts for fewer than 15% of invasive breast cancers Medullary carcinoma accounts for about 5% of cases and generally occurs in younger women Mucinous (colloid) carcinoma is seen in fewer than 5% of invasive breast cancer cases Tubular carcinoma of the breast accounts for 1-2% of all breast cancers Papillary carcinoma is usually seen in women older than 60 years and accounts for approximately 1-2% of all breast cancers Metaplastic breast cancer accounts for fewer than 1% of breast cancer cases, tends to occur in older women (average age of onset in the sixth decade), and has a higher incidence in blacks Mammary Paget disease accounts for 1-4% of all breast cancers and has a peak incidence in the sixth decade of life (mean age, 57 years)

Etiology
Epidemiologic studies have identified a number of risk factors that are associated with an increased risk of a woman developing breast cancer. Several risk factors have been found to be clinically useful for assessing a patients risk of breast cancer. Many of these factors form the basis of breast cancer risk assessment tools currently being used in the practice setting.

Age and gender

Increasing age and female sex are established risk factors for breast cancer. Sporadic breast cancer is relatively uncommon among women younger than 40 years but increases significantly thereafter. The effect of age on risk is illustrated in the SEER (Surveillance, Epidemiology and End Results) data, where the incidence of invasive breast cancer for women younger than 50 years is 44.0 per 100,000 as compared with 345 per 100,000 for women aged 50 years or older.[6] The total and age-specific incidence for breast cancer is bimodal, with the first peak occurring at about 50 years and the second occurring at about 70 years.[7] This bimodal pattern may reflect the influence of age within the different tumor subtypes; poorly differentiated, high-grade disease tend to occur earlier, whereas hormonesensitive, slower-growing tumors tend to occur with advancing age.
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Family history of breast cancer

A positive family history of breast cancer is the most widely recognized risk factor for breast cancer. The lifetime risk is up to 4 times higher if a mother and sister are affected, and it is about 5 times greater in women who have 2 or more first-degree relatives with breast cancer. The risk is also greater among women with breast cancer in a single first-degree relative, particularly if the relative was diagnosed at an early age (50 years). Despite a history indicating increased risk, many of these families have normal results on genetic testing. A family history of ovarian cancer in a first-degree relative, especially if the disease occurred at an early age (< 50 years), has been associated with a doubling of breast cancer risk. This often reflects inheritance of a pathogenic mutation in the BRCA1 or BRCA2 gene. The family history characteristics that suggest increased risk of cancer are summarized as follows: Two or more relatives with breast or ovarian cancer Breast cancer occurring in an affected relative younger than 50 years Relatives with both breast cancer and ovarian cancer One or more relatives with 2 cancers (breast and ovarian cancer or 2 independent breast cancers) Male relatives with breast cancer BRCA1 and BRCA2 mutations Ataxia telangiectasia heterozygotes (quadrupled risk) Ashkenazi Jewish descent (doubled risk) A small percentage of patients, usually with a strong family history of other cancers, have cancer syndromes. These include families with a mutation in the PTEN, TP53, MLH1, MLH2, CDH1, or STK11 gene. To aid in the identification of mutation carriers of BRCA1/2, a number of family historybased risk assessment tools have been developed for clinical use, including the following: BRCAPRO Couch Myriad I and II Ontario Family History Assessment Tool (FHAT) Manchester All of these assessment tools are highly predictive of carrier status and aid in reducing testing costs for the majority of mutation negative families.[8] BRCAPRO, the most commonly used model, identifies approximately 50% of mutation-negative families, avoiding unnecessary genetic testing, and fails to screen only about 10% of mutation carriers. Notably, a significant portion of ovarian cancers not previously considered familial can be attributed to BRCA1 or BRCA2 mutations.[9] This finding has led to the suggestion that women with nonmucinous invasive ovarian cancers may benefit from genetic testing to determine mutation status independent of a strong history or no history of breast cancer. The National Institutes of Health (NIH) provides a Cancer Genetics Services Directory. This is a partial listing of professionals who provide services related to cancer genetics, including cancer risk assessment, genetic counseling, and genetic susceptibility testing.

