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Last Updated: 6/4/2015  

Breast Cancer

Prevention
  • Consider recommending a 5-year course of tamoxifen, raloxifene, or exemestane for primary risk reduction in women at increased risk for breast cancer.

  • Consider prophylactic mastectomy and/or oophorectomy for women with an inherited genetic predisposition.

Screening
  • Consider performing a clinical breast exam annually in women age 40 and older.

  • Recommend screening mammography for women age 50 to 74 every 1 to 2 years; discuss benefits and harms of screening in women age 40 to 49. Individualize screening decisions in women age 75 and older.

  • Consider specialized screening strategies for women at higher risk for breast cancer, in particular women with a genetic predisposition.

Diagnosis
  • Perform ultrasound and/or mammography to evaluate a new abnormal breast exam finding, depending on age.

  • Obtain a tissue diagnosis in women with a suspicious radiologic abnormality or a clinically suspicious breast exam finding; test for hormone receptor status, HER2, and other markers.

  • Perform ultrasound for axillary staging following tissue confirmation of a breast cancer diagnosis before performing definitive surgery.

  • Stage breast cancer using the TNM staging system.

Therapy
  • Select local therapy (mastectomy or breast conservation) based on tumor size, location, and clinical stage of the disease.

  • Perform axillary-node assessment with sentinel lymph-node biopsy or axillary-node dissection in patients with early invasive breast cancer.

  • Provide radiation therapy to patients with invasive breast cancer who were initially treated with breast conservation surgery and to patients who have undergone mastectomy and are at high risk for recurrence.

  • Offer adjuvant systemic hormonal therapy to patients with estrogen receptor-positive tumors.

  • Treat patients with HER2-positive breast cancer with trastuzumab.

  • Treat patients with tumor size >1 cm or positive lymph nodes with adjuvant chemotherapy; consider neoadjuvant chemotherapy for locally advanced disease.

  • Recommend breast-conserving surgery plus radiation therapy for most patients with ductal carcinoma in situ.

  • Consider ovarian ablation or suppression in premenopausal patients with hormone receptor-positive breast cancer.

Consider recommending a 5-year course of tamoxifen, raloxifene, or exemestane for primary risk reduction in women at increased risk for breast cancer. 
  • Address the risk for developing breast cancer by asking about known risk factors, such as current age, age at onset of menarche, age at first live birth, previous or current hormone treatment, alcohol consumption, and family history.

  • Use the Gail Model to calculate risk quantitatively.

  • Consider recommending a 5-year course of oral tamoxifen, 20 mg/d, oral raloxifene, 60 mg/d, or oral exemestane, 25 mg/d, if the patient is postmenopausal, for

    • Women aged 35 years or older with a breast cancer risk of 1.7% or greater in the next 5 years based on the Gail Model

    • Women with LCIS

    • Women who have a life expectancy of more than 10 years

  • Consider tamoxifen for women who are 35 years or older but not postmenopausal.

  • Use the side-effect profile of each drug to individualize prevention decision making.

  • See module Chemoprevention of Breast Cancer.

  • See table Drug Treatment for Breast Cancer.

  • See Breast Cancer Risk Assessment Tool.

Evidence
  • A 2013 U.S. Preventive Services Task Force guideline on medications to reduce the risk for primary breast cancer recommended clinicians engage in shared decision making with women older than age 35 who are at increased risk (5-year risk is 3% or greater). The guideline recommended tamoxifen or raloxifene for patients in whom benefits of treatment outweigh potential harms (i.e., patients for whom breast cancer risk is high and the risk for complications is low) (1).

  • A 2013 ASCO guideline on pharmacologic interventions to reduce the risk for breast cancer defined increased breast cancer risk as a 5-year risk of 1.66% or greater. The guideline recommended discussing a 5-year course of tamoxifen with women aged 35 or older who are at increased risk for breast cancer. In postmenopausal women at increased risk, the guideline recommended discussing treatment with tamoxifen, raloxifene, and exemestane. The guideline noted that tamoxifen and raloxifene should not be used in patients with a history of venous thromboembolism or in those at high risk (2).

  • A 2013 systematic review found that tamoxifen and raloxifene reduced invasive breast cancer by 30% to 60% compared with placebo. Tamoxifen had a greater effect than raloxifene in the STAR study (NSABP P-2 study). Tamoxifen increased the incidence of endometrial cancer and cataracts compared with raloxifene (3).

  • The NSABP Breast Cancer Prevention (P-1) Trial compared 5 years of tamoxifen with placebo in 13,388 women at risk and showed a significant reduction (about 50%) in the risk for developing invasive and noninvasive breast cancer (4). Women were eligible for this study if their 5-year risk for developing breast cancer was 1.66% or greater over the next 5 years according to the Gail Model.

  • The STAR study is a double-blinded trial that randomly assigned 19,747 postmenopausal women to 5 years of either tamoxifen or raloxifene therapy. Eligible women had a 5-year predicted breast cancer risk of 1.66% or higher based on the modified Gail Model. This comparison of tamoxifen and raloxifene yielded an equivalent number of invasive breast cancer occurrences in both groups. The raloxifene group experienced 38% fewer endometrial cancer events compared with the tamoxifen group, although this decrease was not statistically significant and the number of cases was small. There were marginally significant reductions of thromboembolic events, cataracts, and lens replacements in patients treated with raloxifene. The tamoxifen group had fewer noninvasive cancer events, although this difference did not reach statistical significance (5; 6).

  • In 2010, an updated analysis with an 81-month median follow-up of the STAR study was reported. The risk ratio of raloxifene:tamoxifen was 1.24 (CI, 1.05 to 1.47) for invasive breast cancer and 1.22 (CI, 0.95 to 1.59) for noninvasive disease. Compared with initial results, the risk ratios widened over time for invasive breast cancer but narrowed for noninvasive. Toxicity risk ratios (raloxifene:tamoxifen) were 0.55 (CI, 0.36 to 0.83; P=0.003) for endometrial cancer (this difference was not significant in the initial results), 0.19 (CI, 0.12 to 0.29) for uterine hyperplasia, and 0.75 (CI, 0.60 to 0.93) for thromboembolic events. There were no significant mortality differences (7).

  • Patient-reported outcomes from the STAR trial show that patients treated with raloxifene experienced more musculoskeletal symptoms, weight gain, and dyspareunia, whereas patients treated with tamoxifen experienced more vasomotor symptoms, leg cramps, and bladder control problems and gynecologic problems (8; 9).

  • A randomized trial compared exemestane with placebo in women at increased risk for breast cancer. After a median follow-up time of 35 months, patients randomly assigned to exemestane had a lower risk for invasive breast cancer (HR, 0.35 [CI, 0.18 to 0.70]), but more adverse events occurred in the exemestane group (88% vs. 85%; P=0.003) overall, including hot flashes and arthritis symptoms. There was no difference in the rates of serious adverse events (10).

  • A randomized trial compared exemestane, 25 mg daily, with placebo in 4560 postmenopausal women at moderately increased risk. After a median follow-up time of 3 years, the exemestane group had a lower risk for invasive breast cancer (annualized rate, 0.19% vs. 0.55%) and invasive plus noninvasive breast cancer (annualized rate, 0.35% vs. 0.77%). Adverse effects occurred in slightly more patients in the exemestane group (88% vs. 85%), but exemestane did not increase the risks for endometrial cancers, thromboembolism, cardiovascular events, or cataracts (10; 11).

  • A cohort study described ultrasound screening for endometrial abnormalities in 304 women with breast cancer on tamoxifen who were followed for 6 years. Thirty-two percent of ultrasounds were read as having significant pathology; 80% of abnormalities were benign polyps. There were 6 cases of primary endometrial cancer, all of which presented with abnormal bleeding. An endometrial thickness >9mm had a sensitivity of 63% and a specificity of 60% (12).

  • A population-based retrospective cohort study evaluated the impact of SSRI use on mortality in women with breast cancer taking tamoxifen. The use of paroxetine was associated with increased mortality, with a greater effect seen with longer use. There was no increased risk seen with other antidepressants (13).

  • A study used case-control data from the Breast Cancer Demonstration Project to develop the Gail Model, a risk model to predict breast cancer. The Gail model includes current age, age of menarche, age at first live birth, breast cancer in first-degree relatives, previous breast biopsy, and ethnicity (14).

Rationale
  • Tamoxifen and raloxifene can reduce rates of estrogen receptor-positive tumors.

  • Exemestane can reduce the risk for breast cancer in women at increased risk.

  • Although the risk reduction experienced with tamoxifen use is similar across age groups, premenopausal women have a better risk-benefit profile due to a lower risk for complications, such as thromboembolic disease and endometrial cancer. An increased risk for these complications may be restricted to women older than age 50; therefore, recommendations must take into account age and other individual comorbid conditions and risk factors.

Comments
  • Patients who are on risk-reduction therapy with either tamoxifen or raloxifene should undergo a gynecological exam at baseline and annually. There is no need for ultrasound or biopsy monitoring unless the patient is symptomatic (e.g., bleeding). There is no need for a baseline bone mineral density scan while on tamoxifen.

  • Although the Gail Model was derived from a database largely limited to white women, the Breast Cancer Prevention Trial showed that tamoxifen risk reduction offers similar benefits to both white and black women. However, older women and black women may have an increased risk for tamoxifen-related complications (15).

  • Some SSRIs, including citalopram, venlafaxine, and escitalopram, can be coprescribed with tamoxifen without risk for increased recurrence. Other SSRIs, such as fluoxetine, paroxetine, and sertraline, should be avoided if possible. Current evidence suggests there is no justification for routine CYP2D6 testing of individuals before use of tamoxifen for chemoprevention.

  • The enhanced chemopreventive action beyond the treatment period occurs at a time when there are few side effects of the drug which favors the risk:benefit assessment; the benefits of these agents for prevention of breast cancer are less tangible when administered to healthy women (16; 17).

  • The presence or absence of hot flushes should not be taken as an indirect measure of tamoxifen efficacy.

Consider prophylactic mastectomy for women at increased risk for breast cancer, especially women found to have inherited a genetic predisposition. 
  • Consider bilateral prophylactic mastectomy as a preventive option for women with a significantly high risk for developing breast cancer, particularly in women with

    • A documented family history of multiple cases of premenopausal or bilateral cancer with or without ovarian cancer

    • An inherited genetic predisposition, such as

      • Carrying the BRCA1 or BRCA2 gene mutation

      • Carrying a p53 gene mutation (Li-Fraumeni syndrome)

      • Carrying a PTEN gene mutation

Evidence
  • A prospective cohort study compared rates of breast cancer in women with known BRCA1 and BRCA2 mutations who underwent prophylactic mastectomy and matched women with mutations who did not undergo mastectomy. After a median follow-up time of 6.4 years, fewer women in the mastectomy group were diagnosed with breast cancer (1.9% vs. 48.7%), with an adjusted HR of 0.09 (CI, 0.02 to 0.38) (18).

  • A prospective study evaluated rates of breast cancer in 139 women with known BRCA1 and BRCA2 mutations, 76 of whom underwent prophylactic mastectomy. No cases of breast cancer were observed in women who had prophylactic mastectomy after a mean of 3 years (19).

  • A cohort study determined the risk for a variety of cancers in patients with PTEN mutations, compared with population-based expected cancer incidence rates. Patients with the PTEN mutation had increased rates of breast (RR, 25.4 [CI, 19.8 to 32.0]), thyroid (RR, 51.1 [CI, 38.1 to 67.1]), endometrial (RR, 42.9 [CI, 28.1 to 62.8]), renal (RR, 30.6 [CI, 17.8 to 49.4]), and colorectal (RR, 10.3 [CI, 5.6 to 17.4]) cancers and melanoma (RR, 8.5 [CI, 4.1 to 15.6]). The lifetime risk for breast cancer was 85.2% (20).

Rationale
  • Prophylactic mastectomy has been validated as a management option for women at increased risk for developing breast cancer.

Comments
  • These women may be at risk for developing other cancers. Therefore, a complete family history is fundamental to allow for proper cancer risk assessment and counseling about screening and preventive measures. It is essential that details of family cancer history are confirmed before any interventional procedure for risk reduction is undertaken.

  • Many women overestimate their risk, and genetic testing allows accurate risk assessment.

  • Despite prospective data, there is still debate as to the most appropriate local management of women at high risk for breast cancer. Skin-sparing mastectomy with removal of the nipple-areolar complex is the procedure of choice, but nipple preservation can be undertaken provided patients are made aware of a persistent risk for breast cancer within the retained ducts of the nipple-areolar complex.

  • The mean age of patients in most studies of prophylactic mastectomy is 42 years. There is minimal benefit from carrying out this procedure in women over the age of 60 years; gains in life expectancy with bilateral prophylactic mastectomy are typically between 3 and 5 years and may be a matter of months for older patients.

  • Prophylactic mastectomy may not be the most appropriate decision for many high-risk patients. Aggressive screening regimens, including annual MRI, remain an acceptable alternative for some women.

Advise women with a known BRCA1 or BRCA2 mutation to be evaluated by a genetics counselor and educate them about the benefits of prophylactic oophorectomy. 
  • Consider prophylactic oophorectomy in women who have tested positive for a BRCA1 or BRCA2 mutation and have completed childbearing.

  • Advise women who have tested positive for a BRCA1 or BRCA2 mutation and have not completed childbearing to participate in an ovarian cancer screening trial or to undergo regular transvaginal ultrasound and CA125 testing.

  • See module Ovarian Cancer.

Evidence
  • A 2009 systematic review of breast or gynecologic cancer outcomes in carriers of BRCA1 or BRCA2 mutations who had undergone risk-reducing salpingo-oophorectomy included 10 studies. Women with BRCA1 or BRCA2 who underwent prophylactic mastectomy were at lower risk for breast cancer (HR, 0.49 [CI, 0.37 to 0.65]) and ovarian or fallopian-tube cancer (HR, 0.21 [CI, 0.12 to 0.39]). The risk reduction was similar in women with BRCA1 and those with BRCA2 (21).

Rationale
  • Women who have tested positive for a BRCA1 or BRCA2 mutation have a 60% lifetime risk for developing ovarian cancer.

  • Both breast cancer risk and ovarian cancer risk are known to be reduced in BRCA1 and BRCA2 mutation carriers following prophylactic oophorectomy.

Comments
  • Bilateral salpingo-oophorectomy may be more acceptable as a breast cancer risk-reducing strategy than bilateral prophylactic mastectomy for many women with BRCA1 and BRCA2 mutations.

  • There are uncertain issues relating to hormone replacement therapy for control of menopausal symptoms in these relatively young women. A limited period of use at the lowest dose compatible with control of acute climacteric symptoms seems sensible (calcium and vitamin D supplements should be recommended in the longer term for maintenance of bone health).

Consider performing a clinical breast examination annually in women aged 40 and older. Do not routinely recommend monthly breast self-examination. 
  • Consider performing a clinical breast exam annually in women older than age 40 and in younger women if they request it.

  • Do not encourage routine breast self-examination, but instruct women who choose to perform it in optimal technique and encourage breast awareness.

  • Instruct women to report any breast changes or breast symptoms to their health professional immediately.

  • See table Information on Breast Cancer Screening Guidelines.

  • See module Screening for Breast Cancer.

Evidence
  • A 2009 guideline from the U.S. Preventive Services Task Force stated that the evidence was insufficient to support a recommendation regarding clinical breast exam and recommended against teaching breast self-examination (22).

  • A 2011 guideline from the American College of Obstetricians and Gynecologists recommended performing a clinical breast exam every 1 to 3 years for women aged 40 and older and educating women aged 20 and older about breast self-awareness (23).

  • A guideline from the American Cancer Society, updated online in 2013, recommended performing a clinical breast exam every 3 years in women in their 20s and 30s and annually in women aged 40 and older. The guideline recommended that women be informed of the benefits and limitations of breast self-examination beginning in their 20s.

  • A large observational cohort study determined the diagnostic accuracy of clinical breast exam in a community-based screening program. Clinical breast exam had a sensitivity of 58.8% and a specificity of 93.4% (24)

  • A large randomized trial compared breast self-examination instruction and reinforcement to control (no breast self-examination intervention) in 266,064 women employed at factories in China; entire factories were randomly assigned to the intervention or control group. The intervention group received training in breast self-examination initially and after 1 and 3 years, supervised breast self-examination every 6 months for 5 years, and monthly reminders to perform breast self-examination. After 10 years of follow-up, breast cancer mortality did not differ between the groups (RR, 1.04 [CI, 0.82 to 1.33]), but more benign breast lesions were diagnosed in the intervention group and there were more biopsies (25).

Rationale
  • There is no evidence that clinical breast exam prevents breast cancer mortality.

  • Clinical breast exam may detect some cancers missed on imaging, and probably detects many cancers when used as the only screening test.

  • There is no evidence that breast self-examination reduces mortality, and it has been shown to increase invasive procedures.

