BREAST CANCER

Practice EssentialsWorldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and the leading cause of cancer death among women. See the image below.Breast cancer. Intraductal carcinoma, comedo type. Distended duct with intact basement membrane and central tumor necrosis.SeeCutaneous Clues to Diagnosing Metastatic Cancer, a Critical Images slideshow, to help identify various skin lesions that are cause for concern. Also, see theBreast Lumps in Young Women: Diagnostic Approachesslideshow to help manage palpable breast lumps in young women.Signs and symptomsEarly 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 lumpSeeClinical Presentationfor more detail.DiagnosisBreast 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 biopsyPhysical examinationThe following physical findings should raise concern: Lump or contour change Skin tethering Nipple inversion Dilated veins Ulceration Paget disease Edema or peau dorangeIf 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 muscleScreeningEarly detection remains the primary defense in preventing breast cancer. Screening modalities include the following: Breast self-examination Clinical breast examination Mammography Ultrasonography Magnetic resonance imagingUltrasonography 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.BiopsyCore 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.SeeWorkupfor more detail.ManagementSurgery and radiation therapy, along with adjuvant hormone or chemotherapy when indicated, are now considered primary treatment for breast cancer. Surgical therapy may consist of lumpectomy or total mastectomy. Radiation therapy may follow surgery in an effort to eradicate residual disease while reducing recurrence rates. 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 agentsHormone therapy and chemotherapy are the 2 main interventions for treating metastatic breast cancer. Common chemotherapeutic regimens include the following: Docetaxel Cyclophosphamide Doxorubicin Carboplatin Methotrexate TrastuzumabTwo 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.SeeTreatmentandMedicationfor more detail.BackgroundWorldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women. In less-developed countries, it is the leading cause of cancer death in women; in developed countries, however, it has been surpassed by lung cancer as a cause of cancer death in women.[1]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.[2](For discussion of male breast cancer, seeBreast 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.)Adjuvant breast cancer therapies are designed to treat micrometastatic disease or breast cancer cells that have 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. (SeeTreatmentandMedication.)For patient education information, see theBreast Cancer Health Center, as well asBreast Cancer,Mastectomy,Breast Lumps and Pain,Breast Self-Exam, andMammogram.AnatomyThe 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 the breast.PathophysiologyThe 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[3](see the image below): Luminal A Luminal B Basal-like HER2-positiveIntrinsic 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.[4]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)EtiologyEpidemiologic 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 genderIncreasing 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.[5]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.[6]This bimodal pattern may reflect the influence of age within the different tumor subtypes; poorly differentiated, high-grade disease tend to occur earlier, whereas hormone-sensitive, slower-growing tumors tend to occur with advancing age.Family history of breast cancerA 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 two 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 theBRCA1orBRCA2gene.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 two cancers (breast and ovarian cancer or 2 independent breast cancers) Male relatives with breast cancer BRCA1andBRCA2mutations 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 thePTEN, TP53, MLH1, MLH2, CDH1,orSTK11gene.To aid in the identification of mutation carriers ofBRCA1/2, 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) ManchesterAll of these assessment tools are highly predictive of carrier status and aid in reducing testing costs for the majority of mutation negative families.[7]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 toBRCA1orBRCA2mutations.[8]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 aCancer 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 hormonesLate 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.[9, 10, 11, 12, 13]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.[14, 15]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 contralateral breast cancers.[16]Use of SERMs in women at increased risk for breast cancer has prevented invasive ER-positive cancers.[17, 18, 19]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.[20, 21]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.[22]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.[21]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).[23, 24]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.[25]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.[25]Risk is greater among women taking combination HRT than among those taking estrogen-only formulations.[26]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%).[27]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).[28]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 theNational 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 estrogen-only formulations, the US Food and Drug Administration (FDA) currently advises the use of estrogen-plus-progesterone 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).[29]In another randomized clinical trial, no increase in the risk of breast cancer recurrences was observed in women at a median follow up of 4.1 years.[30]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.[31]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 historyA history of breast cancer is associated with a 3- to 4-fold increased risk of a second primary cancer in the contralateral breast.[32, 33, 34]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.[35, 36]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.[35, 36]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.[37]Benign breast lesions, including fibrocystic disease such as fibrocystic change without proliferative breast disease or fibroadenoma, have not been associated with increased risk.[38]Lifestyle risk factorsThe 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.[39, 40, 41, 42]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.[43]ObesityIncreased 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[44, 45] 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: 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[46, 47]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).[48, 49, 50]The mechanism of this relation is unknown.Environmental risk factorsA number of environmental exposures have been investigated in relation to breast cancer risk in humans, including the following[51, 52, 53, 54]: 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.[54, 55]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[56]; evidence suggests that cumulative risk increases with age as a function of age of exposure and type of therapy.[57]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.EpidemiologyUnited States statisticsIn the United States, approximately 231,840 new cases of female invasive breast cancer are predicted to occur in 2015, along with 2350 cases in men.[2]Among US women in 2015, in addition to invasive breast cancer, 60,290 new cases of in situ breast cancer are expected to occur; approximately 83% of these cases are expected to be DCIS, and 12% are expected to be LCIS.[2]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.[58]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.[60, 61, 62, 63]The reason for the decline has been extensively debated. Breast cancer rates decreased significantly after the reports from the Million Women Study[64]and the Womens Health Initiative showing higher numbers of breast cancers in women using combination HRT with estrogen and progestin for menopausal symptoms. The near-immediate 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.[62]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.[58, 61]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.[65]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.[5]This rise is occurring in spite of very low use of HRT by this population[66]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 statisticsThe 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 symptomsThe 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.[1]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.