Reproductive factors and steroid hormones

Late age at first pregnancy, nulliparity, early onset of menses, and late age of menopause have all been consistently associated with an increased risk of breast cancer.[10, 11, 12, 13, 14] Prolonged exposure to elevated levels of sex hormones has long been postulated as a risk factor for developing breast cancer, explaining the association between breast cancer and reproductive behaviors.[15, 16] Clinical trials of secondary prevention in women with breast cancer have demonstrated the protective effect of selective estrogen receptor modulators (SERMs) and aromatase inhibitors on recurrence and the development of
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contralateral breast cancers.[17] Use of SERMs in women at increased risk for breast cancer has prevented invasive ER-positive cancers.[18, 19, 20] These data support estradiol and its receptor as a primary target for risk reduction but do not establish that circulating hormone levels predict increase risk. A number of epidemiologic and pooled studies support an elevated risk of breast cancer among women with high estradiol levels.[21, 22] The Endogenous Hormones and Breast Cancer Collaborative Group (EHBCG) reported a relative risk of 2.58 among women in the top quintile of estradiol levels.[23] Upon thorough review of the collective data, the Breast Cancer Prevention Collaborative Group (BCPCG) prioritized additional factors that might be included in the validation phase of a risk prediction model and gave a high priority score to free plasma estradiol levels.[22] At present, routine measurement of plasma hormone levels is not recommended in the assessment of breast cancer risk. One of the most widely studied factors in breast cancer etiology is the use of exogenous hormones in the form of oral contraceptives (OCs) and hormone replacement therapy (HRT).[24, 25] The overall evidence suggests an approximately 25% greater risk of breast cancer among current users of OCs. The risk appears to decrease with age and time since OC discontinuance. For OC users, risk returns to that of the average population risk about 10 years after cessation. Data obtained from case-control and prospective cohort settings support an increased risk of breast cancer incidence and mortality with the use of postmenopausal HRT.[26] Increased risk of breast cancer has been positively associated with length of exposure, with the greatest risk being observed for hormonally responsive lobular, mixed ductal-lobular, and tubular cancers.[26] Risk is greater among women taking combination HRT than among those taking estrogen-only formulations.[27] In the Womens Health Initiative (WHI) trial, the incidence of invasive breast cancer was 26% higher in women randomly assigned to combination HRT than in those assigned to placebo. In contrast, the use of estrogen (conjugated equine estrogen) alone in women who had undergone hysterectomy was associated with a 23% (but not significant) decrease in breast cancer risk in comparison with placebo at initial reporting. On extended follow-up (median, 11.8 years), estrogen-only therapy for 5-9 years in women with hysterectomy was associated with a significant 23% reduction in the annual incidence of invasive breast cancer (0.27%; placebo, 0.35%).[28] Fewer women died of breast cancer in the estrogen-only arm. These findings contrast with those reported from large observational case-control and prospective cohort studies, where estrogen alone was associated with increased risk (though the increase was consistently less than that associated with combined HRT use).[29] To aid the medical community in the application of HRT, a number of agencies and groups have published recommendations for HRT use in the treatment of menopause and associated bone loss. At present, HRT is not recommended for prevention of cardiovascular disease or dementia or, more generally, for long-term use to prevent disease. Recommendations differ slightly by agency and by country. US and non-US evidence-based treatment recommendations can be found at the National Guidelines Clearinghouse Web site. When prescribing HRT, the clinician should provide a discussion of the most current evidence and an assessment of the potential benefit and harm to the patient. Because of the known risk of endometrial cancer with estrogenonly formulations, the US Food and Drug Administration (FDA) currently advises the use of estrogen-plusprogesterone HRT for the management of menopausal symptoms in women with an intact uterus tailored to the individual patient, at the lowest effective dose for the shortest time needed to abate symptoms. There are currently no formal guidelines for the use of HRT in women at high risk for breast cancer (ie, women with a family history of breast cancer, a personal history of breast cancer, or benign breast disease). Only a few studies have evaluated the effect of HRT after a diagnosis of breast cancer. The largest of these, the HABITS (Hormonal replacement therapy After Breast canceris IT Safe?) study was stopped early because unacceptable rates of breast cancer recurrence and contralateral disease with 2 years of HRT use (hazard ratio, 3.5).[30] In another randomized clinical trial, no increase in the risk of breast cancer recurrences was observed in women at
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a median follow up of 4.1 years.[31] Use of progesterone-containing HRT was limited by intermittent use, with continuous exposure avoided. Combination formulations containing estrogen plus progesterone are contraindicated in women with a prior history of invasive disease, a history of ductal or lobular carcinoma in situ, or a strong family history of breast cancer. This recommendation poses a significant challenge when confronted with a patient suffering severe menopausal symptoms. Many new treatments for menopausal symptoms have been suggested (eg, clonidine, venlafaxine, gabapentin, and combination venlafaxine plus gabapentin). To date, no randomized clinical trials among women at increased risk of breast cancer or women with a history of breast cancer have assessed the overall efficacy or risks associated with these treatments.[32] Use of these agents is controversial and should target the severity of menopausal symptoms. Other hormone-based approaches (eg, low-dose vaginal estrogen for vaginal and urinary symptoms, including dyspareunia) are generally considered to be safer, particularly in patients receiving SERMs. However, these agents may also carry a slight increased risk, in that they are capable of raising estradiol levels, at least transiently, depending on the dose and frequency of administration. Little evidence supports the benefit of commonly used dietary isoflavones, black cohosh, or vitamin E.