Comments
  • Formal breast self-examination can lead to false-positive prompts and heightened anxiety among women. In turn, this leads to more frequent medical consultations and specialist breast referral. Many women have a degree of breast lumpiness, and most are unaware of the subtexture of their breasts; it is inevitable that they will find an area of benign change that they deem suspicious or worrying from time to time.

  • Women should be encouraged to be “breast aware” and become familiar with the normal texture of their breasts. In this way they are more likely to detect any persistent change (lump and/or area of lumpiness) that warrants further evaluation. Women should be reassured that localized areas of tenderness and pain usually indicate benign breast changes.

Recommend screening mammography for women aged 50 to 74 every 1 to 2 years. Consider screening mammography for women aged 40 to 49 and discuss benefits and harms. Individualize screening decisions in women aged 75 and older.  
  • Clinicians should discuss the benefits and harms of screening mammography with average-risk women aged 40 to 49 years and order biennial mammography screening if an informed woman requests it.

  • Clinicians should encourage biennial mammography screening in average-risk women aged 50 to 74 years.

  • Clinicians should not screen average-risk women younger than 40 years or aged 75 years or older for breast cancer or screen women of any age with a life expectancy less than 10 years.

  • Clinicians should not screen average-risk women of any age for breast cancer with MRI or tomosynthesis.

  • Individualize screen decisions in women aged 75 or older, based on breast cancer risk, overall prognosis and comorbid conditions, and personal patient preferences.

  • Reserve specialized imaging, such as ultrasound, scintigraphy with sestamibi, or MRI, for the work-up of abnormalities on clinical exam or mammography.

  • Ensure that screening is done in a certified facility.

  • See table Information on Breast Cancer Screening Guidelines.

  • See table Hazards of Screening Younger Women.

  • See module Screening for Breast Cancer.

Evidence
  • The ACP High Value Care Task Force published advice on screening for cancer and advice on a value framework for cancer screening which provided suggested screening practices for patients at average risk for developing breast, cervical, ovarian, prostate, or colorectal cancers. The task force based their high-value care advice on their narrative review of clinical guidelines and evidence syntheses from the relevant major medical societies, the U.S. Preventive Services Task Force, the American Cancer Society, and additional literature searches on databases for modeling studies and cost estimations (26; 27).

  • A 2007 American College of Physicians guideline on breast cancer screening in women aged 40 to 49 recommended discussion of screening mammography with individualized assessments of the benefits and harms and decisions based on patient preferences (28)

  • A 2009 U.S. Preventive Services Task Force guideline recommended biennial screening mammography beginning at age 50 until age 74, with individualized decision making in women aged 40 to 49 (22).

  • A guideline from the American Cancer Society (updated online in 2013) recommended yearly mammograms starting at age 40, with no upper age described.

  • A 2011 guideline from the American College of Obstetricians and Gynecologists recommended annual screening beginning at age 40 (23).

  • A 2013 Cochrane review of breast cancer screening with mammography included 7 trials, many of which had significant bias. Overall, mammography was associated with lower breast cancer mortality (RR, 0.81 [CI, 0.74 to 0.87]); three trials with adequate randomization showed that mammography did not reduce breast cancer mortality (RR, 0.90 [CI, 0.79 to 1.02]), and 4 trials without adequate randomization showed that mammography did reduce breast cancer mortality (RR, 0.75 [CI, 0.67 to 0.83]). Trials with adequate randomization found that mammography did not reduce total cancer mortality at 10 years (RR, 1.02 [CI, 0.95 to 1.10]) or total mortality at 13 years (RR, 0.99 [CI, 0.95 to 1.03]). Mammography was associated with a greater number of mastectomies (RR, 1.20 [CI, 1.08 to 1.32]) (29).

  • A 2009 systematic review of the effect of screening mammography on mortality for the U.S. Preventive Services Task Force included 8 trials. Screening reduced breast cancer mortality in women aged 39 to 49 (RR, 0.85 [CI, 0.75 to 0.96]; number-needed-to-invite-to-screen, 1904), 50 to 59 (RR, 0.86 [CI, 0.75 to 0.99]; number-needed-to-invite-to-screen, 1339), and 60 to 69 (RR, 0.68 [CI, 0.54 to 0.87]; number-needed-to-invite-to-screen, 377). There were insufficient data to draw conclusions regarding women aged 70 or older. Also reviewed were the potential harms of screening mammography, which included false-positive results, the need for additional imaging, and overdiagnosis in an estimated 1% to 10% (30).

  • A retrospective study done in a population-based screening center compared rates of detection of breast cancer among 31,720 screen-film mammograms and 8478 full-field digital mammograms (with hard-copy image reading). There were no significant differences in detection rates (0.72 vs. 0.68 per 100 screening mammograms), recall rates (3.4% vs. 3.2%), or positive predictive value (31).

  • A retrospective review of the Finnish Cancer Registry found a hazard ratio of 1.90 for distant recurrence among women with tumors detected outside of routine mammographic screening (32).

Rationale
  • Screening mammography decreases breast cancer mortality in women aged 40 to 69, although the magnitude of benefit is less in women younger than 50.

  • The benefits of screening mammography must be weighed against the possible harms, which include false-positive results that can result in biopsies in women without cancer, psychological harm, and unnecessary imaging tests; overdiagnosis (treatment of a cancer that would not become clinically apparent during a woman's lifetime; unnecessarily early treatment of a breast cancer that would have become apparent during a woman's lifetime); unnecessarily early treatment of a breast cancer that would have become apparent but not have shortened the patient's life; possible harm from radiation exposure; procedure-associated pain; and false reassurance.

  • Older women who are likely to die of other diseases may not benefit from breast cancer screening but are still subject to its potential harms.

Comments
  • Early initiation of mammography and clinical screening should be especially considered in high-risk individuals, based either on family history or on the identification of predisposing genetic mutations (33), although there are limited prospective data to support this strategy.

  • Women at high risk (greater than 20% lifetime risk) should have an annual MRI in addition to mammography, and the benefits of adding MRI as a screening tool should be discussed with women at moderate risk (15% to 20% lifetime risk). MRI should also be considered in women with a history of radiation and in women aged 25 or younger with positive genetic pedigrees.

  • An analysis of the relative contributions of screening and new therapies on reducing mortality from breast cancer found that screening contributed between 28% and 65% in 7 different models (34).

  • The medical profession and public are increasingly aware of the potential harms of screening women in their 40s (false-positive results, increased anxiety, unnecessary visits, further imaging and biopsy, false reassurance).

  • The 25% reduction in breast cancer mortality in the United States from 1990 to 2002 was partially attributable to earlier detection with mammographic screening (35). A transient decrease of about 7% in breast cancer incidence after 2002 was attributed to decreased use of hormone therapy (36).

  • Breast cancer risk increases with age, but older women will derive fewer benefits from screening mammography due to limited life expectancy and competing causes of death from comorbidities. False-positive results are a potential downside to screening, and older patients are at higher risk from general anesthesia performed for diagnostic excision biopsies resulting from indeterminate imaging and percutaneous needle biopsy results.

Consider specialized screening strategies for women at higher risk for breast cancer, in particular women with a genetic predisposition.  
  • Consider referring women with a strong family history for breast cancer at a young age (younger than 50), particularly if it is associated with ovarian cancer at any age, for genetic counseling and possibly genetic testing.

  • In this group of women, begin screening 5 to 10 years earlier than the age when breast cancer occurred in a first- or second-degree relative.

  • For women with known BRCA1 and BRCA2 mutations, begin screening around age 25.

  • Consider use of screening MRI in high-risk young women, particularly in women younger than 40, in whom mammography will be insensitive.

  • Consider genetic counseling an integral step before genetic testing.

  • Consider prevention strategies with medication and mastectomy in women at high risk for breast cancer, particularly those with genetic mutations.

  • Consider using the Breast Cancer Risk Assessment Tool to estimate a woman's risk for developing invasive breast cancer compared with a woman of the same age who is at average risk.

Evidence
  • A guideline from the American Cancer Society (updated online in 2013) on screening for breast cancer recommended annual MRI and mammography in women at increased risk (lifetime risk greater than 20%), including those with known BRCA mutations, and recommended considering adding annual MRI in women with a lifetime risk of 15% to 20%.

  • A 2008 systematic review of the diagnostic accuracy of mammography with or without MRI in breast cancer screening included 11 prospective trials of high-risk women. The summary negative likelihood ratio was 0.14 for the combination of MRI and mammography compared with 0.70 for mammography alone. The summary positive likelihood ratio was 16.4 for the combination of MRI and mammography and 24.8 for mammography alone (37).

  • A 2007 systematic review of the accuracy of MRI compared with other strategies for screening young women at high risk for breast cancer included 5 studies. Overall, MRI had a sensitivity of 93% to 100% compared with a sensitivity of 25% to 59% for mammography alone and 49% to 67% for mammography plus ultrasound. The specificity of MRI was difficult to estimate but appeared to be poorer than that of mammography (38).

  • A study pooled data from different cohorts to estimate the average lifetime risk for cancer in patients with BRCA1 and BRCA2 mutations. The average cumulative risks for breast and ovarian cancers by age 70 were 65% (CI, 44% to 78%) and 39% (CI, 18% to 54%), respectively, for patients with BRCA1 and 45% (31% to 56%) and 11% (2.4% to 19%) for those with BRCA2 (39).

Rationale
  • Germ-line mutations in the BRCA1 and BRCA2 genes increase the lifetime risk for developing breast cancer and ovarian cancer and may therefore influence screening and prevention strategies.

  • MRI has been shown to be more accurate than mammography in high-risk young women, but no studies have demonstrated the impact of screening with MRI on mortality or other outcomes.

Comments
  • The BRCA1 and BRCA2 cancer susceptibility genes, located on chromosomes 17q21 and 13q12, respectively, are autosomally dominant genes with variable penetrance.

  • Some ethnic groups (e.g., Ashkenazi Jews, Icelanders, and others) have an increased rate of mutation carriers. The proportion of hereditary cancers is higher within these populations.

  • The pretest probability for a BRCA1 or BRCA2 mutation is higher in women with a strong family history of cancer and/or early age of onset. Mutations within these two genes are uncommon in sporadic forms of breast cancer, and the prevalence within the population is only 0.001% (40).

  • As BRCA1 and BRCA2 are transmitted through an autosomal dominant pattern of inheritance (i.e., either paternal or maternal), a mutation should first be looked for in an affected individual (with a known diagnosis of breast or ovarian cancer, a proband). Once a mutation has been identified within a family, other family members can be tested for that particular mutation.

  • Data seem to suggest that breast cancer survival in these women is similar to survival in women who do not have a mutation in one of these genes (41).

Perform a careful exam in a woman with new breast symptoms, clinical findings, or an abnormal mammogram.  
  • Assess the underlying risk for breast cancer:

    • Review gynecologic and obstetrical history, such as age of menarche, age at first full-term pregnancy, breast feeding, and menopausal status

    • Inquire about the use of hormonal therapies and history of previous breast biopsies

    • Note that the incidence of breast cancer rises with age

    • Carefully review paternal and maternal family history in a woman with new breast symptoms for features suggestive of a genetic syndrome, including bilateral breast cancer, early onset breast cancer (before age 40), male breast cancer, ovarian cancer at any age, and other malignancies, such as prostate cancer, melanoma, and pancreatic cancer.

  • Carefully review potential symptoms suggesting advanced disease, such as weight loss, unusual cough, skeletal pain, or changes in mood or behavior (reported by either the patient or by close relatives).

  • Perform a thorough breast exam, including careful examination of both breasts and supraclavicular/axillary nodal basins.

    • Look for masses, skin changes such as erythema or peau d’orange, dimpling, nipple retraction or discharge, and axillary lymph nodes

    • In this initial clinical examination, aim to establish whether a dominant mass or localized glandular nodularity is present

    • Understand that most of the breast parenchyma is concentrated in the retroareolar region and upper outer quadrant of the breast and that most breast cancers occur in these areas

    • Know that suspicious findings on clinical exam include single lesion, firm consistency, immobility, irregular shape, and rapid growth

  • Note that women with new breast masses generally do not report pain, and symptoms of pain and/or tenderness are more likely to be associated with benign breast changes.

  • See figure Inflammatory Breast Cancer.

  • See figure Peau d’orange.

  • See figure Axillary Vein Thrombosis.

Evidence
  • A 2012 ICSI guideline on the diagnosis of breast disease recommended beginning with a history and physical exam in patients with breast symptoms, and noted that the physical exam should include inspection of the skin and nipple and palpation in the upright and supine positions.

  • A 2012 systematic review of risk factors for breast cancer in women aged 40 to 49 included 66 studies. Risk factors included having one or more first-degree relatives with breast cancer (RR, 1.86 [CI, 1.69 to 2.06]), having a relative diagnosed before age 50 (RR, 2.17 [CI, 1.86 to 2.53]), history of previous breast procedures (RR, 1.51 [CI, 1.36 to 1.67]), and having dense breasts (RR, 2.33 [CI, 2.04 to 2.66], for the most dense compared with the least dense category). Women who were overweight (RR, 0.86 [CI, 0.82 to 0.90]) and obese (RR, 0.74 [CI, 0.68 to 0.81]) were at lower risk than women with low or normal weight (42).

  • A 1999 systematic review assessed the diagnostic accuracy of the breast exam. The screening clinical breast exam had a pooled sensitivity of 54% (CI, 48% to 60%) and a pooled specificity of 94% (CI, 90% to 97%); longer duration of the exam was associated with better sensitivity. The review also described appropriate technique (43).

  • A cohort study used data from the Women's Health Initiative to determine risk factors for breast cancer in women older than 50. Risk factors for breast cancer included older age (HR, 1.22 [CI, 1.17 to 1.26] per standard deviation), white race (HR, 1.18 [CI, 1.10 to 1.28]), previous breast aspirations (HR, 1.18 [CI, 1.15 to 1.22], for any vs. none) or biopsies (HR, 1.33 [CI, 1.26 to 1.42]), breast cancer in a first-degree relative (HR, 1.41 [CI, 1.32 to 1.51]), years of hormone therapy (HR, 1.56 [CI, 1.34 to 1.82], for more than 15 years compared with never use), absence of live births (HR, 0.86 [CI, 0.80 to 0.93], for 1 to 4 births compared with no births), older age at menopause (HR, 1.11 [CI, 1.07 to 1.15], for every 10 years), weight >200 lbs (HR, 1.43 [CI, 1.32 to 1.55]), history of thyroid cancer (HR, 2.04 [CI, 1.55 to 2.68]), more than one serving of alcohol per week (HR, 1.13 [CI, 1.05 to 1.20], compared with none), and having a relative with prostate cancer (HR, 1.15 [CI, 1.06 to 1.25]) (44).

  • The Women's Health Initiative randomized trial compared conjugated equine estrogens with medroxyprogesterone acetate with placebo in almost 17,000 postmenopausal women with an intact uterus. After a mean intervention period of 5.6 years and a mean follow-up of 7.9 years, hormone therapy increased the incidence of invasive breast cancer (HR, 1.25 [CI, 1.07 to 1.46]; P=0.004; number needed to harm, 1285 per year) and disease-specific mortality (HR, 1.96 [CI, 1.0 to 4.04]; P=0.049) (45; 46).

  • A 2013 systematic review of the association between oral contraceptive use and cancer included 44 studies of breast cancer. The risk for breast cancer was slightly higher in ever-users of oral contraceptives (OR, 1.08 [CI, 1.00 to 1.17]), but there was no relationship between duration of use and the risk for cancer (47).

  • A retrospective cohort study evaluated the risk for breast cancer associated with breast symptoms in women who received screening or diagnostic mammograms. Among women having screening mammograms, risk factors for breast cancer included any breast symptoms (OR, 2.1 [CI, 1.6 to 2.7]), lumps (OR, 3.6 [CI, 2.6 to 5.0]), and nipple discharge (OR, 1.8 [CI, 1.0 to 3.4]) (48).

  • A randomized trial compared clinical breast exam to usual care (no screening) in India. Preliminary results after the first screening round estimated that clinical breast exam had a sensitivity of 51.7% and a specificity of 94.3% (49).

  • A population-based cohort study evaluated the proportion of patients with cancer in Sweden with a family history. Among patients with breast cancer, 13.6% had a family history (50).

Rationale
  • Although most patients are now diagnosed with subclinical disease, physical exam findings are helpful in identifying potentially suspicious abnormalities.

Comments
  • Clinical assessment of axillary nodes is notoriously inaccurate, with a 30% error either way; ultrasound is increasingly being used to examine the axillary nodes in patients with a newly diagnosed breast cancer and to potentially deselect patients for sentinel lymph-node biopsy.

  • The observed decrease in breast cancer incidence after 2002 has been attributed to reduced prescriptions for combined estrogen and progestin hormone replacement therapy. One-quarter of women in the U.K. aged 45 to 69 years were taking exogenous hormones in 2000, but this number was halved after 2002 and continues to fall (51).