[1]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.[1]Age-related demographicsThe 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 demographicsIn 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: 84.9/100,000According 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: 12.2/100,000Breast 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.PrognosisDeath 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.[2]The 2015 estimates are 40,730 expected breast cancer deaths (40,290 in women, 440 in men).[2]Prognostic and predictive factorsNumerous 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 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 HER2gene amplification or overexpressionCancerous 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: One to three positive nodes 30-40% Four to nine 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.[67](See the Staging section in this article as well as Medscape Reference articleBreast Cancer Staging.)HER2In 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 receptorHER2 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.[68](SeeBreast Cancer and HER2.)Prognosis by cancer typeDCIS 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.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 one component of invasive micropapillary ductal carcinoma.[69]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 3-year disease-free survival rate of 15-60%.[70]In most case series, large tumor size and advanced stage have emerged as predictors of poor overall survival and prognosis.[71]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%).[72, 73]HistoryMany early breast carcinomas are asymptomatic, particularly if they were discovered during a breast-screening program. Larger tumors may present as a painless mass. Pain or discomfort is not usually a symptom of breast cancer; only 5% of patients with a malignant mass present with breast pain.Often, the purpose of the history is not diagnosis but risk assessment. A family history of breast cancer in a first-degree relative is the most widely recognized breast cancer risk factor.The US Preventive Services Task Force (USPSTF) has updated its 2005 guidelines on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women. The current USPSTF recommendations are as follows[74, 75]: Women who have family members with breast, ovarian, tubal, or peritoneal cancer should be screened to identify a family history that may be associated with an increased risk for mutations in the breast cancer susceptibility genes BRCA1 or BRCA2 Women who have positive screening results should receive genetic counseling and then BRCA testing if warranted Women without a family history associated with an increased risk for mutations should not receive routine genetic counseling or BRCA testingPhysical ExaminationIf the patient has not noticed a lump, then signs and symptoms indicating the possible presence of breast cancer may include the following: Change in breast size or shape Skin dimpling or skin changes (eg, thickening, swelling, or redness) Recent nipple inversion or skin change or other nipple abnormalities (eg, ulceration, retraction, or spontaneous bloody discharge) Nipple discharge, particularly if bloodstained Axillary lumpTo detect subtle changes in breast contour and skin tethering, the examination must include an assessment of the breasts with the patient upright with arms raised. The following findings should raise concern: Lump or contour change Skin tethering Nipple inversion Dilated veins Ulceration Mammary Paget disease Edema or peau dorangeThe nature of palpable lumps is often difficult to determine clinically, but the following features should raise concern: Hardness Irregularity Focal nodularity Asymmetry with the other breast Fixation to skin or muscle (assess fixation to muscle by moving the lump in the line of the pectoral muscle fibers with the patient bracing her arms against her hips)A complete examination includes assessment of the axillae and supraclavicular fossae, examination of the chest and sites of skeletal pain, and abdominal and neurologic examinations. The clinician should be alert to symptoms of metastatic spread, such as the following: Breathing difficulties Bone pain Symptoms of hypercalcemia Abdominal distention Jaundice Localizing neurologic signs Altered cognitive function HeadacheThe clinical evaluation should include a thorough assessment of specific risk factors for breast cancer (seeBreast Cancer Risk Factors).Diagnostic ConsiderationsThe differential diagnosis includes the following: Circumscribed breast lesions Benign breast disease (eg, fibroadenomas and cysts), breast cancer, breast lymphoma, and metastasis to the breast from other primary sites (eg, neuroendocrine or extramedullary acute myeloid leukemia) Skin thickening Inflammatory carcinoma and mastitis Stellate lesions Breast cancer, traumatic fat necrosis, a radial scar, and a hyalinized fibroadenoma Dilated ducts with or without nipple discharge Papilloma, ductal carcinoma, duct ectasia, and fibrocystic diseaseDifferential Diagnoses Breast Abscess and Masses Breast, FibroadenomaProceed toWorkupApproach ConsiderationsBreast cancer evaluation should be an ordered inquiry that begins with symptoms and a general clinical history. This is followed by a sequence that has become formalized as triple assessment, which includes the following components: Clinical examination Imaging (usually mammography, ultrasonography, or both) Needle biopsyThis approach naturally lends itself to a gradually increasing degree of invasiveness, so that a diagnosis can be obtained with the minimum degree of invasiveness and, consequently, the minimum amount of discomfort to the patient. Because the more invasive investigations also tend to be the most expensive, this approach is usually the most economical.The aims of evaluation of a breast lesion are to judge whether surgery is required and, if so, to plan the most appropriate surgery. The ultimate goal of surgery is to achieve the most appropriate degree of breast conservation while minimizing the need for reoperation.Breast cancer is often first detected as an abnormality on a mammogram before it is felt by the patient or healthcare provider. Mammographic features suggestive of malignancy include asymmetry, microcalcifications, and a mass or architectural distortion. If any of these features are identified, diagnostic mammography along with breast ultrasonography should be performed before a biopsy is obtained. In certain cases, breast magnetic resonance imaging (MRI) may be warranted.Breast Cancer ScreeningWhereas early detection has been advocated as a primary defense against the development of life-threatening breast cancer, questions have been raised in the past few years regarding the age at which to initiate, the modality to use, the interval between screenings, whether to screen older women, and even the impact on breast cancerrelated deaths. It is widely believed that breast tumors that are smaller or nonpalpable and that present with a favorable tumor marker profile are more treatable when detected early.A survival benefit of early detection with mammography screening has been demonstrated.[76, 77]A number of screening modalities exist for breast cancer, including clinical breast examination, mammography, ultrasonography, and MRI. (SeeBreast Cancer Screening.)In December 2013, the US Food and Drug Administration (FDA) 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.[78]A warning against the use of nipple aspiration for breast cancer screening is also found in the National Comprehensive Cancer Networks (NCCNs) 2013 guidelines. In addition, the NCCN guidelines state that the test is currently being evaluated for clinical usefulness.MammographyMammography is a low-dose x-raybased modality used to image the breast. It is currently the best available population-based method for detecting breast cancer at an early stage.[77, 79, 80]Mammography is used both for screening to detect a cancer and for diagnostic workup of patients after a tumor is detected. Screening mammography is performed in asymptomatic women, whereas diagnostic mammography is performed in symptomatic women (ie, when a breast lump or nipple discharge is present or when an abnormality is found during screening mammography).Mammography is sensitive to microcalcifications that develop in breast tumors with sensitivity at less than 100 m. Mammography often detects a lesion before it is palpable by clinical breast examination and, on average, 1 to 2 years before noted by breast self-examination.Recent advances in mammography include the development of digital mammography and the increased use of computer-aided diagnosis (CAD) systems.