Prior breast health history

A history of breast cancer is associated with a 3- to 4-fold increased risk of a second primary cancer in the contralateral breast.[33, 34, 35] The presence of any premalignant ductal carcinoma in situ (DCIS) or LCIS confers an 8- to 10-fold increase in the risk of developing breast cancer in women who harbor untreated preinvasive lesions.
[36, 37]

A history of breast biopsy that is positive for hyperplasia, fibroadenoma with complex features, sclerosing adenosis, and solitary papilloma have been associated with a modest (1.5- to 2-fold) increase in breast cancer risk.[36, 37] In contrast, any diagnosis of atypical hyperplasia that is ductal or lobular in nature, especially in a woman under the age of 45 years, carries a 4- to 5-fold increased risk of breast cancer, with the increase rising to 8- to 10-fold among women with multiple foci of atypia or calcifications in the breast.[38] Benign breast lesions, including fibrocystic disease such as fibrocystic change without proliferative breast disease or fibroadenoma, have not been associated with increased risk.[39]

Lifestyle risk factors

The wide variability of breast cancer incidence around the world (eg, the nearly 5-fold difference between Eastern Africa and Western Europe) has long been attributed to differences in dietary intake and reproductive patterns.[40, 41, 42, 43] In general, rates differ according to the level of industrial development: there are more than 80 cases per 100,000 in developed countries, compared with fewer than 40 per 100,000 in less developed countries. As with cancers of the colon and prostate, diets that are rich in grains, fruits, and vegetables; low in saturated fats; low in energy (calories); and low in alcoholthe more common pattern in less industrialized countriesare thought to be protective against breast cancer.[44]