Perform ultrasound and/or mammography to evaluate a new abnormal breast exam finding, depending on age.  
  • Request mammography and ultrasound in women older than age 30 with any new breast symptom or abnormal finding on physical examination, and request ultrasound in women younger than age 30 with an abnormal finding on physical examination

    • Request mammography in women younger than age 30 with sonographic evidence of a carcinoma

    • Note that young women are more likely to have a benign process rather than breast cancer, and breast imaging may not be required at the time of presentation if they are younger than 30 without a discrete breast lump

    • Always compare current and previous imaging studies

  • Consider the pretest probability of breast cancer when interpreting imaging tests:

    • Recognize that a family history of and known genetic predisposition to breast cancer increases the likelihood that a mammographic or clinical abnormality will represent a new breast cancer

    • Recognize that a negative imaging evaluation does not rule out breast cancer, especially in high-risk women

    • Consider the need for tissue diagnosis in high-risk women regardless of the results of imaging tests

  • Obtain ultrasound of the ipsilateral axillary nodes before breast biopsy.

  • If abnormal findings are not being evaluated with biopsy, ensure that the patient understands the need for timely repeated imaging and careful follow-up.

  • Instruct patients to return for further evaluation if a lump increases in size or fails to resolve clinically within a specified period.

  • Ensure that the imaging procedure is performed in a certified facility.

  • See table Evaluation of Clinical Breast Abnormalities.

  • See table Differential Diagnosis of Breast Mass.

Evidence
  • A 2012 ICSI guideline on the diagnosis of breast disease recommended that patients with a breast mass undergo a diagnostic mammogram and ultrasound (age 30 or older) or ultrasound alone (younger than age 30), with further work-up depending on the imaging results.

  • A large prospective cohort study evaluated the accuracy of diagnostic mammography in women with signs and symptoms of breast cancer. Overall, the sensitivity was 85.8% and the specificity was 87.7%. In the multivariate analysis, the sensitivity was higher among women with a self-reported breast lump, with no previous mammogram, and without dense breasts. Patient age did not affect sensitivity (52).

Rationale
  • Although most women with abnormal findings on breast exam (new lump, skin dimpling, nipple retraction, erythema, scaliness of the nipple or breast skin, or nipple discharge) do not have breast cancer, these changes mandate a careful evaluation and follow-up.

  • All suspicious clinical and radiological findings should be considered for possible tissue diagnosis; low risk or stable findings may be followed without any immediate intervention.

Counsel women on the significance of mammographically dense breasts.  
  • Understand that breast density on mammography is associated with an increased risk for being diagnosed with breast cancer but not with breast cancer mortality.

  • In women with mammographically dense breasts:

    • Consider ultrasound as an adjunctive screening tests in women with other risk factors for breast cancer

    • Do not routinely order ultrasound in women without additional risk factors for breast cancer

Evidence
  • A 2014 guideline from the American College of Obstetricians and Gynecologists on the management of women with mammographically dense breasts recommended against additional adjunctive tests (aside from mammography) to screen women with dense breasts unless they have additional risk factors for breast cancer.

  • A 2009 systematic review of the benefits of supplemental ultrasound in women with mammographically dense breasts included six cohort studies. In women with dense breasts, ultrasound led to breast biopsy in 2.3% to 4.7% and to a diagnosis of breast cancer in 0.32%; most of these cancers were early stage (53).

  • A population-based study evaluated the prognostic significance of breast density on mammography in intermediate-risk women. In the multivariate model, dense breasts on mammography were associated with increased risk for breast cancer (OR, 1.9 [CI, 1.3 to 2.8]) (54).

  • A retrospective cohort study evaluated the relationship between breast density and breast cancer mortality in black and white women who were screened for breast cancer in community settings. After adjusting for known risk factors, breast density on mammography was not associated with breast cancer mortality (55).

Rationale
  • Dense breasts on mammography are associated with the diagnosis of breast cancer but not with breast cancer mortality.

Comments
  • Several states mandate that women with dense breasts on screening mammography be informed that they may be at increased risk for breast cancer and that further imaging may be helpful.

Obtain a tissue diagnosis in women with a suspicious radiologic abnormality or a clinically suspicious breast exam finding. 
  • Obtain an image-guided core needle biopsy or fine-needle aspiration for cytology in patients with

    • A suspicious finding on mammogram or ultrasound

    • A suspicious finding on physical exam

    • Mastitis whose symptoms do not resolve after 7 to 10 days of antibiotics

  • Refer patients with mammographic abnormalities to an experienced breast radiologist for tissue sampling under ultrasound guidance or using stereotactic mammography.

  • Do not perform MRI before tissue biopsy in patients with abnormal findings on other imaging tests.

  • If there is spontaneous nipple discharge fluid, express material manually and send a sample for cytopathology examination.

  • If the histopathology confirms invasive breast cancer of high-risk DCIS, request special studies for estrogen/progesterone receptors (immunohistochemistry) and, possibly, for HER2 overexpression (FISH, CISH, or immunohistochemistry).

  • See table Differential Diagnosis of Breast Mass.

Evidence
  • A 2012 ICSI guideline on the diagnosis of breast disease recommended that patients with a breast mass and imaging showing a solid mass undergo imaging-guided core needle biopsy and that patients with a palpable mass and negative imaging be referred to a surgeon.

  • A 2013 guideline from the American Society of Clinical Oncology and the College of American Pathologists recommended HER2 testing in all patients with invasive breast cancer (56).

  • A 2010 systematic review of the accuracy of core needle compared with surgical biopsy for the diagnosis of breast cancer included a total of 107 studies. Surgical biopsy had a pooled sensitivity of 9% to 99%; stereotactic biopsy had a sensitivity of 97.8% to 99.2%; ultrasound-guided biopsy had a sensitivity of 96.5% to 97.7%; MRI-guided biopsy had a sensitivity of 83.3% (in 1 very small study); and freehand biopsy had a sensitivity of 85.5%. Core needle biopsy had a lower rate of complications than surgical biopsy (57).

  • A 2003 systematic review of tests in women with abnormal breast exam or breast imaging findings included 3 studies. Diagnostic mammography had a sensitivity of 87.3% and a specificity of 84.5% in patients with palpable lumps and a sensitivity of 82.3% and a specificity of 91.2% in those with nonpalpable abnormalities. Fine-needle aspirational biopsy had a sensitivity of 77% to 97% and a specificity of 78% to 98% for nonpalpable masses; core biopsy had a sensitivity of 93% to 98% and a specificity of 95% to 100% for nonpalpable masses (58).

  • A prospective cohort study evaluated the diagnostic value of breast ultrasound in 2020 patients undergoing mammography and clinical breast exam. Mammogram with clinical breast exam plus ultrasound had a sensitivity of 96.9% and a specificity of 94.8%; mammogram with clinical breast exam alone had a sensitivity of 91.5% and a specificity of 87.0%. Ultrasound added significantly to the diagnostic performance in patients with breast lumps, especially those younger than age 50 with breast lumps (59).

  • A study evaluated the sensitivity and specificity of immunohistochemical testing to differentiate breast cancer metastases from other metastatic disease. The combination of estrogen and progesterone receptors and gross cystic disease fluid protein 15 had a sensitivity of 83% and a specificity of 98%, although the analysis excluded ovarian cancers (60).

  • A randomized trial compared MRI with no additional imaging before biopsy in patients with suspected nonpalpable breast cancer; the primary outcome was the rate of additional surgical procedures. The rate of primary breast-conserving surgery was similar in both groups, but the MRI group had a higher rate of re-excision due to positive margins (34% vs. 12%; P=0.008) (61).

Rationale
  • Tissue examination is essential for diagnosis and therapeutic management.

  • Hormone receptor and HER2 assays should be done on core biopsy material in order to assist with formulation of a management plan.

Comments
  • A diagnostic excision biopsy potentially increases the number of operative procedures to the breast and should be avoided with appropriate use of image-guided percutaneous biopsy techniques (including use of vacuum-assisted devices).

  • Wide-bore needle biopsy maintains tissue architecture and thus permits diagnosis of invasion on the basis of cancer cells within the stromal compartment (beyond the basement membrane).

  • Be aware that a ductogram may help locate a small intraductal lesion (benign or malignant).

  • Be aware that fine-needle aspiration cannot differentiate between invasive and noninvasive (e.g., DCIS) cancer and that benign proliferative lesions may be difficult to differentiate histologically from malignancy on the basis of fine-needle aspiration only.

  • Note that tissue diagnosis is not necessary for simple benign cysts or most fibroadenomas in patients younger than age 25.

Perform breast imaging in patients with an axillary nodal mass involved with carcinoma. 
  • Perform mammography, and consider ultrasound or MRI imaging in patients with an isolated axillary mass when a primary breast tumor is not clinically obvious.

  • If there is no evidence of a tumor within the breast either on clinical exam or imaging, perform percutaneous core biopsy of the axillary mass for histologic diagnosis.

Evidence
  • A 2010 systematic review of the diagnostic utility of MRI in patients with metastatic axillary lymphadenopathy and no obvious primary breast tumor included 8 studies. A suspicious lesion on breast MRI had a pooled mean sensitivity of 72% and a specificity of 90% in patients with axillary lymphadenopathy (62).

  • A case report described a woman with axillary metastatic disease and an occult primary breast tumor (63).

  • A 1957 case series of patients with isolated unilateral axillary lymphadenopathy reported the final diagnosis after surgical resection. Overall, 70% had nonspecific changes. The most common malignancy found was lymphoma, followed by breast cancer (64).

Rationale
  • Breast cancer is the most common cause of isolated axillary metastases in a postmenopausal woman with no evidence of a primary tumor.

Look for axillary metastases following tissue confirmation of a breast cancer diagnosis (in situ or invasive) before performing definitive surgery. 
  • Perform axillary staging with ultrasound before surgery in patients diagnosed with breast cancer.

  • Do not routinely obtain a bone scan, computed tomography, or tumor markers in patients with either in situ or invasive breast cancer.

    • Reserve computed tomography for patients with large primary tumors or known axillary disease

    • Reserve bone scans for patients with bone pain

  • Perform a limited preoperative assessment since breast surgeries are low-risk procedures.

  • See module Preoperative Evaluation.

Evidence
  • A 2009 NICE (U.K.) guideline on the diagnosis and treatment of early and locally advanced breast cancer recommended performing axillary ultrasound for staging before surgery.

  • A 2010 systematic review of FDG-PET in breast cancer diagnosis and staging included 73 studies. FDG-PET had a sensitivity of 20% for the detection of axillary metastases and of 50% for micrometastases (65).

  • A 2011 systematic review of the accuracy of preoperative ultrasound-guided needle biopsy of axillary nodes in patients undergoing surgery for breast cancer included 31 studies. Ultrasound-guided biopsy had a sensitivity of 79.6% and a specificity of 98.3% for the detection of metastatic axillary lymph nodes (66).

  • A retrospective cohort study assessed the diagnostic value of preoperative axillary lymphadenopathy for the detection of axillary node metastases in patients undergoing surgery for primary breast cancer. Ultrasound had a sensitivity of 62% and a specificity of 77% (65).

  • A 2008 systematic review of MRI for breast cancer staging included 19 studies. MRI detected additional disease in 16% of patients with breast cancer. The summary positive predictive value was 66% (67).

Rationale
  • Breast surgery is a low-risk surgical procedure, and minimal preoperative evaluation is required.

  • Fewer than 5% of patients present with clinical or radiologic evidence of overt metastatic disease, although many will have micrometastatic disease at the time of diagnosis.

  • Screening for metastatic disease is not recommended for patients with in situ tumors.

Comments
  • A 2013 NCCN guideline on the treatment of breast cancer can be accessed by clinicians through the NCCN web site.

  • Most patients with in situ disease only on core biopsy are not by definition at risk for distant metastatic disease, but some will be found to have invasion on final exam of the resected specimen.

  • Staging CT of the chest, abdomen, and pelvis is often recommended for asymptomatic patients with large primary tumors (>5 cm) or confirmed axillary metastases (ultrasound with or without core biopsy).

  • CT with “bone windows” should be done for asymptomatic patients to exclude bone metastases, whereas a bone scan is more appropriate for symptomatic patients (e.g., patients with back or hip pain).

Ensure careful pathologic evaluation of biopsy or surgical specimens. 
  • Understand that accurate pathologic evaluation is critical for determining appropriate additional therapy.

  • Understand that features of the primary tumor in the pathology report include

    • Histologic diagnosis (tumor type)

    • Tumor size

    • Adequacy of margins (particularly radial margins, including medial, lateral, inferior, and superior)

    • Extent of noninvasive component

    • The presence or absence of lymphovascular invasion

  • Understand that lymph node evaluation includes

    • The total number of nodes retrieved

    • The number and size of involved nodes

    • The size of any tumor deposits (macrometastases [>2 mm]), micrometastases [≤2 mm and >0.2 mm]) or isolated tumor cells (≤0.2 mm), and presence of extracapsular extension

  • Recognize that sentinel lymph nodes are subjected to more intensive pathologic scrutiny than routine lymph-node assessment and that isolated tumor cells may only be evident on immunohistochemistry.

  • Note the immunohistochemistry results for estrogen and progesterone receptors and HER2/neu from the core biopsy material; request FISH evaluation of HER2/neu gene amplification for immunohistochemistry scores of 2+.

Evidence
  • A 2013 guideline from the American Society of Clinical Oncology and the College of American Pathologists recommended HER2 testing in all patients with invasive breast cancer (56).

  • A 2010 guideline from the American Society of Clinical Oncology and the College of American Pathologists on immunohistochemical testing in breast cancer recommended that testing be performed for estrogen and progesterone receptors (68).

  • A 2009 NICE (U.K.) guideline on the diagnosis and treatment of early and locally advanced breast cancer recommended testing all cancers for estrogen receptor status and HER2.

Rationale
  • These factors are important to assess adequacy of surgery and need for additional locoregional treatment (cavity re-excision, mastectomy, completion axillary dissection or radiation therapy to the breast, chest wall, or supraclavicular fossa) or systemic therapy (chemotherapy, hormonal therapy, and/or trastuzumab).

  • HER2 status helps guide initial clinical decision making (e.g., neoadjuvant chemotherapy vs. primary surgery).

Stage breast cancer using the TNM staging system.  
  • Consider imaging studies in patients with suspected metastatic disease, including

    • Bone scan in patients with bone pain or elevated alkaline phosphatase

    • Chest x-ray or CT scan in patients with cough, shortness of breath, or other chest complaints

    • Abdominal CT or liver ultrasound in patients with abnormal liver function tests, elevated alkaline phosphatase, or unexplained abdominal pain

  • Use data from the clinical exam, imaging studies, and surgery to determine tumor stage.

  • Understand that tumor staging using a combination of tumor size (T), axillary nodal status (N), and presence or absence of metastatic disease (M) forms the basis of the TNM staging system.

  • Consider performing a mulitgene assay for additional prognostic information.

  • See the National Cancer Institute web site for a description of TNM staging.

Evidence
  • A 2014 NICE (U.K.) guideline on the diagnosis and treatment of advanced breast cancer recommended using x-rays, ultrasound, CT, and MRI to assess visceral involvement; using CT or MRI to assess skeletal metastases; assessing for the risk for pathologic fractures using bone scans or x-rays; and using MRI to assess for bone metastases if other testing is equivocal. The guideline recommended against PET scanning to assess the extent of disease.

  • A 2001 systematic review of the yield of diagnostic testing for the staging of breast cancer included studies of a variety of tests. In studies performed between 1985 and 1995, bone scans detected skeletal metastases in 0.5% of patients with stage I disease, 2.4% with stage II disease, and 8.3% with stage III disease, with false-positive rates of 10% to 22%. Studies of liver ultrasound found the detection of liver metastases in no patients with stage I disease, 0.4% with stage II disease, and 2% with stage III disease, with false-positive rates between 33% and 66%. Chest x-ray detected very few (less than 1.7% in all stages) cases of lung metastases (69).

  • A retrospective cohort study evaluated the diagnostic yield of imaging tests to stage patients with newly diagnosed breast cancer. All patients with metastatic disease on either liver ultrasound or chest x-ray (less than 1% of patients) were previously classified as having stage III disease. Bone scanning detected skeletal metastases in 6.3% of patients, among whom 30% had been previously classified with stage III disease (70).

  • A 2010 assessment of a mulitgene assay in women with newly diagnosed breast cancer included 5 studies addressing the prognostic and predictive value. Overall, the quality of the evidence was poor and the value of the assay was not clear (71).

  • A 2010 editorial discussed changes in the AJCC 7th edition staging manual (72).

Rationale
  • Tumor staging at diagnosis, especially tumor size and axillary nodal status, is the most important prognostic factor and will determine therapy options.

Comments
  • Oncotype DX is an example of a multigene assay. It is expensive ($3000 per assay), and to date, there have been no studies independent of Genomic Health that have critically analyzed the correlation between conventional histopathologic parameters and Oncotype DX recurrence score.

  • Adjuvant! Online is an online tool to help clinicians provide patients with accurate information about the benefits and harms of adjuvant therapies for early breast cancer.