[81]CAD systems have been developed to help the radiologist identify mammographic abnormalities.Digital mammography allows the image to be recorded and stored. With computer technology, digital mammogram images can be magnified and the image modified to improve evaluation of specific areas in question. Digital images can be transmitted electronically, decreasing the time to second opinion without the risk of losing the film.In a cohort study of women aged 50-74 years, which used data from the Ontario Breast Screening Program, computed radiography (CR) was 21% less effective than digital direct radiography (DR) for breast cancer detection; however, DR was equivalent to screen-film mammography (SFM).[82, 83]The US Preventive Services Task Force (USPSTF) estimates the benefit of mammography in women aged 50-74 years to be a 30% reduction in risk of death from breast cancer. For women aged 40-49 years, the risk of death is decreased by 17%.[84]Screening mammographyAlthough mammography guidelines have been in place for more than 30 years, 20-30% of women still do not undergo screening as indicated. The 2 most significant factors governing a womans decision to undergo mammography are physician recommendation and access to health insurance. Nonwhite women and those of lower socioeconomic status remain less likely to obtain mammography services and more likely to present with life-threatening, advanced stage disease.[85, 86]At present, the most widely accepted recommendations in the United States come from the American Cancer Society (ACS), which recommends annual screening mammography, beginning at age 40 years for all women and continuing for as long as a woman is in good health. The ACS recommends clinical breast examinations about every 3 years for women in their 20s and 30s and every year for women 40 and over, with monthly breast self-examination as an option for women starting in their 20s.[87]In contrast, since 2009 the USPSTF has recommended biennial screening mammography for women aged 50-74 years (grade B recommendation). The USPSTF recommends against routine screening mammography in women aged 40-49 years because of high rates of false-negative findings, perceived harm of unnecessary biopsy, and concern for the harm associated with overdiagnosis and overtreatment (grade C recommendation).[86]Instead of routine screening for women 40-49 years old, the USPSTF recommends that clinicians provide screening to selected patients in this age range, depending on individual circumstances and patient preferences. The USPSTF further concluded that for most individuals without signs or symptoms, there is likely to be only a small benefit from screening.Finally, the USPSTF recommends against teaching breast self-examination and concludes that the current evidence is insufficient to assess the benefits and harms of clinical breast examination in women aged 40 years or older or the benefits and harms of screening mammography in women aged 75 years or older.Diagnostic mammographyDiagnostic mammography is more expensive than screening mammography. It is used to determine the exact size and location of breast abnormalities and to image the surrounding tissue and lymph nodes. Women with breast implants or a personal history of breast cancer may require the additional views used in diagnostic mammography as part of their routine screening examination.A ductogram (or galactogram) is sometimes helpful for determining the cause of nipple discharge. In this specialized examination, a fine plastic tube is placed into the opening of the duct in the nipple. A small amount of contrast medium is injected, which outlines the shape of the duct on a mammogram and shows whether a mass is present inside the duct.UltrasonographyUltrasonography has become a widely available and useful adjunct to mammography in the clinical setting. It is generally employed to assist the clinical examination of a suspicious lesion detected on mammography or physical examination. As a screening tool, ultrasonography is limited by a number of factors, most notably its failure to detect microcalcifications and its poor specificity (34%).Originally, ultrasonography was used primarily as a relatively inexpensive and effective method of differentiating cystic breast masses, which did not require sampling, from solid breast masses, which were usually examined with biopsy; in many cases, the results of these biopsies were benign. However, it is now well established that ultrasonography also provides valuable information about the nature and extent of solid masses and other breast lesions and can often provide useful information regarding the staging of the axilla.This imaging technique is also useful in the guidance of biopsies and therapeutic procedures; research is currently under way to evaluate its role in cancer screening.Magnetic resonance imagingIn an effort to overcome the limitations of mammography and ultrasonography, MRI has been explored as a modality for detecting breast cancer in women at high risk and in younger women. A combination of T1, T2, and 3-D contrast-enhanced MRI techniques has been found to possess high sensitivity (approximating 86-100% in combination with mammography and clinical breast examination) to malignant changes in the breast. (SeeMagnetic Resonance Mammography.)Indications for MRIThe high cost and limited availability of MRI, as well as the difficulties inherent in performing and interpreting the studies with high false-positive rates, necessitate that the use of this modality be carefully considered before it is recommended in a patient. The following are current indications for MRI: Characterization of an indeterminate lesion after a full assessment with physical examination, mammography, and ultrasonography Detection of occult breast carcinoma in a patient with carcinoma in an axillary lymph node Evaluation of suspected multifocal or bilateral tumor Evaluation of invasive lobular carcinoma, which has a high incidence of multifocality Evaluation of suspected extensive high-grade intraductal carcinoma Detection of occult primary breast carcinoma in the presence of metastatic adenocarcinoma of unknown origin Monitoring of the response to neoadjuvant chemotherapy Detection of recurrent breast cancerContraindications for MRIConversely, in a number of situations, MRI is contraindicated, usually because of physical constraints that prevent adequate patient positioning. Additional contraindications include the following: Contraindication to gadolinium-based contrast media (eg, allergy or pregnancy) Patients inability to lie prone Marked kyphosis or kyphoscoliosis Marked obesity Extremely large breasts Severe claustrophobiaRelative contraindications also exist. These are essentially based on the high sensitivity but limited specificity of the technique. MRI may not be useful for the following: Cancer-phobic patients at average or low risk of disease for breast cancer, because of the psychological stress associated with false-positive findings Assessment of mammographically detected microcalcificationsNuclear imagingThe following 3 radiotracers are commonly used for breast imaging or scintimammography in either clinical practice or research: Technetium-99m (99mTc)-sestamibi (for myocardial perfusion imaging); this was the first radiopharmaceutical agent to be approved by the US Food and Drug Administration (FDA) for use in scintimammography[88] 99mTc-tetrofosmin (also for myocardial perfusion imaging) 99mTc-methylene diphosphonate (MDP; for bone scintigraphy)Scintimammography is not indicated as a screening procedure for the detection of breast cancer. However, it may play a role in various specific clinical indications, as in cases of nondiagnostic or difficult mammography and in the evaluation of high-risk patients, tumor response to chemotherapy, and metastatic involvement of axillary lymph nodes.In several prospective studies, overall sensitivity of99mTc-sestamibi scintimammography in the detection of breast cancer was 85%, specificity was 89%, and positive and negative predictive values were 89% and 84%, respectively. Similar numbers have been demonstrated for99mTc-tetrofosmin and99mTc-MDP scintimammography.[3]Positron Emission TomographyUsing a wide range of labeled metabolites (eg, fluorinated glucose [18FDG]), positron emission tomography (PET) can detect changes in metabolic activity, vascularization, oxygen consumption, and tumor receptor status.When PET is combined with computed tomography (CT) to assist in anatomic localization (PET-CT), scans can identify axillary and nonaxillary (eg, internal mammary or supraclavicular) lymph node metastasis for the purposes of staging locally advanced and inflammatory breast cancer before initiation of neoadjuvant therapy and restaging high-risk patients for local or distant recurrences.Accuracy of Breast Imaging ModalitiesThe different techniques used in breast imaging vary with respect to sensitivity, specificity, and positive predictive value (see Table 1 below).Table 1. Accuracy of Breast Imaging Modalities(Open Table in a new window)ModalitySensitivitySpecificityPPVIndications