Obesity
Increased risk of postmenopausal breast cancer has been consistently associated with the following: Adult weight gain of 20-25 kg above body weight at age 18[45, 46] Western dietary pattern (high energy content in the form of animal fats and refined carbohydrates) Sedentary lifestyle Regular, moderate consumption of alcohol (3-5 alcoholic beverages per week) The Western lifestyle (ie, chronic excess energy intake from meat, fat, and carbohydrates and lack of exercise) strongly correlates with development of the following:
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Obesity, particularly abdominal obesity Chronic hyperinsulinemia Higher production and availability of insulinlike growth factor (IGF)-1 Increased levels of endogenous sex hormones through suppression of sex hormonebinding globulin[47, 48] Studies of dietary fat, total energy, and meat intake levels have largely been inconsistent in population studies of adult women with regard to risk of breast cancer. In contrast, epidemiologic studies have more consistently found a positive relation between breast cancer risk and early-life exposures such as diet, obesity, and body size (including height).[49, 50, 51] The mechanism of this relation is unknown.

Environmental risk factors

A number of environmental exposures have been investigated in relation to breast cancer risk in humans, including the following[52, 53, 54, 55] : Tobacco smoke (both active and passive exposure) Dietary (eg, charred and processed meats) Alcohol consumption Environmental carcinogens (eg, exposure to pesticides, radiation, and environmental and dietary estrogens) Of these environmental exposures, only high doses of ionizing radiation to the chest area, particularly during puberty, have been unequivocally linked with an increased risk of breast cancer in adulthood.[55, 56] Because of the strong association between ionizing radiation exposure and breast cancer risk, medical diagnostic procedures are performed in such a way as to minimize exposure to the chest area, particularly during adolescence. Women with a history of radiation exposure to the chest area should be examined and counseled regarding their risk of breast cancer on the basis of the timing and dose of the previous exposure. A patient treated for Hodgkin lymphoma with Mantel radiation that includes the breasts in the radiation field has a 5-fold higher risk of developing breast cancer. This risk increases markedly for women treated during adolescence[57] ; evidence suggests that cumulative risk increases with age as a function of age of exposure and type of therapy.[58] Current evidence does not support a significant and reproducible link between other environmental exposures and breast cancer risk. Thus, a number of factors remain suspect but unproven.

Epidemiology
United States statistics
In the United States, approximately 232,340 new cases of female invasive breast cancer are predicted to occur in 2013, along with 2240 cases in men.[3] Among US women in 2011, in addition to invasive breast cancer, 57,650 new cases of in situ breast cancer were expected to occur; approximately 83% of these cases were expected to be DCIS, and 11% were expected to be LCIS.[59] The incidence of breast cancer in the United States increased rapidly from 1980 to 1987, largely as a consequence of the widespread use of mammography screening, which led to increased detection of asymptomatic small breast tumors. After 1987, the increase in overall rates of invasive breast cancers slowed significantly, specifically among white women aged 50 years or older. Incidence over this period of time varied dramatically by histologic type. Common ductal carcinomas increased modestly from 1987 to 1999, whereas invasive lobular and mixed ductal-lobular carcinomas increased dramatically during this time period.[60] For women under the age of 50, breast cancer rates have remained stable since the middle to late 1980s. Rates of DCIS have stabilized since 2000.[59] Whereas a decline in invasive breast cancer rates was evident as early as 1999, rates decreased dramatically in women aged 50 years or older between 2001 and 2004. During this same period, no significant change was observed in the incidence of ER-negative cancers or cancers in women younger than 50 years. The decline in rates from 2001 to 2004 was greatest between 2002 and 2003 and was limited to non-Hispanic whites.[61, 62, 63,
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64]