Consult a surgeon or breast radiologist for biopsy of any suspicious clinical or mammographic breast abnormality; refer patients to a comprehensive breast center if available. 
  • Obtain appropriate consultation from a radiologist specializing in breast disease and a surgeon to perform a biopsy of any suspicious breast mass.

  • Understand that image-guided needle biopsy is the preferred initial technique, with open biopsy reserved for indeterminate core biopsy/cytology results or technically challenging cases (e.g., abnormalities lying close to the chest wall).

  • Consult an appropriate oncology specialist for help with further management (staging and treatment) of breast cancer once a diagnosis has been confirmed on tissue biopsy.

Evidence
  • A retrospective study assessed the accuracy of a diagnosis of benign breast disease at a comprehensive breast clinic. Among 7004 patients discharged with benign disease over a 3-year period, 29 developed breast cancer (0.4%) (73).

  • A retrospective cohort study evaluated the impact of surgeon specialization on patient outcomes from breast cancer in Scotland. After controlling for confounders, after implementation of a screening program, patients under the care of specialized breast surgeons had lower mortality than those under the care of generalist surgeons (RR, 0.89 [CI, 0.78 to 1.00]) (74).

Rationale
  • Interdisciplinary consultation is necessary for accurate evaluation of mammographic abnormalities and to obtain a tissue diagnosis for any suspicious palpable or nonpalpable abnormality.

Consult appropriate specialists to provide patients with optimal multifaceted breast cancer care. 
  • Consider consulting the following specialists in the management of patients with breast cancer:

    • Breast radiologists for ongoing imaging surveillance

    • Breast surgeons for definitive surgical treatment and breast reconstruction as needed

    • Radiation therapists for postoperative radiation

    • Medical oncologists for determining the role for adjuvant systemic therapy

    • Physical therapists specializing in lymphedema therapy and postaxillary surgery rehabilitation

    • Social workers for assistance with financial and work-related issues arising from therapy

    • Psychologists and/or psychiatrists when diagnosis- and treatment-related anxiety and/or depression arises

Evidence
  • Consensus.

Rationale
  • The optimal treatment of breast cancer often involves complex decisions, and patients are likely to benefit from a multidisciplinary approach.

Comments
  • Breast centers may be organized in either a one-stop setting in which a patient sees all the different specialists during one visit or in a more traditional setting in which separate appointments with providers from different specialties are scheduled. There are no data to suggest one system is better than the other.

Consider hospitalizing patients with breast cancer who require definitive surgery or breast reconstruction. 
  • Consider hospitalization of patients with breast cancer for lumpectomy (wide local excision), mastectomy, sentinel lymph-node biopsy, axillary-node dissection, or reconstructive procedures with tissue transfer techniques, such as TRAM, DIEAP, or latissimus dorsi flap.

  • Note that some of these procedures can frequently be performed as ambulatory surgery in patients with a new diagnosis of operable breast cancer.

  • Understand that patients choosing immediate breast reconstruction with implant or flap-based techniques, such as TRAM, DIEAP, or latissimus dorsi flap, will require a short hospitalization ranging typically from 5 to 8 days.

  • Hospitalize patients who are acutely ill with more advanced stages of breast cancer and require intensive diagnostic and management intervention.

Evidence
  • Mainly consensus.

Rationale
  • The need for hospitalization of patients with breast cancer depends on the procedure required and available resources both in and outside the hospital.

Comments
  • Most patients undergoing nonreconstructive surgery for breast cancer require only a brief period of hospitalization. Lumpectomy (wide local excision) and sentinel lymph-node biopsy are increasingly being done as day-case procedures (no wound drains required).

  • Patients undergoing either mastectomy and/or axillary dissection can potentially be discharged with drains in situ. The drains can be removed by local practice nurses provided they have received appropriate training and work closely with hospital-based physicians. Patients undergoing immediate breast reconstruction can sometimes be discharged before removal of all drains (especially the donor site on the back after latissimus dorsi flap reconstruction).

Select local therapy (mastectomy or breast conservation) based on tumor size, location, and clinical stage of the disease. 
  • Consider lumpectomy and postoperative radiation therapy

    • For patients with unifocal disease

    • When breast conservation surgery is likely to achieve surgical margin clearance together with a good cosmetic result (e.g., tumors <3 cm in size and located >2 cm from the edge of the nipple-areolar complex)

    • Consider MRI of the breasts for selected patients in whom breast conservation therapy is contemplated (lobular phenotype, to clarify unifocality when suspicion of satellite lesions on mammography or ultrasound exists, to assess the contralateral breast in patients with a genetic predisposition to breast cancer)

  • Recognize the probable need for mastectomy in patients with multicentric disease or when a poor cosmetic result is predicted due to a relatively large tumor in a small breast (unfavorable tumor/breast size ratio).

    • Consider immediate whole breast reconstruction with autologous tissue transfer or silicone implant for patients who require mastectomy

  • Consider primary systemic therapy to reduce tumor size (downstage) and permit breast conservation in patients who would otherwise require a mastectomy or as initial management of locally advanced disease which may be technically inoperable at presentation (e.g., large tumors >5 cm invading chest wall or skin)

  • Understand that patient preference may influence the choice of primary surgical treatment, particularly in older patients for whom issues of body image and sexual functioning may be less important.

  • Understand that the primary goal of surgery in patients with evidence of metastatic disease at presentation is palliative and aims to maximize locoregional control without attaining cure.

Evidence
  • A 2009 NICE (U.K.) guideline on the management of early and locally advanced breast cancer recommended surgery and systemic therapy for patients with early invasive breast cancer, and advised considering preoperative systemic therapy for those who are initially not candidates for breast-conserving therapy. The guideline also recommended that patients with DCIS be offered breast-conserving surgery with a 2-mm disease-free margin.

  • A 2006 guideline from the American College of Radiology, the American College of Surgeons, the College of American Pathologists, and the Society of Surgical Oncology for breast conservation therapy for invasive breast cancer stated that contraindications to breast-conserving therapy include pregnancy, 2 or more tumors in separate breast quadrants or evidence of diffuse calcifications, previous irradiation to the same breast region, and positive margins after a previous surgical attempt. Relative contraindications included collagen vascular disease, tumor size >4 to 5 cm, and breast size (75).

  • A 2005 meta-analysis of neoadjuvant vs. adjuvant chemotherapy for early stage breast cancer included 9 randomized trials with 3946 participants. There was no difference in mortality, disease progression, or recurrence between the groups, although the neoadjuvant group had a higher rate of local or regional recurrence (RR, 1.22 [CI, 1.04 to 1.43]) (76).

  • A 2011 Cochrane review of immediate versus delayed reconstruction after breast cancer surgery included 1 randomized trial with 64 participants and a high risk for bias. There were no apparent differences between the groups (77).

  • A randomized trial compared lumpectomy, lumpectomy plus radiation therapy, and mastectomy in women with invasive breast cancer. After a follow-up time of 20 years, there was no difference in overall survival or disease-free survival among the groups (78).

  • A randomized trial compared breast-conserving therapy plus radiation therapy with radical mastectomy in women with invasive breast cancer and tumors up to 2 cm in diameter. After a follow-up time of 20 years, mortality did not differ between the groups (41% to 42%). Rates of local recurrence were higher in the breast-conserving therapy group (8.8% vs. 2.3%; P<0.001) (79).

  • A 2006 Cochrane review of surgery versus primary endocrine therapy for patients aged 70 and older with breast cancer included 6 trials. Surgery did not improve overall survival (HR, 0.98 [CI, 0.74 to 1.30], for surgery compared with endocrine therapy; HR, 0.86 [CI, 0.73 to 1.00], for surgery plus endocrine therapy compared with endocrine therapy alone) but did improve progression-free survival (HR, 0.65 [CI, 0.53 to 0.81], for surgery plus endocrine therapy compared with endocrine therapy alone) (80).

  • A cohort study evaluated the prognostic importance of preoperative MRI in women undergoing breast-conserving surgery for DCIS or early invasive breast cancer. After a median follow-up time of 4.6 years, patients who received MRI and those who did not had similar rates of local recurrence (3% vs. 4%, respectively), mortality, and disease-specific mortality (81).

  • A cohort study evaluated the association between preoperative MRI (for planning) and outcomes after breast-conserving therapy. Preoperative MRI was performed in 27% of patients. In the multivariate model, the provision of MRI was not associated with ipsilateral recurrence (HR, 1.7; P=0.60) (82).

  • A multicenter, randomized trial compared MRI with no additional imaging in patients undergoing breast-conserving surgery; the primary outcomes were repeat surgery or mastectomy within 6 months. Rates of reoperation were 19% in both groups (P=0.77) (83).

  • In a study involving 1468 patients, the overall mastectomy rate was determined by a combination of factors (surgical recommendation, patient choice, and failure of breast-conservation surgery) (84).

Rationale
  • The main objective of breast-conservation surgery or mastectomy with immediate reconstruction is to preserve or restore body image and self-esteem without compromising breast cancer survival.

  • Neoadjuvant (or primary) chemotherapy may improve overall survival and increase the chance of breast conservation; its effectiveness depends on the individual tumor sensitivity to particular chemotherapeutic agents.

Comments
  • A Web-based tool has been developed as a predictive nomogram for ipsilateral breast tumor recurrence after breast-conserving surgery. This tool uses published relative-risk ratios for seven clinicopathologic variables, and a modification of the original nomogram has been devised using two independent population-based data sets (involving 7811 and 644 patients). The nomogram predicted an overall risk for ipsilateral breast tumor recurrence of 4% at 10 years, with an observed estimate of 2.8%. This nomogram is accurate for most patients at low (less than 3%) to moderate (3% to 5%) risk or recurrence, but overestimates risk in a minority of higher risk (5% to 10%; greater than 10%) patients (85).

  • Breast-conservation surgery is initially recommended and attempted in up to three quarters of patients, but more than one third (37.9%) of these require an additional surgical procedure (re-excision, 26%; mastectomy, 11.9%).

  • A survey of radiation oncologists assessed attitudes toward surgical margins after breast-conservation surgery. Among European respondents, a “negative” margin was defined as no tumor cells at the margin by 27.6%, no tumor cells within 1 mm by 11.2%, and no tumor cells within 2 mm by 8.8%; among American respondents, the corresponding percentages were 46%, 7.4%,and 21.8%, respectively (86).

  • Patients who develop ipsilateral in-breast recurrence after breast conservation can be treated with mastectomy or further local excision; when both surgical resection and radiotherapy have been used as treatment for the primary tumor, recurrence in the breast should be treated by mastectomy.

  • Most patients who undergo mastectomy for early breast cancer do not require radiotherapy; it might be argued that the costs of postlumpectomy radiation can help offset any additional cost of reconstructive surgery following mastectomy.

  • It is sometimes recommended that radiotherapy be undertaken before chemotherapy in patients deemed to be at high risk for local relapse. Conversely, patients considered to be at increased risk for distant relapse may benefit from commencement of systemic therapy as soon as possible.

  • An increase of 150% in rates of contralateral prophylactic mastectomy among women undergoing mastectomy for unilateral breast cancer in the U.S. between 1998 and 2003 was determined based on the Surveillance, Epidemiology, and End Results database. This increase is more pronounced in younger, non-Hispanic white women (87).

  • There is accumulating evidence that obesity (BMI >30) is associated with a significantly higher rate of major complications following both implant and flap-based breast-reconstruction techniques. Fat necrosis within transposed tissue and donor site morbidity are more frequent in obese patients and have prompted some health care providers to impose upper limits on BMI for both immediate and delayed breast reconstruction (BMI threshold of 30 to 35) (88; 89; 90).

Perform axillary-node assessment with sentinel lymph-node biopsy or axillary-node dissection in patients with early invasive breast cancer.  
  • Perform sentinel lymph-node resection during surgery in patients with invasive breast cancer without apparent lymph-node involvement.

    • If nodal involvement with any tumor deposit >0.2 mm is detected by sentinel lymph-node biopsy, make certain that a staging axillary-node dissection is completed for the majority of patients to ensure adequate locoregional control of the disease

    • Recognize that contraindications for sentinel lymph-node biopsy include tumors >5 cm and/or an inflammatory component, clinically positive axilla (with abnormal nodes on ultrasound), and possibly a large hematoma or seroma after an initial diagnostic excisional procedure

  • Perform axillary lymph-node dissection in patients with invasive breast cancer whose preoperative evaluation revealed lymph-node spread.

    • Recognize that some younger patients (under 40 years) with T2 tumors of higher grade are more appropriately managed at the outset with axillary lymph-node dissection due to a high probability of nodal involvement

  • Do not routinely recommend surgical axillary-node assessment in patients with noninvasive (in situ) carcinoma.

  • Recognize that patients with stage IV (metastatic) disease derive no benefit from staging axillary-node evaluation or mastectomy, unless required for local control.

  • Recognize that sentinel lymph-node biopsy can be done either before or after neoadjuvant systemic therapies (chemotherapy or endocrine therapy).

Evidence
  • A 2014 ASCO guideline on sentinel lymph node biopsy in women with early-stage breast cancer recommended against axillary lymph node dissection in women without nodal metastases and in women with early-stage cancer with one or two positive lymph nodes who plan to undergo breast-conserving surgery plus radiation therapy. The guideline stated that axillary node dissection can be performed in women with early-stage breast cancer with one or two lymph nodes who plan to undergo mastectomy. The guideline stated that sentinel node biopsy may be performed in patients with multicentric tumors, DCIS if mastectomy is performed, prior breast surgery, and in those undergoing neoadjuvant chemotherapy (91).

  • A 2006 guideline from the American College of Radiology, the American College of Surgeons, the College of American Pathologists, and the Society of Surgical Oncology for breast-conservation therapy for invasive breast cancer recommended axillary evaluation in patients undergoing breast-conserving therapy. The guideline recommended sentinel node resection for most patients (once the surgeon is skilled at identifying the sentinel node) or axillary dissection for patients with known tumor spread to lymph nodes (75).

  • A 2008 systematic review of rates of axillary recurrence after a negative sentinel lymph-node resection included 48 studies with almost 15,000 patients. The overall axillary recurrence rate was 0.3% for sentinel lymph node-negative patients after a median follow-up of 34 months (92).

  • The NSABP B-32 multicenter study randomly assigned 5611 women with invasive breast cancer operated on by more than 200 surgeons to either sentinel lymph-node resection plus axillary lymph-node dissection or sentinel lymph-node resection alone, with axillary lymph-node dissection only if sentinel lymph nodes were positive. After a mean follow-up time of 8 years, rates of overall (91.8% and 90.3%) and disease-free survival (82.4% and 81.5%) did not differ between the two groups (93).

  • A randomized trial compared axillary-node dissection to no dissection in women with early-stage breast cancer and 1 to 2 positive sentinel nodes, all of whom underwent breast-conserving surgery and radiation therapy. After a median follow-up time of 6.3 years, overall survival and disease-free survival did not differ between the groups (94).

  • A 2009 meta-analysis of six randomized, controlled trials compared volume-controlled drainage vs. no or short-term drainage after axillary dissection for breast cancer surgery among a total of 561 patients. Those patients randomly assigned to volume-controlled drainage (drain removed only when <30 to 50 mL over 24 hours) were significantly less likely to develop clinically relevant seromas compared with patients without drains or short-term removal. However, the former group stayed in the hospital for a longer period (95).

Rationale
  • The presence and characteristics of involved lymph nodes (such as number, presence of extracapsular involvement, and matted nodes) may influence choice of locoregional and systemic adjuvant therapy.

  • When the sentinel lymph node does not contain metastases, the remaining nonsentinel lymph nodes are likewise presumed to be tumor free; conversely, if tumor deposits are found in the sentinel lymph node, there is potential nonsentinel lymph-node involvement.

Comments
  • Some women with positive sentinel nodes may not need full axillary-node dissection.

  • The technique of blue dye-assisted node sampling is a development of the original blind sampling technique and allows a more targeted sampling and standardization of techniques (96).

  • Standardized sentinel lymph-node biopsy training programs have been introduced in the U.K. and Germany.

  • Primary systemic therapy has been considered a relative contraindication for subsequent sentinel-node biopsy, but data suggest that this technique can be used to accurately stage the axilla either before or after primary chemotherapy (97).

Provide radiation therapy to patients with invasive breast cancer who were initially treated with breast-conservation surgery and to those who have undergone mastectomy and are at high risk for recurrence.  
  • Recommend radiation therapy in patients initially treated with lumpectomy.

    • Note that whole breast irradiation may not be necessary in selected women aged 70 or older

    • Consider breast-conservation surgery (pathologically negative margin required) plus tamoxifen or an aromatase inhibitor without breast irradiation in women older than age 70 with clinically negative lymph nodes and ER-positive, T1 breast cancer

  • Consider radiation therapy after mastectomy in patients with breast cancer and

    • Close surgical margins

    • Dermal invasion

    • Four or more positive axillary lymph nodes

    • T3 tumors, regardless of nodal involvement

    • Some women with 1 to 3 pathologically involved lymph nodes, based on the patient-specific balance of benefits and harms

  • Be aware that potential long-term effects of postmastectomy radiation therapy may include cardiovascular toxicity, particularly in treatment plans that encompass the left chest wall and chain of internal mammary nodes. This effect may be a lesser issue with modern techniques; thus, it is important that modern techniques of radiotherapy are used with standardized fractionation treatment.