Mammography63-95% (>95% palpable, 50% impalpable, 83-92% in women older than 50 y; decreases to 35% in dense breasts)14-90% (90% palpable)10-50%

(94% palpable)

Initial investigation for symptomatic breast in women older than 35 y and for screening; investigation of choice for microcalcification

Ultrasonography68-97% palpable74-94% palpable92% (palpable)Initial investigation for palpable lesions in women younger than 35 y

MRI86-100%21-97% (< 40% primary cancer)52%Scarred breast, implants, multifocal lesions, and borderline lesions for breast conservation; may be useful in screening high-risk women

Scintigraphy76-95% palpable, 52-91% impalpable62-94% (94% impalpable)70-83% (83% palpable, 79% impalpable)Lesions >1 cm and axilla assessment; may help predict drug resistance

PET96% (90% axillary metastases)100%Axilla assessment, scarred breast, and multifocal lesions

MRI = magnetic resonance imaging; PET = positron emission tomography; PPV = positive predictive value.

Breast BiopsyPercutaneous vacuum-assisted large-gauge core-needle biopsy (VACNB) with image guidance is the recommended diagnostic approach for newly diagnosed breast tumors. Core biopsies can minimize the need for operative intervention (and subsequent scarring, and provide accurate pathologic diagnosis for appropriate management.Excisional biopsy, as the initial operative approach, has been shown to increase the rate of positive margins. Open excisional biopsy is reserved for lesions where the diagnosis remains equivocal despite imaging and core biopsy assessment or for benign lesions that the patient chooses to have removed. Because wide clearance of the lesion is usually not the goal in diagnostic biopsies, unnecessary distortion of the breast is thereby avoided. Ongoing audit is essential to help reduce an excessive benign-to-malignant biopsy ratio.HistologyBreast cancers usually are epithelial tumors of ductal or lobular origin. The following features are all important in deciding on a course of treatment for any breast tumor: Size Status of surgical margin Presence or absence of estrogen receptor (ER) and progesterone receptor (PR) Nuclear and histologic grade Proliferation Vascular invasion Tumor necrosis Quantity of intraductal component HER2 statusHistologic gradeHistologic grade is the best predictor of disease prognosis in carcinoma in situ, but it is dependent on the grading system used, such as the Van Nuys classification (high-grade, low-grade comedo, low-grade noncomedo). The grading of invasive carcinoma is also important as a prognostic indicator, with higher grades indicating a worse prognosis (see Table 2 below).Table 2. Grading System in Invasive Breast Cancer (Modified Bloom and Richardson)(Open Table in a new window)Score

1> 2> 3

A. Tubule formation>75%10-75%< 10%

B. Mitotic count/HPF (microscope- and field-dependent)< 77-12>12

C. Nuclear size and pleomorphismNear normal; little variationSlightly enlarged; moderate variationMarkedly enlarged; marked variation

Grade I cancer if total score (A + B + C) is 3-5

Grade II cancer if total score (A + B + C) is 6 or 7

Grade III cancer if total score (A + B + C) is 8 or 9

HPF = high-power field.

Ductal carcinoma in situIncreased use of screening mammography has resulted in a dramatic increase in the detection of ductal carcinoma in situ (DCIS). Approximately 64,000 cases of DCIS are diagnosed annually in the United States. About 90% of DCIS cases are identified on mammography as suspicious calcifications: linear, clustered, segmental, focal, or mixed distribution.DCIS is broadly divided into 2 subtypes: comedo (ie, cribriform, micropapillary, and solid; see the first image below) and noncomedo (see the second image below). The likelihood of progression or local recurrence, as well as the prognosis, varies in accordance with the DCIS subtype present (see Table 3 below).Breast cancer. Intraductal carcinoma, comedo type. Distended duct with intact basement membrane and central tumor necrosis.Breast cancer. Intraductal carcinoma, noncomedo type. Distended duct with intact basement membrane, micropapillary, and early cribriform growth pattern.Table 3. Ductal Carcinoma in Situ Subtypes(Open Table in a new window)DCIS CharacteristicComedoNoncomedo

Nuclear gradeHighLow

Estrogen receptorOften negativePositive

DistributionContinuousMultifocal

NecrosisPresentAbsent

Local recurrenceHighLow

PrognosisWorseBetter

DCIS = ductal carcinoma in situ.