The reason for the decline has been extensively debated. Breast cancer rates decreased significantly after the reports from the Million Women Study [65] and the Womens Health Initiative showing higher numbers of breast cancers in women using combination HRT with estrogen and progestin for menopausal symptoms. The nearimmediate decrease in the use of combination HRT for that purpose has been widely accepted as a primary explanation for the decrease in breast cancer rates.[63] However, Jemal and Li argued that the decline in breast cancer incidence started earlier than the reduction in combination HRT use and that the decline is due in part to a saturation in mammographic screening mammography that produced a plateau in incidence when such screening stabilized in the late 1990s.[60, 62] Saturation of the population would be predicted to reduce the pool of undiagnosed or prevalent cases. For women aged 69 years or older, breast cancer rates started to decline as early as 1998, when screening first showed a plateau. This observation is consistent with the prediction that if widespread screening and earlier detection are effective, they should result in a peak incidence among women during the sixth and seventh decades of life, followed by a decline. This is exactly the pattern now being reported for screened populations.[66] The second observation noted by Jemal et al was that despite evidence for a plateau effect, screening saturation alone could not explain the dramatic declines or the pattern of decline. The decline in incidence was observed only for ER-positive tumors and not for ER-negative ones; these findings support the competing hypothesis that exposure to HRT as estrogen in combination with synthetic progesterone promoted the growth of undetected tumors. Under this scenario, withdrawal of combination HRT at the population level may have resulted in regression or a slowing of tumor growth. The latter, it has been argued, would result in a delay in detection. Overall, incidence figures from 2005-2009, for which the most recent data are currently available, suggest that overall new breast cancer case rates have remained fairly stable since the initial drop. It is notable, however, that the annual percentage change from 2005 to 2009 increased in women aged 65-74 years by 2.7% during this period, rates that parallel 2001 incidence figures for this age group.[6] This rise is occurring in spite of very low use of HRT by this population[67] and suggests that the drop in combination HRT use immediately after 2002 may not have resulted in a sustained decrease in new breast cancer cases. At present, it is unclear whether decreased use of combination HRT has resulted in a sustained reduction in the incidence of breast cancer at the population level or has shifted the age at which preexisting disease would become detectable. Longer-term follow-up of post-2002 trends in relation to combination HRT use are needed to address this question.

International statistics
The final decades of the 20th century saw worldwide increases in the incidence of breast cancer, with the highest rates reported in Westernized countries. Reasons for this trend are largely attributed to introduction of screening mammography. Changes in reproductive patternsparticularly fewer children and later age at first birthmay also have played a role, as may changes in lifestyle factors, including the following: Western dietary patterns Decreased physical activity Rising obesity rates More widespread use of exogenous hormones for contraception and treatment of menopausal symptoms The beginning of the 21st century saw a dramatic decrease in breast cancer incidence in a number of Westernized countries (eg, the United Kingdom, France, and Australia). These decreases paralleled those noted in the United States and reflected similar patterns of mammography screening and decreased use of combination HRT.[2] In 2008, there were an estimated 1.38 million new cases of invasive breast cancer worldwide. The 2008 incidence of female breast cancer ranged from 19.3 cases per 100,000 in Eastern Africa to 89.9 cases per 100,000 in Western Europe.[2]
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With early detection and significant advances in treatment, death rates from breast cancer have been decreasing over the past 25 years in North America and parts of Europe. In many African and Asian countries (eg, Uganda, South Korea, and India), however, breast cancer death rates are rising.[2]

Age-related demographics
The incidence rate of breast cancer increases with age, from 1.5 cases per 100,000 in women 20-24 years of age to a peak of 421.3 cases per 100,000 in women 75-79 years of age; 95% of new cases occur in women aged 40 years or older. The median age of women at the time of breast cancer diagnosis is 61 years.[59] Rates of in situ breast cancer stabilized among women 50 years and older in the late 1990s; this is consistent with the proposed effects of screening saturation. However, the incidence of in situ breast cancer continues to increase in younger women.[59]