  • Understand that radiation therapy after lumpectomy can be delayed for up to 6 months after surgery; this delay also applies to the subset of patients for whom postmastectomy irradiation is indicated.

  • Use a hypofractionated 3-week schedule (accelerated partial breast radiation) with reduced total dosage of radiotherapy to the whole breast as an alternative to the standard 5-week schedule without risk for poorer local control or cosmetic outcomes.

  • For patients receiving preoperative chemotherapy, base decisions about radiation therapy on preoperative chemotherapy tumor characteristics .

Evidence
  • A 2009 NICE (U.K.) guideline on the management of early and locally advanced breast cancer recommended breast radiotherapy in patients who have had breast-conserving surgery for early-stage breast cancer and in those who have undergone mastectomy who have 4 or more positive lymph nodes or tumor involvement at resection margins.

  • A 2001 ASCO guideline on postmastectomy radiation therapy recommended radiation therapy after mastectomy to patients with 4 or more positive lymph nodes and those with T3 or stage II tumors, and stated that there was insufficient evidence to recommend for or against radiation therapy in patients with 1 to 3 positive lymph nodes or in those receiving neoadjuvant chemotherapy (98).

  • A 2011 systematic review and individual patient meta-analysis of the effect of radiotherapy compared with no therapy after breast-conserving therapy included 10,801 participants from 17 randomized trials. Overall, radiotherapy reduced the 10-year recurrence rate (35.0% vs. 19.3%, P<0.00001) and the 15-year risk for death from breast cancer (25.2% vs. 21.4%, P=0.00005) (99).

  • A randomized trial compared lumpectomy plus tamoxifen plus radiation therapy with lumpectomy plus tamoxifen, both for 5 years, in women older than age 70 with clinical stage I, ER-positive breast cancer. Locoregional recurrence rates were 1% in the lumpectomy, radiation, and tamoxifen arm, and 4% in the lumpectomy plus tamoxifen arm (P<0.001). There were no differences in overall survival, disease-free survival, or need for mastectomy (100).

  • A randomized trial compared tamoxifen plus radiation therapy with tamoxifen alone in women aged 70 or older with ER-positive breast cancer after lumpectomy. After a follow-up time of 10 years, there were more local or regional recurrences in the tamoxifen alone group (10% vs 2%), but rates of distant metastases and disease-specific and overall survival did not differ between the groups (101).

  • A randomized trial compared modified radical mastectomy plus chemotherapy and radiation therapy with mastectomy plus chemotherapy in patients with lymph-node-positive breast cancer. After a 20-year follow-up, the radiation therapy group had better overall survival (47% vs. 37%, P=0.03) and lower recurrence rates (102).

  • A Danish randomized trial compared tamoxifen with postoperative radiation therapy with tamoxifen alone in 1708 node-positive or stage III breast cancer patients who underwent mastectomy. The overall survival rate at 10 years was 54% for the irradiated group compared with 48% for the nonirradiated group (P<0.001) (103).

  • A randomized trial compared standard whole breast irradiation with 50 Gy in 25 fractions over 35 days to a hypofractionated schedule involving a total dose of 42.5 Gy in 16 fractions over 22 days in patients who had undergone breast-conservation surgery for invasive cancer with clear surgical margins and negative axillary nodes. At 10 years' follow-up, there was no significant difference in rates of local recurrence between the standard (control) arm (6.7%) and the hypofractionated arm (6.2%). Similarly, cosmetic outcomes were not inferior for the hypofractionated arm (69.8%) compared with the standard (control) arm (71.3%) (104).

Rationale
  • The addition of radiotherapy to surgery has been shown to result in lower local recurrence rates and to improve overall survival after more prolonged follow-up to 15 years.

Comments
  • The NCCN has created guidelines for the treatment of breast cancer, which are available to clinicians on the NCCN web site.

  • A randomized trial evaluated the order of therapy after breast-conserving surgery, comparing radiation therapy followed by chemotherapy and chemotherapy followed by radiation therapy. After a follow-up time of approximately 11 years, there were no differences in metastases or survival between the groups (105).

  • In patients also receiving adjuvant chemotherapy as part of their initial breast cancer treatment, it is acceptable to delay postlumpectomy radiation therapy for up to 6 months.

  • There is a decrease in invasive breast cancer recurrences with additional “boost” radiation (photons, brachytherapy, or electron beam) to the tumor bed. This therapy is beneficial in patients with positive lymph nodes, vascular invasion, or close margins (106; 107).

  • Patients with fewer than four positive nodes may be candidates to participate in ongoing randomized trials of radiation vs. observation following mastectomy.

  • For older patients, comorbidities can reduce life expectancy, and additional local control from radiotherapy (3% to 6% absolute risk reduction) may not be clinically significant (108; 100). Nonetheless, older patients tolerate breast radiotherapy well, and even those with favorable low-risk, node-negative breast cancer derive absolute benefit in terms of local control. A randomized, controlled trial found no significant impairment of quality of life from breast irradiation in this group of patients (109).

Offer adjuvant systemic hormonal therapy to patients with ER-positive breast cancer. 
  • Offer adjuvant tamoxifen for at least 5 years in all premenopausal patients with hormone receptor-positive invasive breast cancer, unless it is contraindicated.

    • In premenopausal women with ER-positive breast cancer who cannot take tamoxifen (e.g., because of thromboembolic disease), render the patient postmenopausal with a luteinizing hormone-releasing hormone agonist, pelvic irradiation, or laparoscopic oophorectomy and then treat with an aromatase inhibitor.

    • After 5 years, continue hormonal therapy based on hormonal status with either tamoxifen (if the patients remains premenopausal) or an aromatase inhibitor (if the patient is postmenopausal).

  • Offer hormonal therapy to postmenopausal women with ER-positive breast cancer. Options include:

    • Upfront therapy with an aromatase inhibitor for 5 years

    • Sequenced therapy with tamoxifen for 2 to 3 years or 5 years followed by an aromatase inhibitor for an additional 5 years

    • Tamoxifen for 10 years in women in whom an aromatase inhibitor is contraindicated or poorly tolerated

  • Recognize that tamoxifen and aromatase inhibitors are not recommended for patients whose tumors show no evidence of estrogen receptor and/or progesterone receptor staining by immunohistochemistry.

  • Note that treatment with tamoxifen for 10 years vs. 5 years in both pre- and postmenopausal women with high-grade breast cancer may reduce mortality.

  • Administer tamoxifen sequentially after chemotherapy, not concurrently.

  • See table Drug Treatment for Breast Cancer.

Evidence
  • A 2014 ASCO guideline on hormonal therapy for patients with hormone-positive breast cancer recommended that postmenopausal women with hormone receptor-positive breast cancer receive an aromatase inhibitor for 5 years, tamoxifen for 10 years, or tamoxifen for either 2 to 3 or 5 years followed by 5 years of an aromatase inhibitor. The guideline recommended that premenopausal women be treated with tamoxifen for 5 years followed by other therapy or continued tamoxifen (for up to 10 years) (110).

  • A 2009 NICE (U.K.) guideline on the management of early and locally advanced breast cancer recommended systemic hormonal therapy for patients with early-stage breast cancer.

  • A 2006 Cochrane review of surgery vs. primary endocrine therapy for patients aged 70 and older with breast cancer included 6 trials. Surgery did not improve overall survival (HR, 0.98 [CI, 0.74 to 1.30], for surgery compared with endocrine therapy; HR, 0.86 [CI, 0.73 to 1.00], for surgery plus endocrine therapy compared with endocrine therapy alone) but did improve progression-free survival (HR, 0.65 [CI, 0.53 to 0.81], for surgery plus endocrine therapy compared with endocrine therapy alone) (80).

  • A 2005 systematic review and individual patient meta-analysis by the Early Breast Cancer Trialists' Collaborative Group addressed hormonal therapy for early breast cancer. In patients with ER-positive disease, 5 years of adjuvant tamoxifen reduced breast cancer mortality, with an overall RR of 0.76 (P<0.00001) and an RR of 0.68 (P<0.001) in patients with known ER-positive tumors. Tamoxifen did not appear to reduce mortality in patients with ER-negative tumors (111).

  • A 2011 systematic review and meta-analysis of tamoxifen in patients with breast cancer evaluated the effect in ER-positive and ER-negative disease. In patients with ER-positive disease, tamoxifen reduced the recurrence rate for 10 years (RR, 0.53, for years 0 to 4, and RR, 0.8, for years 5 to 9) and reduced breast cancer mortality for 15 years: 0 to 4 years (RR, 0.71), 5 to 9 years (RR, 0.66), and 10 to 14 years (RR, 0.68). Tamoxifen did not reduce recurrence or mortality in patients with ER-negative disease (112).

  • A 2009 Cochrane review of aromatase inhibitors for advanced breast cancer in postmenopausal women included 31 trials. Compared with other hormonal therapies, aromatase inhibitors resulted in a lower mortality rate (HR, 0.90 [CI, 0.84 to 0.97]). There were no clear data suggesting relative benefit from specific agents, but letrozole may have been superior to anastrozole. Side effects were similar among agents, and included hot flushes and arthralgia and lower rates of vaginal bleeding and thromboembolic events compared with other hormonal therapies (113).

  • A 2010 meta-analysis of randomized trials of aromatase inhibitors estimated absolute reductions in recurrence and mortality for aromatase inhibitors as either initial monotherapy or following early switching from 2 years of tamoxifen therapy compared with 5 years of tamoxifen. Upfront aromatase inhibitor therapy was associated with an absolute recurrence reduction of 2.9% and a decrease in breast cancer mortality of 1.1% at 5 years. Similar reductions were found for comparison of an early switch policy with 5 years of tamoxifen (3.1% and 0.7% for recurrence and mortality, respectively). There was no evidence of any increase in non-breast-cancer deaths (114).

  • A randomized trial compared 5 years of tamoxifen, 5 years of letrozole, and split therapy (2 to 3 years of one followed by 2 to 3 years of the other) in postmenopausal women with ER-positive breast cancer. After a median follow-up of 71 months, there were no differences in disease-free survival between 5 years of letrozole compared with tamoxifen for 2 years followed by letrozole (HR, 1.05 [CI, 0.84 to 1.32]) or letrozole for 2 years followed by tamoxifen (HR, 0.96 [CI, 0.76 to 1.21]). There were no differences in overall survival among the groups (115).

  • A neuropsychological side study of the prospective, randomized Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial examined cognitive functioning in postmenopausal breast cancer patients. Neuropsychological assessments were done before and after 1 year of hormonal therapy (no chemotherapy). Tamoxifen was found to be associated with a significantly lower level of functioning in verbal memory and executive functioning compared with exemestane for which there was no evidence of any cognitive impairment (116).

  • The randomized phase-3 TEAM trial compared exemestane alone for 5 years to sequenced therapy after 2 to 3 years of tamoxifen. There was a higher incidence of gynecologic symptoms, venous thrombosis, and endometrial abnormalities for sequential treatment but more frequent reporting of musculoskeletal adverse events, hypertension, and hyperlipidemia in the exemestane-only arm (117).

  • The SABRE trial examined the addition of risedronate to anastrozole therapy to prevent aromatase inhibitor-induced bone loss. For postmenopausal women at high risk for fragility fracture, risedronate therapy at a dosage for prevention and treatment of osteoporosis resulted in a significant increase in bone mineral density in the lumbar spine (3%, P=0.006) and hip (2%, P=0.0104) (118).

  • A randomized trial compared 5 additional years of tamoxifen with placebo in 12,894 women with early breast cancer who had already completed 5 years of treatment with tamoxifen. Among patients with ER-positive disease, allocation to continue tamoxifen reduced the risk for breast cancer recurrence (18.0% vs. 20.1%, P=0.02), breast cancer mortality (9.7% vs. 11.6%, P=0.01), and overall mortality (18.6% vs. 21.1%, P=0.01) (119).

Rationale
  • Many patients with early-stage breast cancer will have micrometastatic foci of tumor at distant sites at the time of presentation. They are likely to benefit from adjuvant systemic therapy with hormonal therapy, chemotherapy, or both in terms of disease-free and overall survival.

  • Systemic therapies contribute to a reduction in rates of locoregional relapse in addition to prolonging overall survival.

Comments
  • Some postmenopausal hormone receptor-positive women at very low risk for relapse may derive minimal additional benefit from use of an aromatase inhibitor as adjuvant systemic treatment and should receive tamoxifen only.

  • The absolute benefits of an aromatase inhibitor for the average patient are very small in the first 36 months, and some argue that any additional benefit of an aromatase inhibitor during the first 2 to 3 years is difficult to justify. Fewer than 5% of patients have an early relapse in the first 2 to 3 years while receiving tamoxifen as adjuvant therapy.

  • Younger women should be more aggressively managed with systemic therapies, including chemotherapy, tamoxifen, ovarian suppression, and trastuzumab.

  • The relative benefits of aromatase inhibitors compared with tamoxifen in terms of antitumor efficacy may depend on expression of two functional alleles of the enzyme cytochrome P450 2D6 (CYP2D6), which mediates conversion of tamoxifen to the active metabolite endoxifen. A retrospective analysis of genomic variants of this enzyme among 1325 breast cancer patients found that disease-free survival (but not overall survival) was significantly impaired among patients whose tumors expressed nonfunctional or reduced-function alleles of this enzyme (HR, 1.29 [CI, 1.03 to 1.61]) (120). In a later study, however, no association between CYP2D6 metabolism phenotypes and breast cancer-free interval was observed among patients who received tamoxifen monotherapy without previous chemotherapy, and CYP2D6 phenotypes of reduced enzyme activity were not associated with worse disease control. There did seem to be an association, however, with increased hot flushes, contrary to the hypothesis (121).

Treat patients with tumor size >1 cm or positive lymph nodes with adjuvant chemotherapy. 
  • Offer 3 to 6 months of chemotherapy with hormonal therapy in breast cancer patients with

    • Tumors >1 cm and no axillary-node involvement (stage I)

    • Tumors >2 cm, positive axillary nodes, or both (stage II)

    • Involvement of internal mammary nodes, matted axillary adenopathy, inflammatory breast cancer, or all three (stage III)

  • Do not exclude the use of adjuvant chemotherapy for healthy elderly patients with high-risk disease manifested by large primary tumors, positive nodes, or high-risk histologic features (a non-anthracycline-based regimen can be used, which is less cardiotoxic). However, understand that there are insufficient data to make definitive recommendations regarding chemotherapy for patients older than age 70.

  • See table Drug Treatment for Breast Cancer.

Evidence
  • A 2009 NICE (U.K.) guideline on the management of early and locally advanced breast cancer recommended docetaxel to patients with lymph node-positive breast cancer.

  • A 2008 systematic review and individual patient meta-analysis of adjuvant chemotherapy for ER-negative breast cancer included 6000 participants from 46 trials. In women younger than age 50, chemotherapy reduced breast cancer mortality (RR, 0.73; P=0.0002) and overall mortality (RR, 0.75; P=0.0003). In women aged 50 to 69, chemotherapy reduced breast cancer mortality (RR, 0.86; P=0.0004) and overall mortality (RR, 0.87; P=0.0009). There were too few patients aged 70 or older to draw conclusions (122).

  • A 2005 systematic review and individual patient meta-analysis by the Early Breast Cancer Trialists' Collaborative Group addressed hormonal therapy for early breast cancer. Anthracycline-based chemotherapy for 6 months reduced breast cancer mortality in women younger than age 50 (RR, 0.706; P<0.00001) and aged 50 to 69 (RR, 0.879; P<0.0001). When directly compared, anthracycline-based chemotherapy was superior to regimens containing cyclophosphamide, methotrexate, and fluorouracil (111).

  • A randomized, controlled trial involved a three-way comparison of cyclophosphamide, doxorubicin, and fluorouracil followed by tamoxifen, the same chemotherapeutic agents and concurrent tamoxifen, or tamoxifen alone in postmenopausal women with node-positive breast cancer. The 10-year disease-free survival rates for these groups were 60%, 53%, and 48%, and the differences were significant (123).

  • The Taxotere as Adjuvant Chemotherapy (TACT) I trial involving 4000 patients found no significant benefit in terms of disease-free and overall survival from adding four cycles of docetaxel to one of two standard anthracycline-containing regimens (124).

  • A randomized trial compared adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide with fluorouracil, doxorubicin, and cyclophosphamide in higher-risk node-negative patients. After a median follow-up time of 77 months, the disease-free survival rate was higher in the docetaxel group (87.8% vs. 81.8%, P=0.01) (125).