Lobular carcinoma in situLobular carcinoma in situ (LCIS) arises from the terminal duct apparatus and shows a rather diffuse distribution throughout the breast, which explains its presentation as a nonpalpable mass in most cases (see the images below). Over the past 25 years, the incidence of LCIS has doubled, currently standing at 2.8 per 100,000 women. The peak incidence is in women aged 40-50 years.Breast cancer. Lobular carcinoma in situ. Enlargement and expansion of lobule with monotonous population of neoplastic cells.Breast cancer. Lobular carcinoma in situ. Enlargement and expansion of lobule with monotonous population of neoplastic cells.Infiltrating ductal carcinomaInfiltrating ductal carcinoma is the most commonly diagnosed breast tumor (accounting for 75% of breast cancers) and has a tendency to metastasize via lymphatic vessels. This lesion has no specific histologic characteristics other than invasion through the basement membrane (see the image below). DCIS is a frequently associated finding on pathologic examination.Breast cancer. Infiltrating ductal carcinoma. Low-grade carcinoma with well-developed glands invading fibrous stroma.Infiltrating lobular carcinomaInfiltrating lobular carcinoma has a much lower incidence than infiltrating ductal carcinoma, accounting for 15-20% of invasive breast cancers. Histologically, it is characterized by the "single-file" arrangement of small tumor cells. Like ductal carcinoma, infiltrating lobular carcinoma typically metastasizes to axillary lymph nodes first. However, it also has a tendency to be multifocal and have discontinuous areas of involvement, making mammographic and even MRI staging imprecise.Medullary carcinomaMedullary carcinoma is relatively uncommon (5%) and generally occurs in younger women. Most patients present with a bulky palpable mass and axillary lymphadenopathy. Diagnosis of this type of breast cancer depends on the following histologic triad: Sheets of anaplastic tumor cells with scant stroma Moderate or marked stromal lymphoid infiltrate Histologic circumscription or a pushing borderDCIS may be observed in the surrounding normal tissues. Medullary carcinomas are typically high-grade lesions that are negative for ER, PR, and HER2 and that commonly demonstrate mutation ofTP53.Mucinous carcinomaMucinous (colloid) carcinoma is another rare histologic type, seen in fewer than 5% of invasive breast cancer cases. It usually presents during the seventh decade of life as a palpable mass or appears mammographically as a poorly defined tumor with rare calcifications.Mucin production is the histologic hallmark. There are 2 main types of lesions, A and B, with AB lesions possessing features of both. Type A mucinous carcinoma represents the classic variety, with larger quantities of extracellular mucin (see the image below), whereas type B is a distinct variant with endocrine differentiation.Breast cancer. Colloid (mucinous) carcinoma. Nests of tumor cells in pool of extracellular mucin.DCIS is not a frequent occurrence in this setting, though it may be found. Most cases are ER- and PR-positive, but HER2 overexpression is rare. Additionally, these carcinomas predominantly express glycoproteins MUC2 and MUC6.Tubular carcinomaTubular carcinoma of the breast is an uncommon histologic type, accounting for only 1-2% of all breast cancers. Characteristic features of this type include a single layer of epithelial cells with low-grade nuclei and apical cytoplasmic snoutings arranged in well-formed tubules and glands.Tubular components make up more than 90% of pure tubular carcinomas and at least 75% of mixed tubular carcinomas. This type of breast cancer has a low incidence of lymph node involvement and a very high overall survival rate. Because of its favorable prognosis, patients are often treated with only breast-conserving surgery and local radiation therapy.Papillary carcinomaPapillary carcinoma of the breast (see the image below) encompasses a spectrum of histologic subtypes. There are 2 common types: cystic (noninvasive form) and micropapillary ductal carcinoma (invasive form). This form of breast cancer is usually seen in women older than 60 years and accounts for approximately 1-2% of all breast cancers. Papillary carcinomas are centrally located in the breast and can present as bloody nipple discharge. They are strongly ER- and PR-positive.Breast cancer. Papillary carcinoma. Solid papillary growth pattern with early cribriform and well-developed thin papillary fronds.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 similar to that of infiltrating ductal carcinoma, even though about 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. Additionally, lymph node metastasis is seen frequently in this subtype (70-90% of cases).[89]Metaplastic breast cancerMetaplastic breast cancer (MBC) accounts for fewer than 1% of breast cancer cases. It tends to occur in older women (average age of onset in the sixth decade) and has a higher incidence in blacks. It is characterized by a combination of adenocarcinoma plus mesenchymal and epithelial components.A wide variety of histologic patterns includes the following: Spindle-cell carcinoma Carcinosarcoma Squamous cell carcinoma of ductal origin Adenosquamous carcinoma Carcinoma with pseudosarcomatous metaplasia Matrix-producing carcinomaThis diverse group of malignancies is identified as a single entity on the basis of a similarity in clinical behavior. Compared with infiltrating ductal carcinoma, MBC tumors are larger, faster-growing, commonly node-negative, and typically negative for ER, PR, and HER2.Mammary Paget diseaseMammary Paget disease is relatively rare, accounting for 1-4% of all breast cancers. The peak incidence is seen in the sixth decade of life. This adenocarcinoma is localized within the epidermis of the nipple-areola complex and is composed of the histologic hallmark Paget cells within the basement membrane. Paget cells are large, pale epithelial cells with hyperchromatic, atypical nuclei, dispersed between the keratinocytes singly or as a cluster of cells.Lesions are predominantly unilateral, developing insidiously as a scaly, fissured, oozing, or erythematous nipple-areola complex. Retraction or ulceration of the nipple is often noted, along with symptoms of itching, tingling, burning, or pain. In situ or invasive breast cancer is found in approximately 85% of patients with Paget disease. Thus, all diagnosed patients require a careful breast examination and mammographic evaluation, with additional imaging, including breast MRI, if the mammogram is negative.Breast Cancer StagingThe American Joint Committee on Cancer (AJCC) staging system groups patients into four stages according to the TNM system, which is based on tumor size (T), lymph node status (N), and distant metastasis (M). (See Table 4 below.)Table 4. TNM Staging System for Breast Cancer(Open Table in a new window)StageTumorNodeMetastases