Race- and ethnicity-related demographics

In the United States, the incidence of breast cancer is higher in non-Hispanic whites than in women of other racial and ethnic groups. Among women younger than 40 years, African Americans have a higher incidence. In addition, a larger proportion of African-American women are diagnosed with larger, advanced-stage tumors (>5 cm) and are more likely to die of breast cancer at every age.[59] According to the American Cancer Society (ACS), breast cancer rates among women from various racial and ethnic groups are as follows [59] : Non-Hispanic white: 125.4/100,000 African American: 116.1/100,000 Hispanic/Latina: 91.0/100,000 American Indian/Alaska Native: 89.2/100,000 Asian American/Pacific Islander: 84.9/100,000 According to the ACS, death rates from breast cancer among women from various racial and ethnic groups are as follows: Non-Hispanic white: 23.9/100,000 African American: 32.4/100,000 Hispanic/Latina: 15.3/100,000 American Indian/Alaska Native: 17.6/100,000 Asian American/Pacific Islander: 12.2/100,000 Breast cancer death rates among women in most racial and ethnic groups in the US have been declining since the early 1990s, except in American Indian and Alaska Native populations, among whom rates have remained stable.

Prognosis
Death rates from breast cancer in the United States have decreased steadily in women since 1990. Breast cancer mortality fell by 24% between 1990 and 2000 for women aged 30-79 years. The largest decrease in mortality has been seen in women younger than 50 years (3.3% per year) compared with those aged 50 years and older (2.0% per year). The decrease in breast cancer death rates is thought to represent progress in both earlier detection and improved treatment modalities.[3] The 2013 estimates are 39,920 expected breast cancer deaths (39,510 women, 410 men).
[3]

Prognostic and predictive factors

Numerous prognostic and predictive factors for breast cancer have been identified by the College of American Pathologists (CAP) to guide the clinical management of women with breast cancer. Breast cancer prognostic
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factors include the following: Axillary lymph node status Tumor size Lymphatic/vascular invasion Patient age Histologic grade Histologic subtypes (eg, tubular, mucinous [colloid], or papillary) Response to neoadjuvant therapy ER/PR status HER2 gene amplification or overexpression Cancerous involvement of the lymph nodes in the axilla is an indication of the likelihood that the breast cancer has spread to other organs. Survival and recurrence are independent of level of involvement but are directly related to the number of involved nodes. Patients with node-negative disease have an overall 10-year survival rate of 70% and a 5-year recurrence rate of 19%. In patients with lymph nodes that are positive for cancer, the recurrence rates at 5 years are as follows: 1-3 positive nodes 30-40% 4-9 positive nodes 44-70% >10 positive nodes 72-82% Hormone receptorpositive tumors generally have a more indolent course and are responsive to hormone therapy. ER and PR assays are routinely performed on tumor material by pathologists; immunohistochemistry (IHC) is a semiquantitative technique that is observer- and antibody-dependent. This prognostic information can guide physicians in making therapeutic decisions. Pathologic review of the tumor tissue for histologic grade, along with the determination of ER/PR status and HER2 status, is necessary for determining prognosis and treatment. Evaluation of lymph node involvement by means of sentinel lymph node biopsy or axillary lymph node dissection is generally necessary as well.[68] (See Staging.)

HER2
In the past, HER2 overexpression was associated with a more aggressive tumor phenotype and a worse prognosis (higher recurrence rate and increased mortality), independent of other clinical features (eg, age, stage, and tumor grade), especially in patients who did not receive adjuvant chemotherapy. Prognosis has improved with the routine use of HER2-targeted therapies, which consist of the following: Trastuzumab Monoclonal antibody Pertuzumab Monoclonal antibody Lapatinib A small-molecule oral tyrosine kinase inhibitor Trastuzumab-emtansine An antibody-drug conjugate directed specifically to the HER2 receptor HER2 status has also been shown to predict response to certain chemotherapeutic agents (eg, doxorubicin). Retrospectively analyzed results from clinical trials have shown that HER2-positive patients benefit from anthracycline-based regimens, perhaps because of the frequent coamplification of topoisomerase II with HER2. Preliminary data also suggest that HER2 positivity may predict response to and benefit from paclitaxel in the adjuvant setting.[69] (See Breast Cancer and HER2.)