  • A randomized trial compared standard chemotherapy to capecitabine in women older than age 65 with invasive breast cancer. The trial was stopped early since patients in the cepecitabine group were more likely to have recurrence or death (HR, 2.09 [CI, 1.38 to 3.17]) (126). More than two thirds of patients in this study were aged 70 to 79 with more than half having tumors measuring <2 cm and one third being node-negative. Of note, capecitabine was associated with better quality of life during treatment. Quality of life was similar for both groups at 1 year (127).

Rationale
  • Many patients with early-stage breast cancer will have micrometastatic foci of tumor at distant sites at the time of presentation. They are likely to benefit from adjuvant systemic therapy with hormonal therapy, chemotherapy, or both in terms of disease-free and overall survival. Systemic therapies contribute to a reduction in rates of locoregional relapse in addition to prolonging overall survival. Patients with HER2-positive breast cancer tumors >1 cm benefit from trastuzumab therapy.

  • HER2 together with the estrogen receptor and progesterone receptor are the best-characterized molecular predictive markers.

Comments
  • High-dose chemotherapy with autologous stem-cell rescue is not used in the adjuvant treatment of high-risk breast cancer patients.

  • More prospective data are needed to determine the optimal therapeutic regimen for elderly patients.

  • Although TP53 gene status has prognostic value, mutated forms of TP53 are not predictive of preferential sensitivity to taxane-based chemotherapy in the neoadjuvant setting (128).

Treat patients with HER2-positive breast cancer with trastuzumab. 
  • Unless contraindicated, offer trastuzumab for adjuvant therapy in patients with HER2-positive breast cancer receiving chemotherapy.

  • Treat with trastuzumab for 1 year.

  • Note the risk for heart failure with this drug.

  • See table Drug Treatment for Breast Cancer.

Evidence
  • A 2014 ASCO guideline on the treatment of HER2-positive breast cancer recommended that patients with HER2-positive breast cancer be treated with specific HER2 therapy, using the combination of trastuzumab, pertuzumab, and a taxane as first-line therapy (129).

  • A 2009 NICE (U.K.) guideline on the management of early and locally advanced breast cancer recommended trastuzumab 3 times per week for 1 year in patients with invasive HER2-positive breast cancer.

  • A 2012 Cochrane review of trastuzumab for HER2-positive early breast cancer included 8 trials with 11,991 participants. Trastuzumab improved disease-free survival (HR, 0.60 [CI, 0.50 to 0.71]) and overall survival (HR, 0.66 [CI, 0.57 to 0.77]) compared with standard therapy, but increased the risk for heart failure (HR, 5.11 [CI, 3.00 to 8.72]) (130).

  • A randomized, open-label, noninferiority trial compared 6 months with 12 months of therapy with trastuzumab in patients with HER2-positive breast cancer after surgery and chemotherapy. After a median follow-up time of 42.5 months, 2-year disease-free survival was higher in the 12-month group (HR, 1.28 [CI, 1.05 to 1.56.) and was beyond the noninferiority margin. More patients in the 12-month group experienced a cardiac event (5.7% vs.1.9%; P<0.0001) (131).

Rationale
  • Patients with HER2-positive breast cancer tumors >1 cm benefit from trastuzumab therapy.

  • HER2 together with the estrogen receptor and progesterone receptor are the best characterized molecular predictive markers.

Consider combined modality therapy in patients with locally advanced breast cancer.  
  • Consider neoadjuvant chemotherapy, surgery, and radiation in patients with

    • Inflammatory breast cancer

    • Tumors that exceed 5 cm in size or involve the skin and chest wall

    • Matted axillary lymphadenopathy on clinical examination

  • Include a 5-year course of hormonal therapy for patients with estrogen- or progesterone-receptor-positive disease.

  • Include 1 year of trastuzumab as adjuvant therapy if the tumor is HER2 positive. Add trastuzumab to chemotherapy for the first 6 cycles for at least 9 weeks of therapy.

  • Consider preoperative chemotherapy with anthracycline plus a taxane to render inoperable cancers operable.

  • See table Drug Treatment for Breast Cancer.

Evidence
  • A 2011 consensus statement on the management of inflammatory breast cancer from an international expert panel recommended a multidisciplinary approach, including primary chemotherapy, surgery, and radiation therapy, with trastuzumab for all patients who are HER2-positive. A minimum of six cycles of primary chemotherapy over a period of 4 to 6 months with an anthracycline and taxane was recommended (132).

  • A 2004 guideline from Health Canada on the treatment of locally advanced breast cancer recommended combined modality treatment, including surgery, chemotherapy, and radiation therapy. The guideline recommended either neoadjuvant or primary (postsurgical) chemotherapy containing an anthracycline, hormonal therapy for patients with hormone receptor-positive tumors, locoregional radiothrerapy, and modified radical mastectomy if feasible (133).

  • A 2011 systematic review of chemotherapy for locally advanced or metastatic breast cancer included 4 randomized trials and 1 nonrandomized trial. Most trials included venorelbine. No randomized trials found a difference in overall survival between the groups. For progression-free survival, gemcitobine plus vinorelbine was superior to vinorelbine alone in one study. Overall survival was generally less than 16 months across studies (134).

  • An observational case series reported on 70 patients treated at a single cancer center for locally advanced breast cancer. Patients were treated with radiation, surgery, and chemotherapy. Disease-free survival rates were 34% at 5 years and 32% at 10 years, and the median overall survival was 3.5 years (135).

  • The randomized, controlled, superiority NOAH trial studied preoperative chemotherapy with trastuzumab followed by adjuvant trastuzumab vs. neoadjuvant chemotherapy alone in patients with HER2-positive locally advanced or inflammatory breast cancer (comparison group HER2-negative cohort). Trastuzumab significantly improved 3-year event-free survival (71% vs. 56%; HR, 0.56; P=0.013). Only 2% of patients developed heart failure (136).

  • The phase 3 randomized GeparQuattro study compared epirubicin/cyclophosphamide plus docetaxel with or without capecitabine in patients with large operable or locally advanced breast cancer. The groups did not differ with regard to rates of complete pathologic response rates at surgery (137).

  • A phase 3 randomized study comparing docetaxel with vinorelbine in combination with trastuzumab for HER2-positive patients with metastatic or locally advanced breast cancer did not show increased efficacy but did show significantly fewer adverse side effects for vinorelbine. The latter can be used as an alternative first-line option to docetaxel plus trastuzumab (138).

  • A 2000 narrative review discussed locally advanced breast cancer (139).

Rationale
  • Women with high-risk stage II (multiple positive nodes) and stage III disease (particularly those with inflammatory disease) have an extremely high risk for having synchronous micrometastatic disease and subsequent systemic recurrence. Primary chemotherapy is therefore a more rational approach and has improved outcomes.

  • This group of patients is also at high risk for locoregional failure and will usually receive chest-wall radiotherapy and possibly supraclavicular irradiation (especially when more than four axillary nodes contain metastases).

  • Nodal downstaging can occur following neoadjuvant chemotherapy; thus, it is possible to pathologically discern the nodes that were previously “positive” but no longer contain tumor.

  • Preoperative chemotherapy with anthracycline plus a taxane is being increasingly recognized as effective in rendering inoperable cancer operable and achieving a good response.

Comments
  • Addition of newer biological therapies to induction regimens (such as lapatinib and bevacizumab) remains controversial and continues to be studied.

Recommend breast-conserving surgery plus radiation therapy for most patients with ductal carcinoma in situ. 
  • Recommend lumpectomy plus radiation for most patients with DCIS.

  • Consider alternate therapies based on individual patient risks and preferences, including

    • Modified radical mastectomy

    • Lumpectomy alone without radiation

  • Note that there is no evidence that survival differs among the three treatment options.

  • Consider mastectomy with sentinel lymph-node biopsy in women with extensive breast involvement with DCIS determined by assessment of mammography and pathology findings; this procedure is potentially curative (98%) in the absence of invasive disease.

Evidence
  • A 2009 NICE (U.K.) guideline on the management of early and locally advanced breast cancer recommended that patients with DCIS receive local resection followed by radiation therapy but not hormonal therapy.

  • A 2009 Cochrane review of the addition of radiotherapy to breast-conservation surgery for treatment of DCIS included 4 studies with 3925 participants. Three trials compared addition of radiotherapy only while the fourth compared use of both radiotherapy and tamoxifen in a two-by-two factorial design. Radiotherapy resulted in a significant reduction in both ipsilateral invasive recurrence (HR, 0.50 [CI, 0.32 to 0.72]; P=0.001) and ipsilateral DCIS recurrence (HR, 0.61 [CI, 0.39 to 0.95]; P=0.03). No significant long-term toxicity from radiotherapy was found (140).

  • A retrospective cohort study described outcomes in 300 patients with DCIS treated with either mastectomy or local resection with radiation therapy. Disease-specific and overall survival did not differ based on treatment, but patients who underwent mastectomy had better disease-free survival (98% vs. 81%; P=0.0004) (141).

Rationale
  • Most women with noninvasive breast cancer can be treated with breast conservation.

  • Mastectomy should be reserved for selected cases, such as women with multifocal, multiquadrant involvement, women with significant risk factors (personal history of contralateral breast cancer, strong family history), and personal preference including concerns about psychological impact and cosmetic outcome.

Comments
  • Some controversy remains about whether a subgroup of patients with small, low-grade, DCIS may be treated with lumpectomy without radiation therapy.

  • Postoperative radiation therapy can be omitted as part of the treatment plan in very-low-risk DCIS.

Consider using tamoxifen following breast-conservation procedures in women with DCIS. 
  • Consider prescribing a 5-year course of adjuvant tamoxifen for women with ER-positive DCIS treated with lumpectomy with or without radiation therapy.

  • Consider enrolling postmenopausal patients with DCIS in a clinical trial comparing tamoxifen with an aromatase inhibitor.

  • See table Drug Treatment for Breast Cancer.

Evidence
  • A 2009 NICE (U.K.) guideline on the management of early and locally advanced breast cancer recommended that patients with DCIS receive local resection followed by radiation therapy but not hormonal therapy.

  • A 2012 Cochrane review of tamoxifen for DCIS after surgery included 2 randomized trials with 3375 participants. Tamoxifen reduced rates of both ipsilateral (HR, 0.75 [CI, 0.61 to 0.92]) and contralateral (RR, 0.50 [CI, 0.28 to 0.87]) DCIS and of contralateral invasive cancer (RR, 0.57 [CI, 0.39 to 0.83]), with a trend toward a reduction in ipsilateral invasive cancer (RR, 0.79 [CI, 0.62 to 1.01]). Tamoxifen did not reduce all-cause mortality (142).

Rationale
  • Women with DCIS treated with breast conservation are at risk for developing a new breast cancer event, invasive or noninvasive, ipsilateral or contralateral.

  • Aromatase inhibitors may offer risk reduction for new breast cancer events.

Comments
  • There is currently no evidence to support the use of aromatase inhibitors as adjuvant therapy in the routine management of patients with DCIS (whether treated with lumpectomy or mastectomy).

  • The benefit of tamoxifen for ER-negative DCIS is not known.

Individualize therapy based on prognostic factors and other patient factors. 
  • Use prognostic factors to predict future recurrence or death from breast cancer, including

    • Patient age

    • Comorbities

    • Tumor size

    • Tumor grade

    • Number of involved axillary lymph nodes

    • HER2 tumor status (possibly)

  • Consider using published algorithms and/or the validated computer-based model Adjuvant! Online to estimate the 10-year disease-free and overall survival rates.

  • Consider using gene assays that employ reverse transcriptase PCR, such as Oncotype Dx and MammaPrint, to help with decision making regarding systemic adjuvant chemotherapy and hormonal therapy use in early-stage, axillary lymph node-negative, hormone receptor-positive tumors >0.5 cm.

  • Consider withholding adjuvant systemic therapy in patients with no axillary involvement and

    • Tumors ≤0.5 cm or microinvasion only

    • Favorable and less frequent histologic types of invasive breast cancer, such as tubular, colloid, and mucinous carcinomas measuring <1.0 cm

    • Hormone receptor-positive invasive ductal and lobular carcinomas measuring 0.6 to 1.0 cm with favorable features (no angiolymphatic invasion, low S-phase, low histologic grade [usually grade I], low-risk Oncotype DX result)

  • See table Drug Treatment for Breast Cancer.

Evidence
  • A 2009 NICE (U.K.) guideline on the management of early and locally advanced breast cancer recommended considering using Adjuvant! Online to estimate prognosis and inform treatment decisions.

  • A 2008 systematic review evaluated the validity of three prognostic tests that have been approved for clinical application in the U.S., including Oncotype DX, MammaPrint, and H/I. The tests are based on a 21-gene profile, a 70-gene profile, and expression of the HOXB13/IL7BR genes, respectively. The Oncotype DX and H/I assays measure gene expression with reverse-transcriptase PCR, and the MammaPrint assay uses complementary DNA microarray technology requiring fresh frozen tissue. Overall, the review found that prognostic tests may improve the accuracy of prognostic estimates (143).

  • A study used a database of 4083 patients with breast cancer to validate the Adjuvant! Online prediction model. The predicted and observed 10-year outcomes for event-free survival, disease-specific survival, and overall survival were all within 1% (144).

  • A study validated the Adjuvant! Online model in a cohort of 5380 patients from the Netherlands with breast cancer. The observated and estimated rates of overall survival were not significantly different, and were consistent in most subgroups except for women younger than age 40, in whom the model overestimated survival by approximately 4% (145).

  • A study validated the prognostic accuracy of the Oncotype DX assay in archival tissue from treated node-negative, estrogen receptor-positive tumors from patients treated with tamoxifen. Patients were classified by the assay as low (51% of patients), intermediate (22%), or high (27%) risk for recurrence. Rates of recurrence over 10 years were 6.8% in the low-risk group, 14.3% in the intermediate-risk group, and 30.5% in the high-risk group (146).

  • A study validated the predictive value of Oncotype DX estimates of recurrence risk in patients from the NSABP B-14 and NSABP B-20 trials with node-negative, estrogen receptor-positive tumors. Rates of recurrence were 4.0%, 7.2%, and 15.8% for patients with low (<18), intermediate (18 to 30), and high (≥31) scores, respectively (147).

  • A 2010 assessment of a mulitgene assay in women with newly diagnosed breast cancer included 5 studies addressing the prognostic and predictive value. Overall, the quality of the evidence was poor and the value of the assay was not clear (71).

Rationale
  • Tumor size and number of positive nodes are important prognostic factors in patients with breast cancer; very small tumors in patients with negative nodes are less likely to be associated with micrometastases at distant sites and therefore may require a less aggressive treatment approach.

  • In women with increased comorbid illnesses, online tools such as Adjuvant! Online can help clinicians estimate risk for relapse and benefits of systemic therapy (endocrine and/or chemotherapy). Adjuvant! Online incorporates all of the prognostic factors except for HER2 tumor status.

Comments
  • Hormone receptor status is a strong predictor of benefit from endocrine therapies, such as tamoxifen, selective estrogen receptor modulators, or aromatase inhibitors, but it is a weak prognostic factor. Patients at low risk for relapse derive less absolute benefit from adjuvant systemic therapies and may suffer significant side effects (e.g., hot flashes, bone attrition) for minimal gains in terms of their disease outcome.

  • Adjuvant!Online is a Web-based resource that was derived from SEER data and that calculates risk for death at 10 years for individual patients together with absolute survival benefits from adjuvant systemic therapies (hormonal, chemotherapy, and combined chemo-hormonal). This decision-aid tool is based on tumor size, grade, nodal status, estrogen receptor status, age, and comorbidities.

  • The updated version of Adjuvant! Online will incorporate HER2 status.

  • Oncotype DX testing has only been validated in a hormone receptor-positive, node-negative breast cancer population treated with 5 years of tamoxifen.

  • Prognostic estimates can be optimized by combining Oncotype DX recurrence score and clinicopathologic information instead of simply combining the Oncotype DX recurrence score and Adjuvant! result. The recurrence score should be used for estimating relative chemotherapy benefit (148).

  • A genomic index has been developed from expression profiles of genes that are coexpressed with estrogen receptor alpha. This genomic index for sensitivity to endocrine therapy is significantly associated with distant relapse or risk for death in patient cohorts treated with either tamoxifen only or chemoendocrine therapy. The index is not prognostic in the untreated cohorts and appeared to indicate intrinsic sensitivity of tumors to adjuvant endocrine therapy (149).

Consider ovarian ablation or suppression in addition to systemic endocrine therapy and chemotherapy in premenopausal patients with hormone receptor-positive breast cancer.  
  • Depending upon the clinical circumstances and patient preferences, consider the following ablation options:

    • Bilateral oophorectomy (irreversible)

    • Pelvic irradiation (irreversible)

  • Consider ovarian suppression with monthly injections of an LHRH agonist (goserelin or leuprolide) for 2 to 5 years (reversible).

  • Recognize that ovarian ablation does not add any benefit in overall survival or disease-free survival when added to chemotherapy or tamoxifen in a premenopausal patient).

  • See table Drug Treatment for Breast Cancer.