Stage 0TisN0M0

Stage IT1N0M0

Stage IIAT0

T1

T2

N1

N1

N0

M0

M0

M0

Stage IIBT2

T3

N1

N0

M0

M0

Stage IIIAT0

T1

T2

T3

N2

N2

N2

N1-2

M0

M0

M0

M0

Stage IIIBT4

T4

T4

N0

N1

N2

M0

M0

M0

Stage IIICAny TN3M0

Stage IVAny TAny NM1

Primary tumor (T)Tumor size definitions are as follows: Tx Primary tumor cannot be assessed T0 No evidence of primary tumor Tis DCIS Tis LCIS Tis Paget disease of the nipple with no tumor (Paget disease associated with a tumor is classified according to the size of the tumor) T1 Tumor 2 cm in greatest diameter T1mic Microinvasion 0.1 cm in greatest diameter T1a Tumor >0.1 but not >0.5 cm in greatest diameter T1b Tumor >0.5 but not >1 cm in greatest diameter T1c Tumor >1 cm but not >2 cm in greatest diameter T2 Tumor >2 cm but not >5 cm in greatest diameter T3 Tumor >5 cm in greatest diameter T4 Tumor of any size, with direct extension to (a) the chest wall or (b) skin only, as described below T4a Extension to the chest wall, not including the pectoralis T4b Edema (including peau dorange) or ulceration of the skin of the breast or satellite skin nodules confined to the same breast T4c Both T4a and T4b T4d Inflammatory diseaseRegional lymph nodes (N)Clinical regional lymph node definitions are as follows: Nx Regional lymph nodes cannot be assessed (eg, previously removed) N0 No regional lymph node metastasis N1 Metastasis in movable ipsilateral axillary lymph node(s) N2 Metastasis in ipsilateral axillary lymph node(s) fixed or matted, or in clinically apparent ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis N2a Metastasis in ipsilateral axillary lymph nodes fixed to one another or to other structures N2b Metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph nodes N3 Metastasis in ipsilateral infraclavicular or supraclavicular lymph node(s) with or without axillary lymph node involvement, or clinically apparent ipsilateral internal mammary lymph node(s) and in the presence of axillary lymph node N3a Metastasis in ipsilateral infraclavicular lymph node(s) N3b Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) N3c Metastasis in ipsilateral supraclavicular lymph node(s)Distant metastasisMetastases are defined as follows: Mx Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasisThe 5-year survival rates are highly correlated with tumor stage, as follows: Stage 0, 99-100% Stage I, 95-100% Stage II, 86% Stage III, 57% Stage IV, 20%This prognostic information can guide physicians in making therapeutic decisions. Pathologic review of the tumor tissue for histologic gradealong with determination of ER, PR, and HER2 statusis necessary for determining prognosis.Lymph node assessmentEvaluation of lymph node involvement by means of sentinel lymph node biopsy or axillary lymph node dissection (ALND) has also been considered necessary for staging and prognosis.A 2014 update on sentinel lymph node biopsy for patients with early-stage breast cancer by the American Society of Clinical Oncology (ASCO) advises that sentinel lymph node biopsy may be offered to the following patients[90]: Women with operable breast cancer and multicentric tumors Women with DCIS who will be undergoing mastectomy Women who previously underwent breast and/or axillary surgery Women who received preoperative/neoadjuvant systemic therapyAccording to the ASCO guidelines, sentinel lymph node biopsy should not be performed in patients with any of the following: Large or locally advanced invasive breast cancer (tumor size T3/T4) Inflammatory breast cancer DCIS (when breast-conserving surgery is planned) PregnancyASCO recommendations regarding ALND in patients who have undergone sentinel lymph node biopsy are as follows: ALND should not be performed in women with no sentinel lymph node (SLN) metastases In most cases, ALND should not be performed in women with one to two metastatic SLNs who are planning to undergo breast-conserving surgery with whole-breast radiotherapy ALND should be offered to women with SLN metastases who will be undergoing mastectomyThe 2014 National Comprehensive Cancer Network (NCCN) breast cancer guidelines state that lymph node dissection is optional in the following cases[67]: Strongly favorable tumors When no result would affect the choice of adjuvant systemic therapy Elderly patients Patients with comorbid conditionsAlso seeBreast Cancer Stagingfor summarized information.Additional TestingThe 2014 NCCN guidelines recommend the following laboratory studies for all asymptomatic women with early-stage breast cancer (stages I and II): Complete blood count (CBC) with differential Liver function tests (LFTs) and alkaline phosphataseIn addition, imaging studies (eg, chest x-ray, chest CT, or CT of the abdomen and pelvis) can be considered for women with stage III (locally advanced or inflammatory breast cancer) or symptomatic disease. Tumor markers (carcinoembryonic antigen [CEA] and CA15.3 or CA27.29) may also be obtained in these patients.[67, 91]HER2 testingAlthough several methods for HER2 testing have been developed, approximately 20% of current HER2 testing may be inaccurate; accordingly, the American Society of Clinical Oncology (ASCO) and CAP have recommended guidelines to ensure the accuracy of HER2 testing. Breast cancer specimens should initially undergo HER2 testing by a validated immunohistochemistry (IHC) assay (eg, HercepTest; Dako, Glostrup, Denmark) for HER2 protein expression.[92](SeeBreast Cancer and HER2.)The scoring method for HER2 expression is based on the cell membrane staining pattern and is as follows: 3+ Positive for HER2 protein expression; uniform intense membrane staining of more than 30% of invasive tumor cells 2+ Equivocal for HER2 protein expression; complete membrane staining that is either nonuniform or weak in intensity but has circumferential distribution in at least 10% of cells, or uniform intense membrane staining in 30% or less of tumor cells 1+ Weak or incomplete membrane staining in any tumor cells 0 Negative for HER2 protein expression; no stainingBreast cancer specimens with equivocal IHC results should undergo validation with aHER2gene amplification method, such as fluorescence in situ hybridization (FISH). More centers are relying on FISH alone for determining HER2 status.In general, FISH testing is thought to be more reliable than IHC, but it is more expensive. Equivocal IHC results can be seen in 15% of invasive breast cancers, whereas equivocalHER2FISH results are seen in fewer than 3% of invasive breast cancer specimens and those that had previously been consideredHER2positive. Discordant results (IHC 3+/FISH negative or IHC < 3+/FISH positive) have been observed in approximately 4% of specimens. Currently, no data support excluding this group from treatment with trastuzumab.Newer methodologies for establishing HER2 status, including reverse transcriptasepolymerase chain reaction (RT-PCR) and chromogenic in situ hybridization (CISH), have been developed. The HER2 CISH PharmDX Kit (Dako Denmark A/S, Glostrup, Denmark) was approved by the FDA in November 2011. The