Prognosis by cancer type

DCIS is divided into comedo (ie, cribriform, micropapillary, and solid) and noncomedo subtypes, a division that provides additional prognostic information on the likelihood of progression or local recurrence. Generally, the prognosis is worse for comedo DCIS than for noncomedo DCIS (see Histology). Approximately 10-20% of women with LCIS develop invasive breast cancer within 15 years after their LCIS diagnosis. Thus, LCIS is considered a biomarker of increased breast cancer risk.
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Infiltrating ductal carcinoma is the most commonly diagnosed breast tumor and has a tendency to metastasize via lymphatic vessels. Like ductal carcinoma, infiltrating lobular carcinoma typically metastasizes to axillary lymph nodes first. However, it also has a tendency to be more multifocal. Nevertheless, its prognosis is comparable to that of ductal carcinoma. Typical or classic medullary carcinomas are often associated with a good prognosis despite the unfavorable prognostic features associated with this type of breast cancer, including ER negativity, high tumor grade, and high proliferative rates. However, an analysis of 609 medullary breast cancer specimens from various stage I and II National Surgical Adjuvant Breast and Bowel Project (NSABP) protocols indicates that overall survival and prognosis are not as good as previously reported. Atypical medullary carcinomas also carry a poorer prognosis. Overall, patients with mucinous carcinoma have an excellent prognosis, with better than 80% 10-year survival. Similarly, tubular carcinoma has a low incidence of lymph node involvement and a very high overall survival rate. Because of the favorable prognosis, these patients are often treated with only breast-conserving surgery and local radiation therapy. Cystic papillary carcinoma has a low mitotic activity, which results in a more indolent course and a good prognosis. However, invasive micropapillary ductal carcinoma has a more aggressive phenotype, even though approximately 70% of cases are ER-positive. A retrospective review of 1400 cases of invasive carcinoma identified 83 cases (6%) with at least 1 component of invasive micropapillary ductal carcinoma.[70] Additionally, lymph node metastasis is frequently seen in this subtype (incidence, 70-90%), and the number of lymph nodes involved appears to correlate with survival. For metaplastic breast cancer, the majority of published case series have demonstrated a worse prognosis than with infiltrating ductal carcinoma, even when adjusted for stage, with a 3-year overall survival rate of 48-71% and 3year disease-free survival rate of 15-60%.[71] In most case series, large tumor size and advanced stage have emerged as predictors of poor overall survival and prognosis.[72] Nodal status does not appear to impact survival in metaplastic breast cancer. Paget disease of the breast is associated with an underlying breast cancer in 75% of cases. Breast-conserving surgery can achieve satisfactory results, but at the risk of local recurrence. Poor prognostic factors include a palpable breast tumor, lymph node involvement, histologic type, and an age of less than 60 years. Paget disease with a palpable mass usually has an invasive component and a lower 5-year survival rate (20-60%). Those that do not have an underlying palpable mass have a higher 5-year survival rate (75-100%).[73, 74]