Evidence
  • A 2011 statement from ASCO endorsed a guideline from Cancer Care Ontario on ovarian ablation for women with breast cancer. The guideline recommended ovarian ablation only for women who will not otherwise receive systemic therapy due to intolerance or refusal. When ovarian ablation is performed, the guideline recommended that monthly injection be used (150).

  • A 2009 Cochrane review of ovarian ablation with LHRH agonists in premenopausal women with early breast cancer included 14 trials with various interventions and comparison therapies. There were too few data on each comparison to draw firm conclusions. LHRH monotherapy was similar to older chemotherapeutic regimens in terms of survival, and appeared to be similar to tamoxifen alone. LHRH plus tamoxifen appeared to be superior to tamoxifen alone and LHRH plus chemotherapy had a similar efficacy to LHRH alone in 1 study (151).

  • A 2007 individual patient meta-analysis of LHRH antagonists in premenopausal women with hormone-receptor-positive breast cancer included data from 11,906 women from 16 trials. When used as the sole systemic therapy, LHRH did not reduce recurrence (RR, 0.72 [CI, 0.50 to 1.04]) or death after recurrence (RR, 0.82 [CI, 0.47 to 1.43]). In combination with chemotherapy and/or tamoxifen, LHRH reduced recurrence (RR, 0.87 [CI, 0.78 to 0.98]) and death from recurrence (RR, 0.85 [CI, 0.73 to 0.98]). The impact was similar to that of chemotherapy (152).

  • A randomized trial compared an LHRH analogue with placebo in 281 premenopausal women undergoing chemotherapy for breast cancer; the primary outcome was early menopause. The LHRH analogue group had a lower rate of premature ovarian failure at 12 months (rate of early menopause in chemotherapy only and chemotherapy/LHRH analogue groups 25.9% vs. 8.9%, respectively [CI, -16% to -7.9%]; P<0.0001) (153).

  • A randomized trial compared an LHRH analogue with placebo in 60 premenopausal women undergoing chemotherapy for hormone-insensitive breast cancer. The groups did not differ with regard to rates of menopause at 6 months (154).

Rationale
  • Most premenopausal women will have at least a temporary cessation of ovarian function while on chemotherapy.

  • It remains unclear whether patients with permanent amenorrhea will have a better survival outcome.

Comments
  • Ovarian suppression with LHRH agonists suppresses luteinizing hormone and the release of follicle-stimulating hormone from the pituitary, which reduces ovarian estrogen production.

  • Ovarian ablation is most commonly achieved by either laparoscopic oophorectomy or pelvic/ovarian irradiation. Surgical ablation causes an immediate fall in hormone levels, whereas pelvic irradiation suppresses overall ovarian function, much like LHRH agonists, causing hormone levels to decrease gradually over time.

  • An advantage of LHRH agonists is their potentially reversible effects upon cessation of treatment, which allows subsequent conception for women who are diagnosed with breast cancer before they have completed their family.

  • Menstrual activity is more likely to resume in women younger than 40 years at the time of chemotherapy, and these women should be considered for ovarian suppression. Up to 80% of women younger than 35 years will retain or regain menstrual function after chemotherapy compared with 30% of women older than 39 years (155).

  • The role of adjuvant ovarian ablation or suppression in premenopausal women with hormone receptor-positive breast cancer is incompletely defined. Trials of LHRH agonists are currently seeking to answer two questions:

    • Can LHRH agonists (with or without tamoxifen) provide an alternative to chemotherapy in patients with estrogen receptor-positive disease?

    • Do LHRH agonists confer any additional benefit when combined with standard treatment (surgery ± radiotherapy ± tamoxifen ± chemotherapy)?

Consider primary systemic neoadjuvant therapy before definitive surgery in selected patients with locally advanced breast cancer. 
  • Consider 3 to 6 months of primary systemic therapy with an anthracycline- or taxane-based regimen before surgery in patients with operable breast cancer who are not initial candidates for breast-conservation therapy because of a large tumor and who would otherwise require a mastectomy.

  • For women in whom neoadjuvant therapy is planned,

    • Use regimens that are recommended for postoperative adjuvant therapy

    • Include trastuzumab for patients with HER2-positive tumors

    • Consider hormonal therapy, preferably with an aromatase inhibitor, for women with hormone receptor-positive tumors, particularly older women

  • Recognize that preoperative chemotherapy is not indicated unless invasive breast cancer is confirmed.

  • Recognize that preoperative chemotherapy has no demonstrated overall survival advantage over postoperative adjuvant chemotherapy in patients with stage II tumors.

  • See table Drug Treatment for Breast Cancer.

Evidence
  • A 2014 NICE (U.K.) guideline on the management of early and locally advanced breast cancer recommended offering preoperative systemic therapy to patients with early invasive breast cancer who prefer breast-conservation surgery that cannot initially be performed.

  • A 2007 Cochrane review of neoadjuvant chemotherapy in women with operable breast cancer included 14 studies with 5500 participants. Compared with postoperative chemotherapy, neoadjuvant chemotherapy did not affect overall survival (HR, 0.98 [CI, 0.87 to 1.09]), but did increase rates of both breast conservation and local recurrence. Rates of local recurrence were not increased among patients who had surgery even in the case of complete response to chemotherapy (HR, 1.12 [CI, 0.92 to 1.37]). Among patients receiving neoadjuvant therapy, those with complete pathologic response had a better overall prognosis (156).

  • A randomized trial compared neoadjuvant letrozole with tamoxifen in 324 postmenopausal women with hormone-positive breast cancer who were ineligible for breast-conservation surgery. More patients in the letrozole group responded to therapy (60% vs. 41%; P=0.004) and were able to undergo breast-conservation surgery (48% vs. 36%; P=0.036) (157).

  • A randomized trial compared neoadjuvant anastrazole, tamoxifen, or both for 3 months in 330 postmenopausal women with ER-positive operable or potentially operable invasive breast cancer. After 3 months, tumor response rates and rates of breast-conservation surgery did not differ among the groups (158).

  • A randomized trial compared neoadjuvant paclitaxel followed by cyclophosphamide, epirubicin, and fluorouracil to the same regimen plus trastuzumab in 42 women with HER2-positive operable breast cancer. Rates of pathologic complete response were higher in the trastuzumab group (65.2% vs. 26.0%; P=0.016) (159).

  • A phase III randomized trial compared trastuzumab with lapatinib when added to chemotherapy and cyclophosphamide followed by docetaxel in 620 women with untreated, HER2-positive, primary invasive breast cancer. Pathologic complete response was achieved in 30.3% of patients who received trastuzumab plus chemotherapy compared with 22.7% of patients who received lapatinib plus chemotherapy (P=0.04) (160).

  • A randomized trial compared lapatinib, trastuzumab, or both added to weekly paclitaxel as neoadjuvant therapy in 455 women with HER2-positive breast cancer with tumors >2cm. The pathologic complete response rate was higher in the combination therapy group than in the trastuzumab group (51.3% vs. 29.5%; P=0.0001); the trasuzumab group and the lapitinib group did not differ significantly (161).

Rationale
  • In some patients, preoperative chemotherapy can make breast-conservation therapy possible.

Comments
  • The optimal regimen for primary chemotherapy remains to be determined but usually contains an anthracycline (doxorubicin [Adriamycin]/epirubicin) and a taxane (docetaxel/paclitaxel). Epirubicin is generally associated with lower cardiotoxicity and fewer gastrointestinal side effects.

  • Complete pathologic response rates appear higher among patients with estrogen receptor-negative tumors, but do not always correlate with improved overall survival (162).

  • Consider alternate chemotherapeutic agents in patients treated with neoadjuvant therapy whose tumors fail to respond to a few cycles of chemotherapy.

Focus on symptom palliation and disease control in patients with metastatic breast cancer. 
  • Recognize that systemic treatment in metastatic breast cancer can both prolong survival and enhance quality of life, but is not curative.

  • For systemic treatment,

    • Consider the use of single-agent chemotherapy in patients with metastatic breast cancer

    • Treat patients with hormone receptor-positive disease who have bone or visceral metastases with hormonal therapy

    • Consider a combination of hormonal therapy and trastuzumab in hormone receptor and HER2-receptor co-positive metastatic breast cancer

    • Consider a combination of trastuzumab and lapatinib in trastuzumab-refractory metastatic breast cancer

    • Consider pertuzumab or trastuzumab emtansine for first- and second-line treatment of HER2-positive metastatic breast cancer in patients with good performance status

    • Consider the addition of everolimus to exemestane in hormone receptor-positive metastatic breast cancer that progresses or recurs during therapy with nonsteroidal aromatase inhibitors

  • In patients with destructive or symptomatic bone disease,

    • Consider radiation therapy, bisphosphonates (pamidronate, zolodronic acid, or ibidronate), or both

    • Understand that surgical stabilization may be needed before radiation therapy

  • Implement specific interventions to control pain, treat anemia, prevent pathologic fractures, and address psychosocial issues.

  • Consider mastectomy to control locoregional disease.

  • Retest available tissue at time of relapse for hormonal and HER2 status (which can differ in primary and metastatic lesions).

  • See table Drug Treatment for Breast Cancer.

  • See module Pain.

Evidence
  • A 2014 NICE (U.K.) guideline on the management of advanced breast cancer recommended endocrine therapy as the first-line treatment for most patients with ER-positive advanced disease, reserving chemotherapy for patients with ER-positive disease with imminently life-threatening or highly symptomatic manifestations. The guideline favored an aromatase inhibitor for most postmenopausal patients with ER-positive tumors, with tamoxifen plus ovarian suppression in premenopausal women. The guideline recommended sequential therapy when chemotherapy is used, with docetaxel as the first agent. The guideline also mentioned the use of trasuzumab and emphasized the importance of supportive and palliative care.

  • A 2003 ASCO update on the role of bisphosphonates in women with breast cancer recommended intravenous pamidronate or zolodronic acid for women with metastatic disease on bone destruction on plain x-rays, and recommended against starting bisphosphonate therapy in women with evidence of bone involvement but without bone destruction (163).

  • A 2003 Cochrane review of chemotherapy compared with endocrine therapy for metastatic breast cancer included 8 trials with 817 participants. Endocrine therapy and chemotherapy did not differ with regard to survival, but chemotherapy resulted in a higher response rate (RR, 1.25 [CI, 1.01 to 1.54]). Chemotherapy appeared to have more side effects, but results for quality of life were mixed (164).

  • A 2009 Cochrane review of aromatase inhibitors compared with other hormonal therapies for advanced hormone receptor-positive breast cancer included 37 studies with more than 11,000 patients. Aromatase inhibitors were associated with a significant survival benefit (HR, 0.90 [CI, 0.84 to 0.97]) (113).

  • A 2009 Cochrane review of single-agent compared with combination chemotherapy for metastatic breast cancer included 43 trials with 9742 participants. Combination chemotherapy was associated with lower mortality (HR, 0.88 [CI, 0.83 to 0.93]) and improved time to disease progression (HR, 0.78 [CI, 0.74 to 0.82]). In terms of specific agents, combination therapy resulted in lower mortality compared with taxane alone (HR, 0.82 [CI, 0.75 to 0.89]) but not anthracycline alone (HR, 0.94 [CI, 0.86 to 1.02]). Combination therapy resulted in significantly more nausea and vomiting, neutropenia, and alopecia (165).

  • A 2005 Cochrane review of autologous bone-marrow or stem-cell transplantation for metastatic breast cancer compared with conventional chemotherapy included 6 randomized trials. The rate of treatment-related death was higher in the transplantation group (RR, 4.07 [CI, 1.39 to 11.88]), and no significant difference existed in long-term overall survival (166).

  • A 2012 Cochrane review of bisphosphonates for breast cancer included 34 randomized trials. Compared with placebo or no bisphosphonates, bisphosphonates reduced skeletal events (RR, 0.85 [CI, 0.77 to 0.94]); intravenous zolodronic acid, pamidronate, and ibidronate appeared to be the most effective agents. Compared with bisphosphonates, denosumab reduced skeletal events (RR, 0.78 [CI, 0.72 to 0.85]). Bisphosphonates improved bone pain in 6 out of 11 studies but improved quality of life in only a few studies. Bisphosphonate therapy did not reduce bone metastases (RR, 0.73 [CI, 0.40 to 1.33]) (167).

  • The Evaluation of Faslodex versus Exemestane Clinical trial (EFECT) was a randomized trial comparing the pure antiestrogen fulvestrant with the steroidal aromatase inhibitor exemestane in 693 postmenopausal hormone receptor-positive women with metastatic breast cancer previously treated with a nonsteroidal aromatase inhibitor. Overall response rates and time to progression did not differ between the groups (168).

  • A randomized trial compared capecitabine with capecitabine plus trastuzumab in patients with HER2-positive metastatic breast cancer that progressed on trastuzumab. Response rates were higher in the combination group (48.1% vs. 27.0%; P=0.0115), but the groups did not differ with regard to overall survival (25.5 months vs. 20.4 months) (169).

  • A randomized phase III study (TAnDEM) compared the combination of anastrozole plus trastuzumab with anastrozole alone in postmenopausal women with hormone/HER2-receptor co-positive metastatic breast cancer. The combination group had longer progression-free survival (4.8 months vs. 2.4 months; P=0.0016) (170).

  • A randomized trial compared letrozole plus lapatinib to letrozole plus placebo in patients with ER-positive metastatic breast cancer. Among HER2-positive patients, those on combination therapy had longer progression-free survival (8.2 vs. 3.0 months, p=0.019). Among HER2-negative patients, combination therapy and therapy with letrozole alone were equivalent (171).

  • A randomized trial compared placebo plus trastuzumab plus docetaxel (control group) with pertuzumab plus trastuzumab plus docetaxel (pertuzumab group) as first-line treatment in 808 patients with HER2-positive metastatic breast cancer. Treatment was continued until the time of disease progression or the development of toxic effects that could not be effectively managed. The median progression-free survival was 12.4 months in the control group compared with 18.5 months in the pertuzumab group (172). A follow-up report found that overall survival was lower in the pertuzumab group (28% vs. 38%) (173).

  • A randomized trial compared trastuzumab emtansine (T-DM1) to lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer who had previously been treated with trastuzumab and a taxane. Median progression-free survival, as assessed by independent review, was 9.6 months with T-DM1 vs. 6.4 months with lapatinib plus capecitabine. The objective response rate was higher with T-DM1 (43.6% vs. 30.8% with lapatinib plus capecitabine). Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%) (174).

  • A phase III, randomized trial compared everolimus plus exemestane with exemestane and placebo in the adjuvant setting or to treat advanced disease (or both) in 724 patients with hormone receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor. At the interim analysis, median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators. Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (175).

  • A retrospective, single-institution review of all breast cancer patients between 1997 and 2002 presenting with an intact tumor and synchronous metastatic disease evaluated the pathological attributes and optimal timing for surgery in patients who present with stage IV breast cancer and an intact primary. Multivariate analysis revealed patients having only one site of metastasis, negative margins, and white race had improved progression-free survival, and patients who underwent surgery in the 3- to 8.9-month or later period had improved metastatic progression-free survival as well (176).

Rationale
  • Metastatic breast cancer is an incurable disease; however, most patients can benefit from treatment that aims to adequately manage symptoms and improve survival.

  • Mastectomy in the context of distant disease is generally done to prevent uncontrolled locoregional disease or if there has been remarkable response to neoaduvant systemic chemotherapy with the bulk of disease burden remaining only in the breast.

Comments
  • Some patients, particularly those with soft tissue or bone-only involvement by metastatic disease, are likely to be among the 5% to 15% of patients who are alive after 10 years (177).

Encourage patients with breast cancer to assume a primary role in their treatment planning, and discuss issues related to primary treatment options and recovery from surgery. 
  • Discuss the following issues with patients undergoing evaluation and treatment of breast cancer:

    • Imaging and biopsy modalities

    • Definitive surgical options, including breast conservation vs. mastectomy

    • Recovery from surgery, including physical therapy to avoid lymphedema

    • Breast reconstruction

    • Need for assessment of axillary lymph nodes in most cases

    • Indications for and potential side effects of radiation therapy

    • Indications for and potential side effects of hormonal and chemotherapeutic agents

    • Psychosocial issues, including family dynamics and available support systems

Evidence
  • Consensus.

Rationale
  • Evaluation and treatment of breast cancer is complex and involves ongoing decision making that should be guided both by published data and individual patient preference.

Comments
  • Patients must be fully informed before giving consent, from the point when they first consider participating in a mammography screening program through to being patients managed by multidisciplinary teams when diagnosed with early breast cancer or as trial participants.

  • Patients should be made aware that research is necessary to address well-informed uncertainties and should be introduced to the concept of assignment within a clinical trial (178). Patients often struggle to understand randomization (e.g., why it is needed and what it means in practical terms).

  • It is sensible to avoid immediate breast reconstruction in patients with unrealistic expectations or psychological problems.

  • Patients should be forewarned of potential problems with any aspect of treatment; they are more likely to cope with unpleasant symptoms if they have been informed in advance that such symptoms may occur.