interpretation for HER2 FISH testing (ratio of HER2 to chromosome 17 centromere [HER2/CEP17] and gene copy number) is as follows: PositiveHER2amplification HER2:CEP17 ratio is greater than 2.2 orHER2gene copy is greater than 6.0 EquivocalHER2amplification HER2:CEP17 ratio of 1.8-2.2 orHER2gene copy of 4.0-6.0 NegativeHER2amplification HER2:CEP17 ratio is less than 1.8 orHER2gene copy of less than 4.0Molecular profiling assaysThe OncotypeDx assay (Genomic Health, Inc, Redwood City, CA) has been approved by the US Food and Drug Administration (FDA) for women with early-stage ER-positive, node-negative breast cancer treated with tamoxifen, where the recurrence score (RS) correlated with both relapse-free interval and overall survival. This assay is an RT-PCRbased assay of 21 genes (16 cancer genes and 5 reference genes) performed on paraffin-embedded breast tumor tissue.By using a formula based on the expression of these genes, an RS can be calculated that correlates with the likelihood of distant recurrence at 10 years. Breast tumor RSs and risk levels are as follows: < 18, low risk 18-30, intermediate risk >30, high riskFurthermore, in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 and B-20 studies, the OncotypeDx assay was shown retrospectively to predict benefit from chemotherapy and hormonal therapy in hormone-sensitive, node-negative tumors.[93]Similarly, among women with 1- to 3-node-positive, hormone receptor-positive disease, the OncotypeDx recurrence score was a significant predictor of recurrence, with a 21% decrease in recurrence risk for each 10-point drop in RS.Women with a low RS showed a significantly greater improvement in disease-free survival (DFS) with the addition of tamoxifen; no additional benefit was derived from the addition of chemotherapy. In contrast, women with a high RS had a significant improvement in DFS with the addition of chemotherapy to hormonal therapy (tamoxifen).The benefit of adding chemotherapy to hormonal therapy in tumors with an intermediate score is still controversial. TheTrial Assigning Individualized Options for Treatment [TAILORx], a large, prospective, randomized phase III study sponsored by the National Cancer Institute (NCI), is addressing this important question.TheMammaPrintassay (Agendia, The Netherlands) is a genetic test that measures the activity of 70 genes to determine the 5- to 10-year relapse risk for women diagnosed with early breast cancer. It was approved for use by the FDA in 2007 and is an alternative platform toOncotype DX. MammaPrint test results are reported as either a low-risk or a high-risk RS: A low-risk score means that the cancer has a 10% risk of coming back within 10 years without any additional treatments after surgery A high-risk score means that the cancer has a 29% risk of coming back within 10 years without any additional treatments after surgeryApproach ConsiderationsSurgery is considered primary treatment for early-stage breast cancer; many patients are cured with surgery alone. The goals of breast cancer surgery include complete resection of the primary tumor with negative margins to reduce the risk of local recurrences and pathologic staging of the tumor and axillary lymph nodes (ALNs) to provide necessary prognostic information.Adjuvant treatment of breast cancer is designed to treat micrometastatic disease (ie, breast cancer cells that have escaped the breast and regional lymph nodes but which have not yet had an established identifiable metastasis). Adjuvant treatment for breast cancer involves radiation therapy and systemic therapy (including a variety of chemotherapeutic, hormonal and biologic agents).SeeBreast Cancer Treatment Protocolsfor summarized information.Treatment of Invasive Breast CancerSurgical treatment of invasive breast cancer may consist of lumpectomy or total mastectomy. In breast cancer patients who have clinically negative nodes, surgery typically includes sentinel lymph node (SLN) dissection for staging the axilla. (SeeSurgical Treatment of Breast Cancer.)In the AMAROS trial, which involved patients with cT1-2N0 breast cancer up to 5 cm and clinically node-negative axillae who were undergoing either breast conservation or mastectomy with SLN mapping, axillary radiotherapy was found to be a better treatment option than ALN dissection (ALND) in women with a positive SLN.[94]In this study, 744 of the patients with a positive SLN went on to receive ALND, and 681 received axillary radiotherapy.[94]After 5 years of follow-up, the axillary recurrence rate was 0.54% in the ALND group and 1.03% in the radiotherapy group, and there were no significant differences between the groups with respect to either disease-free survival (86.9% vs 82.7%) or overall survival (93.3% vs 92.5%). The rate of lymphedema in the ALND group after 5 years, however, was twice the rate seen in the radiotherapy group (28% vs 14%).Ten-year follow-up results from the multicenter UK Standardization of Breast Radiotherapy (START) trials confirm that 3-week hypofractionated adjuvant radiotherapyin which lower total doses of radiotherapy are delivered in fewer, larger doses (fractions)is as effective and safe as the international standard 5-week regimen for women with early-stage breast cancer following primary surgery. Additionally, the hypofractionated regimen may cause less damage to surrounding normal breast tissue.[95, 96]Lumpectomy marginsThe following consensus guideline, released by the Society of Surgical Oncology and the American Society for Radiation Oncology, addresses margins for breast-conserving surgery with whole-breast irradiation (WBI) in stages I and II invasive breast cancer[97, 98]: Positive margins are associated with at least a 2-fold increase in ipsilateral breast tumor recurrence (IBTR) Negative margins optimize IBTR; this risk is not significantly lowered by wider margin widths IBTR rates are reduced with the use of systemic therapy; in patients who do not receive adjuvant systemic therapy, margins wider than no ink on tumor are not needed Biologic subtypes do not indicate the need for margins wider than no ink on tumor Margin width should not determine the choice of WBI delivery technique, fractionation, and boost dose. Wider negative margins than no ink on tumor are not indicated for patients with invasive lobular cancer; classic lobular carcinoma in situ (LCIS) at the margin is not an indication for reexcision; the significance of pleomorphic LCIS at the margin is not clear Young age is associated with an increased risk for IBTR after breast-conserving therapy, an increased risk for local relapse on the chest wall after mastectomy, and adverse biologic and pathologic features; an increased margin width does not nullify the increased risk for IBTR in young patients An extensive intraductal component (EIC) identifies patients who may have a large residual ductal carcinoma in situ (DCIS) burden after lumpectomy; when margins are negative, there is no evidence of an association between an increased risk for IBTR and EICPostlumpectomy radiation therapyThe purpose of radiation therapy after breast-conserving surgery is to eradicate local subclinical residual disease while reducing local recurrence rates by approximately 75%. On the basis of results from several randomized controlled studies, irradiation of the intact breast is considered standard of care, even in the lowest-risk disease with the most favorable prognostic features.