Contributor Information and Disclosures

Author Alison T Stopeck, MD Associate Professor of Medicine, Arizona Cancer Center, University of Arizona Health Sciences Center; Director of Clinical Breast Cancer Program, Arizona Cancer Center; Medical Director of Coagulation Laboratory, University Medical Center; Director of Arizona Hemophilia and Thrombosis Center Alison T Stopeck, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Clinical Oncology, American Society of Hematology, Hemophilia and Thrombosis Research Society, and Southwest Oncology Group Disclosure: Genentech Honoraria Speaking and teaching; AstraZeneca Honoraria Speaking and teaching; AstraZeneca Grant/research funds Other Coauthor(s) Patricia A Thompson, PhD Assistant Professor, Department of Pathology, University of Arizona, Tucson Disclosure: Nothing to disclose. Chief Editor Jules E Harris, MD Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center
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Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research Disclosure: Nothing to disclose. Additional Contributors Leona Downey, MD Assistant Professor of Internal Medicine, Section of Oncology and Hematology, University of Arizona, Arizona Cancer Center Leona Downey, MD is a member of the following medical societies: American Geriatrics Society, American Society of Clinical Oncology, and Southwest Oncology Group Disclosure: Nothing to disclose. Manjit Singh Gohel, MD, MRCS, MB, ChB Specialist Registrar, Division of Breast and Endocrine Surgery, Northwick Park Hospital Disclosure: Nothing to disclose. Harold Harvey, MD Professor, Department of Medicine, Pennsylvania State University Disclosure: Nothing to disclose. Kanchan Kaur, MBBS, MS (General Surgery), MRCS (Ed) Consulting Breast and Oncoplastic Surgeon, Medanta, The Medicity, India Disclosure: Nothing to disclose. Julie Lang, MD Assistant Professor of Surgery and the BIO5 Institute, Director of Breast Surgical Oncology, University of Arizona College of Medicine Julie Lang, MD is a member of the following medical societies: American College of Surgeons, American Society of Breast Surgeons, American Society of Clinical Oncology, Association for Academic Surgery, and Society of Surgical Oncology Disclosure: Genomic Health Grant/research funds Speaking and teaching; Agendia Grant/research funds Speaking and teaching; Surgical Tools Grant/research funds Research; Sysmex Grant/research funds Research Robert B Livingston, MD Professor of Clinical Medicine and Director, Clinical Research Shared Services, Arizona Cancer Center Robert B Livingston, MD is a member of the following medical societies: American Association for Cancer Research, American Federation for Clinical Research, and American Society of Clinical Oncology Disclosure: Nothing to disclose. Hanan Makhoul, MD Staff Physician, Department of Internal Medicine, University of Arkansas School of Medicine Disclosure: Nothing to disclose. Issam Makhoul, MD Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences Issam Makhoul, MD is a member of the following medical societies: American Society of Clinical Oncology and American Society of Hematology Disclosure: Nothing to disclose. Robert C Shepard, MD, FACP Associate Professor of Medicine in Hematology and Oncology at University of
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North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physician Executives, American College of Physicians, American Federation for Clinical Research, American Federation for Medical Research, American Medical Association, American Medical Informatics Association, American Society of Hematology, Association of Clinical Research Professionals, Eastern Cooperative Oncology Group, European Society for Medical Oncology, Massachusetts Medical Society, and Society for Biological Therapy Disclosure: Nothing to disclose. Hemant Singhal, MD, MBBS, FRCSE, FRCS(C) Senior Lecturer, Director of Breast Service, Department of Surgery, Imperial College School of Medicine; Consultant Surgeon, Northwick Park and St Marks Hospitals, UK Hemant Singhal, MD, MBBS, FRCSE, FRCS(C) is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada and Royal College of Surgeons of Edinburgh Disclosure: Nothing to disclose. Carl V Smith, MD The Distinguished Chris J and Marie A Olson Chair of Obstetrics and Gynecology, Professor, Department of Obstetrics and Gynecology, Senior Associate Dean for Clinical Affairs, University of Nebraska Medical Center Carl V Smith, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Council of University Chairs of Obstetrics and Gynecology, Nebraska Medical Association, and Society for Maternal-Fetal Medicine Disclosure: Nothing to disclose. Wiley Souba, MD Chairman, Professor, Department of General Surgery, Pennsylvania State College of Medicine; Chief Surgeon, The Milton S Hershey Medical Center Disclosure: Nothing to disclose. Rachel Swart, MD, PhD Assistant Professor of Medicine, Department of Hematology and Oncology, Arizona Cancer Center, University of Arizona Rachel Swart, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society of Clinical Oncology, Arizona Medical Association, and Southwest Oncology Group Disclosure: Roche Grant/research funds Other Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment Simon Thomson, MB, BCh, MD, FRCS Specialist Registrar, Department of Breast and Endocrine Surgery, Northwick Park Hospital, UK Simon Thomson, MB, BCh, MD, FRCS is a member of the following medical societies: British Medical Association Disclosure: Nothing to disclose.

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