[67]There are 2 general approaches used to deliver radiation therapy: conventional external-beam radiotherapy (EBRT) and partial-breast irradiation (PBI). Whole-breast radiotherapy (WBRT) consists of EBRT delivered to the breast at a dose of 50-55 Gy over 5-6 weeks. This is often followed by a boost dose specifically directed to the area in the breast where the tumor was removed.Common side effects of radiation therapy include fatigue, breast pain, swelling, and skin desquamation. Late toxicity (lasting 6 months after treatment) may include persistent breast edema, pain, fibrosis, and skin hyperpigmentation. Rare side effects include rib fractures, pulmonary fibrosis, cardiac disease (left breast treatment), and secondary malignancies such as radiation-induced sarcoma (0.5%).PBI is employed in early-stage breast cancer after breast-conserving surgery as a way of delivering larger fraction sizes while maintaining a low risk of late effects. Techniques that can deliver this therapy include interstitial brachytherapy (multiple catheters placed through the breast) and intracavitary brachytherapy (a balloon catheter inserted into the lumpectomy site [ie, MammoSite]).Treatment is typically administered twice daily for 5 days. In several nonrandomized studies, these techniques have shown low local recurrence rates comparable to those of EBRT.The American Society of Breast Surgeons (ASBrS) recommends the following selection criteria when patients are being considered for treatment with accelerated PBI[99]: Age 45 years Invasive ductal carcinoma or ductal carcinoma in situ (DCIS) Total tumor size (invasive and DCIS) 3 cm Negative microscopic surgical margins of excision ALN- or SLN-negativePotential complications of PBI are catheter placement followed by removal secondary to inadequate skin spacing, infection, seroma, fibrosis, chronic pain, or disease recurrence.An observational study using data from the SEERMedicare linked database on 35,947 women aged 66 years and older who had invasive breast cancer (79.9%) or DCIS (20.1%) determined that standard EBRT was associated with a higher 5-year breast preservation rate than either lumpectomy alone or brachytherapy was.[100, 101, 102]However, the study data did not reflect use of the newest forms of brachytherapy, a limitation that may reduce the real-world applicability of these findings.Single-dose radiotherapyAccording to 2 major studies, single-dose radiotherapy delivered during or soon after surgery for breast cancer is a viable alternative to conventional EBRT in selected patients who are at low risk for local recurrence.[103]In the TARGIT-A trial, more than 3400 patients with early breast cancer were randomized to either 1 intraoperative dose of 20 Gy using a spherical applicator or EBRT delivered according to standard schedules over several weeks. Breast cancer mortality overall was similar in the TARGIT and EBRT groups (2.6% vs 1.9%), but there were significantly fewer non-breast-cancer deaths with TARGIT than with EBRT (1.4% vs 3.5%). Overall mortality rates were 3.9% with TARGIT and 5.3% with EBRT.[104]In the ELIOT study, 1305 patients were randomized after lumpectomy to receive either intraoperative radiotherapy or EBRT. The 5-year event rate for ipsilateral breast tumor recurrence was 4.4% with ELIOT and 0.4% with EBRT. Overall survival at 5 years was similar in the 2 groups (34 vs 31 deaths), and there was no significant difference between groups in the rate of breast-cancer-related deaths.[105, 106]Postmastectomy radiation therapyClinical practice guidelines developed by the American Society of Clinical Oncology (ASCO), along with several prospective, randomized clinical trials, recommend that postmastectomy radiation therapy be performed according to the following criteria[4]: Positive postmastectomy margins Primary tumors >5 cm Involvement of 4 lymph nodesPatients with more than 4 positive lymph nodes should also undergo prophylactic nodal radiation therapy at doses of 45-50 Gy to the axillary and supraclavicular regions. For patients in whom ALND shows no node involvement, axillary radiation therapy is not recommended.Meta-analyses have shown that postmastectomy radiation therapy combined with regional nodal radiation therapy significantly decreases the rate of local relapse and breast cancer mortality.The benefit of radiation therapy for women with 1-3 positive ALNs has been uncertain. Nonetheless, a meta-analysis of 22 clinical studies found that among women with 1-3 positive nodes (1314 patients) following mastectomy and axillary dissection for early breast cancer, postmastectomy radiotherapy reduced the breast cancer mortality rate by 20% and reduced the recurrence rate by 32%. These benefits were similar among women with 1, 2, or 3 positive nodes. Mean follow-up was 11 years. Radiotherapy also benefited patients with 4 or more positive nodes, while no benefit was seen for those with node-negative disease. Among women with 4 or more positive nodes, radiotherapy reduced breast cancer mortality by 13% and overall recurrence by 21%.[107, 108]Systemic Adjuvant Therapy for Breast CancerAdjuvant treatment of breast cancer is designed to treat micrometastatic disease (ie, breast cancer cells that have escaped the breast and regional lymph nodes but which have not yet had an established identifiable metastasis). Treatment is aimed at reducing the risk of future recurrence, thereby reducing breast cancer-related morbidity and mortality. Depending on the model of risk reduction, adjuvant therapy has been estimated to be responsible for 35-72% of the reduction in mortality. (SeeAdjuvant Therapy for Breast Cancer.)Treatment of Carcinoma in SituDuctal carcinoma in situCurrently, the standard treatment of DCIS is surgical resection with or without radiation. Adjuvant radiation and hormonal therapies are often reserved for younger women, patients undergoing lumpectomy, or those with the comedo subtype.In the United States, approximately 30% of women with DCIS are treated with mastectomy with or without reconstruction, 30% with conservative surgery alone, and 40% with conservative surgery followed by WBRT. ALND or SLND is not routinely recommended for patients with DCIS. Studies have identified metastasis to the ALNs in 10% of patients.In DCIS, WBRT is delivered over 5-6 weeks after surgery, reducing the local recurrence rate by approximately 60%. Roughly 50% of local recurrences are invasive breast cancer. Meta-analyses of randomized controlled trials have demonstrated slightly higher rates of contralateral breast cancer with radiation therapy than with observation (3.85% vs 2.5%) after surgery for DCIS. Studies comparing a