  • A trained breast care nurse navigator should be present at the time of diagnosis and during discussion of management options. This person can subsequently act as a key worker and be a primary point of contact for the patient.

Instruct patients about potential benefits and side effects of postoperative radiation therapy. 
  • Inform patients of the side effects of postoperative radiation therapy, including

    • Skin toxicity

    • Mild fatigue

  • Urge patients to avoid sun exposure while on therapy and to use skin moisturizers to minimize toxicity effects.

Evidence
  • Consensus.

Rationale
  • Most patients will develop acute skin toxicity, perhaps similar to a first-degree burn, and should carefully follow recommendations from their radiation oncologist to hasten recovery.

Comments
  • Patients often fear radiotherapy. It is important to emphasize that radiotherapy produces local symptoms affecting mainly the breast, is less commonly associated with systemic disturbance (compared with chemotherapy), and is most often transient, lasting up to a few months.

Instruct patients about potential benefits and short- and long-term side effects of systemic therapy. 
  • Describe the benefits of chosen therapy in terms of improved mortality or rates of recurrence.

  • Inform patients receiving chemotherapy that nausea is a potential side effect and provide them with an effective antinausea regimen. Advise adequate hydration.

  • Make patients aware of potential long-term effects of adjuvant therapy, including

    • Permanent amenorrhea following chemotherapy and associated risks for menopausal complications, such as osteoporosis, coronary disease, hot flushes, and sexual dysfunction

    • Late onset ventricular dysfunction following anthracyclines

    • Potentially reversible ventricular dysfunction following trastuzumab therapy

    • Myelodysplastic disorders following anthracyclines and alkylating agents

    • Cognitive dysfunction after chemotherapy

    • Mild to moderate weight gain not associated with any specific therapy

    • Vitamin D depletion and risk for osteoporosis in patients on an aromatase inhibitor

    • Risk for endometrial cancer in patients on tamoxifen

  • Emphasize the importance of regular exercise therapy to combat weight gain.

  • Instruct patients taking aromatase inhibitors about the need for vitamin D repletion and periodic DEXA scans.

  • Instruct patients taking tamoxifen about the need to have an annual gynecologic examination and to notify their primary care provider of any abnormal vaginal bleeding (particularly if postmenopausal) that would mandate an evaluation to exclude endometrial cancer.

  • In patients with metastatic disease, discuss choice of treatments that involves trade-offs between toxicity and palliation of symptoms and prolongation of life.

Evidence
  • A 2005 systematic review of cognitive impairment following chemotherapy for breast cancer included 6 studies. Studies generally found evidence for cognitive impairment with chemotherapy. The magnitude of the impairment varied; prospective studies found improvement in impairment over time (179).

  • A 2000 narrative review article discussed primary care for survivors of breast cancer (180).

Rationale
  • Decisions about adjuvant treatment often involve personal decisions weighing treatment morbidity against the potential risk for recurrence.

Discuss with patients the importance of ongoing follow-up after completion of initial therapy. 
  • Inform patients about the importance of

    • Annual mammographic follow-up of the contralateral breast and ipsilateral conserved breast

      • If treated with breast conservation, start 6 months after completion of therapy

    • Routine visits with members of the cancer care team every 3 to 6 months in the first 5 years after primary therapy

      • After the first 5 years of follow-up, patients may have annual follow-up with either a cancer specialist or a primary care provider with an interest in women's health issues

    • Coordinating cancer care with the patient's primary care providers (internal medicine specialist or gynecologist) to avoid duplication of efforts

    • Specific targeted blood test or imaging studies only if it is necessary to evaluate specific complaints suggesting disease recurrence (see Follow-up)

  • Explain to patients that other routine follow-up testing is not needed.

Evidence
  • A 2013 ASCO guideline on follow-up after primary therapy for breast cancer recommended physical exams every 3 to 6 months for 3 years, every 6 to 12 months for years 4 and 5, and annually thereafter. The guideline recommended that women with breast-conserving therapy have a mammogram after 1 year (as long as it is 6 months after radiation therapy) and annually thereafter. The guideline did not recommend other routine testing (181).

  • A 2005 Cochrane review of follow-up strategies for women treated with early breast cancer included 4 randomized trials with 3055 participants. Two trials compared clinical follow-up visits plus mammography to a more intensive strategy; there were no differences in disease-free (HR, 0.84 [CI, 0.71 to 1.00]) or overall (HR, 0.96 [CI, 0.80 to 1.15]) survival. One trial compared follow-up provided by specialists with that provided by general practitioners and found no difference in time to recurrence or quality of life but found higher satisfaction among patients treated by general practitioners. One trial compared more frequent with less frequent visits and found no difference in physician calls and consultations (182).

Rationale
  • Informed patients can participate appropriately in their own care.

Schedule regular follow-up visits and perform annual mammography. 
  • Schedule follow-up visits for patients every 3 to 6 months for the first 3 years, every 6 to 12 months in years 4 and 5, and annually thereafter.

  • At each visit,

    • Perform a physical exam including breast exam (in women who have had breast-conservation surgery)

    • Ask patients about medication adherence and reinforce the importance of adherence

    • Ask about side effects from therapies, such as hormonal therapies

    • Recommend an active lifestyle and ideal body weight (BMI 20 to 25) for optimal overall health and outcome

  • Avoid overlap among visits to primary care and specialist physicians to avoid duplication of effort.

  • Perform recommended cancer screening:

    • Perform annual mammograms, with the first one 1 year after the diagnosis of breast cancer and at least 6 months after the completion of radiation therapy

    • Follow standard recommendations for colon cancer screening

    • Provide routine gynecological care

  • See module Screening for Colorectal Cancer.

Evidence
  • A 2013 ASCO guideline on follow-up after primary therapy for breast cancer recommended physical exams every 3 to 6 months for 3 years, every 6 to 12 months for years 4 and 5, and annually thereafter. The guideline recommended that women with breast-conserving therapy have a mammogram after 1 year (as long as it is 6 months after radiation therapy) and annually thereafter. The guideline did not recommend other routine testing (181).

  • A 2005 Cochrane review of follow-up strategies for women treated with early breast cancer included 4 randomized trials with 3055 participants. Two trials compared clinical follow-up visits plus mammography with a more intensive strategy; there were no difference in disease-free (HR, 0.84 [CI, 0.71 to 1.00]) or overall (HR, 0.96 [CI, 0.80 to 1.15]) survival. One trial compared follow-up provided by specialists with that provided by general practitioners and found no difference in time to recurrence or quality of life but found higher satisfaction among patients treated by general practitioners. One trial compared more frequent with less frequent visits and found no difference in physician calls and consultations (182).

  • A 2011 systematic review addressed surveillance in women with breast cancer. A review of effectiveness included 8 studies and found that a surveillance strategy that includes mammography prevents mortality compared with a strategy without mammography. A review of the diagnostic accuracy of tests for breast cancer recurrence included 9 studies. Mammography had a sensitivity of 64% to 67% and a specificity between 85% and 97%. MRI had a sensitivity between 93% and 100% and a specificity between 88% and 96% (183).

  • A randomized trial compared point-of-need access with regular 6-monthly review in 237 breast cancer patients. After a follow-up time of 2 years, the groups had similar quality of life and psychological morbidity (184).

  • A case-control study of 369 women with ER-positive tumors who developed a second primary breast cancer compared with 734 matched control patients who did not develop a second primary tumor showed an association of obesity (BMI >30), smoking, and alcohol consumption with risk for contralateral breast cancer (185).

  • A prospective study of 1490 women diagnosed with stage I-III breast cancer showed an association of high fruit and vegetable consumption and physical activity with improved survivorship, regardless of obesity (186).

  • A 2005 narrative review of medication adherence noted that predictors of poor adherence include the presence of side effects associated with the medication and incomplete understanding of the benefits associated with its regular use (187).

  • A 2000 narrative review discussed the primary care of breast cancer survivors (180).

Rationale
  • Although prompt diagnosis of metastatic disease does not increase chances of survival, it can minimize potential morbidity.

  • Early diagnosis of second malignancies is key in enhancing survival chances.

Comments
  • Nurse-led follow-up may represent a more cost-effective strategy for monitoring breast cancer survivors who have a low risk for relapse, but depends on well-trained staff who adhere to clear and comprehensive guidelines.

  • Women (particularly if older than age 50) on adjuvant tamoxifen have an approximately 1% cumulative risk for developing endometrial cancer (188).

  • With increasing breast cancer survivorship, more patients are alive who have previously been treated for breast cancer. It is estimated that for 2008 the prevalence of breast cancer survivors in the U.K. was just over half a million women (representing 12% of the population over 65 years) (189).

Do not perform routine blood tests or imaging procedures to look for metastatic disease in the absence of specific symptoms.  
  • Do not order routine hemograms, blood chemistry studies, tumor markers for breast cancer, routine bone scans, chest radiographs, CT scans, MRI scans, PET scans, or ultrasound examinations in asymptomatic patients.

    • Note indications for specific testing

    • Consider the use of dedicated breast MRI for post-therapy surveillance and follow-up in women at high risk for bilateral disease, such as carriers of BRCA1 and BRCA2 mutations

    • In women with intact uteruses taking adjuvant tamoxifen, conduct yearly gynecologic assessments and evaluate vaginal spotting. Do not, however, perform routine endometrial biopsy or ultrasonography in asymptomatic women

Evidence
  • A 2013 ASCO guideline on follow-up after primary therapy for breast cancer recommended physical exams every 3 to 6 months for 3 years, every 6 to 12 months for years 4 and 5, and annually thereafter. The guideline recommended that women with breast-conserving therapy have a mammogram after 1 year (as long as it is 6 months after radiation therapy) and annually thereafter. The guideline did not recommend other routine testing, including blood tests (181).

  • A 2006 ACOG committee opinion on tamoxifen and uterine cancer stated that symptoms of endometrial hyperplasia should be evaluated in postmenopausal women on tamoxifen. The statement noted that premenopausal women on tamoxifen are not at increased risk for uterine cancer (190).

  • A cohort study evaluated the risk for breast cancer recurrence among patients with a history of breast cancer with and without BRCA1 and BRCA2 mutations. The rate of contralateral breast cancer was higher in women with genetic mutations, but the rate of ipsilateral recurrence was the same as in control patients (191).

Rationale
  • Early detection of asymptomatic metastatic breast cancer does not appear to affect survival.

  • Additional testing may lead to false-positive and false-negative results.

Comments
  • Avoid undertaking tests on demand for the main purpose of reassuring patients.

  • The routine use of PET or CT scanning for detection of recurrent breast cancer is not considered to be cost-effective in a managed health care system. Conventional imaging modalities should be used initially and PET or CT scanning used in special circumstances, such as determination of a primary lesion when a patient presents with a secondary deposit in the breast tissue (192).

Encourage patients with breast cancer to alert their physician about symptoms suggesting recurrence or spread of disease or side effects of treatment. 
  • Ask patients about new symptoms, such as another breast mass, weight loss, fatigue, bone or abdominal pain, and neurologic symptoms suggesting recurrent or progressive disease or a secondary hematologic malignancy.

  • Ask about and address symptoms of short- and long-term complications from radiation and hormonal and chemotherapy.

Evidence
  • Consensus.

Rationale
  • Although most new symptoms after initial breast cancer treatment are unlikely to be related to cancer recurrence, prompt identification of recurrence may help decrease disease morbidity.

  • Some of these symptoms may also be associated with secondary hematologic malignancies (myelodysplastic syndrome or leukemia) following systemic chemotherapy.

Work with patients to manage potential short- and long-term complications of therapy. 
  • For lymphedema, reduce arm lymph production and injury by

    • Avoiding punctures or injuries to the ipsilateral arm, and advising patients to gently perform nail and cuticle care

    • Minimizing injections and blood pressure checks, avoiding strenuous physical and weight-bearing activities, and avoiding tight clothing or jewelry on the ipsilateral arm

    • Considering early referral to a physical therapist

  • Consider postoperative arm massage by an experienced physical therapist to reduce pain and improve shoulder function following lymph-node dissection surgery.

  • Consider initiating growth factor support to improve the patient's quality of life while undergoing chemotherapy.

  • Avoid dismissing as irrelevant any cognitive dysfunction following adjuvant therapy.

  • Recognize the symptoms of fatigue and depression early and intervene; treat depression with individual or group counseling or short- or long-term drug therapy.

    • Avoid certain SSRIs (e.g., paroxetine, fluoxetine) in patients on tamoxifen

  • Recognize that fewer than one third of women older than age 40 will permanently resume menstrual activity after chemotherapy.

    • Meaure bone mineral density in menopausal women and in those on an adjuvant aromatase inhibitor

    • Discourage the use of estrogen, progesterone, or selective ER modulators for the treatment of osteoporosis or osteopenia in women with breast cancer

    • Encourage the use of a bisphosphonate to improve bone mineral density, and advise the patient to take supplemental calcium and vitamin D

  • Discourage the use of hormonal birth-control methods for women with continued menstruation, regardless of hormone-receptor status of the tumor, and recommend alternative methods, such as intrauterine devices, barrier methods, and tubal ligation or vasectomy for the partner, in those with no intention of future pregnancy.

Evidence
  • A 2010 Cochrane review of nonhormonal therapies for hot flushes in women with breast cancer included 16 randomized trials. SSRIs, SNRIs, gabapentin, and clonidine effectively reduced hot flushes; nonpharmacologic therapies were not effective (193).

  • A randomized trial compared early physiotherapy involving manual lymphatic drainage, massage of scar tissue, and progressive shoulder exercises with education in patients who underwent surgery for breast cancer. After one year, fewer patients in the intervention group developed lymphedema (7% vs. 25%; P=0.01) (194).

  • In a substudy of the NSABP B-32 trial examining patient-reported outcomes for patients undergoing either sentinel lymph-node biopsy or the same followed by completion axillary lymph-node dissection, arm morbidity was greater following formal dissection. However, although arm symptoms were significantly greater for the axillary dissection group at 6 months (mean, 4.8 vs. 3.0; P<0.001) and at 12 months (3.6 vs. 2.5; P=0.006), with more prolonged follow-up (12 to 36 months), reported outcomes were similar for the two groups with fewer than 15% having residual arm symptoms or activity limitation of moderate or severe degree (195).

  • A cohort study assessed cognitive dysfunction and mood in women undergoing chemotherapy or after chemotherapy and in healthy controls. More patients in the chemotherapy groups had severe cognitive impairment, but mood did not differ from controls (196).

  • A side study of the TEAM trial found no significant impairment of cognitive function in women using exemestane after 1 year of endocrine treatment. By contrast, those receiving tamoxifen only had lower neuropsychological scores in verbal memory and executive functioning (116).

  • A retrospective analysis of all adverse gynecological events with the ATAC trial found a significantly higher incidence among women in the tamoxifen arm compared with those taking anastrozole (34.2% vs. 20.5%; P<0.001) (197).

  • A 2001 narrative review discussed the problem of lymphedema (198).

  • A 2011 narrative review discussed chronic pain following breast cancer treatment, noting that it affects between 25% and 60% of patients (199).

  • A 2008 narrative review of drug interactions in the treatment of breast cancer and depression discussed tamoxifen interactions and noted that concomitant use of tamoxifen with certain SSRIs (e.g., paroxetine and fluoxetine) may decrease plasma levels of endoxifen, an active metabolite of tamoxifen (200).

  • A 2009 narrative review of reproductive care of young women with breast cancer discussed nonhormone methods of birth control (201).

Rationale
  • Lymphedema may occur in up to 20% of women and correlates with the extent of surgical dissection and radiation to the axilla. A combination of axillary dissection and radiotherapy is associated with lymphedema rates of up to 40%.

  • Cognitive dysfunction is a relatively common occurrence of unknown cause.

  • Fatigue, often of uncertain cause, and depression are common symptoms that can significantly interfere with patients' recovery and resumption of normal activities.

  • Patients are at risk for menopausal-related issues, such as osteoporosis, coronary disease, hot flushes, and dyspareunia, at a much younger age.

Comments
  • Consensus; there is a need for well-designed, randomized trials to determine the best approach to managing lymphedema (202).

  • Citalopram, escitalopram, fluvoxamine, sertraline, gabapentin, and venlafaxine appear to have little or no effect on tamoxifen metabolism.

  • Anecdotal evidence is abundant that fatigue and depression can significantly interfere with patients' quality of life.

Follow patients with metastatic disease closely and treat for symptom palliation. 
  • Discuss with patients their goals and objectives so that treatment can be tailored to their needs, including the desire to continue working, engaging in hobbies or physical activities, and caring for family members.

  • Instruct patients to watch for new symptoms, such as weight loss, fatigue, bone or abdominal pain, and new neurologic symptoms, which may be early signs of potentially devastating complications, such as cord compression or weight-bearing bone fractures; a change in personality or behavior seen by close family members or friends may indicate the presence of brain metastases.

  • Follow patients receiving chemotherapy every 3 to 4 weeks; follow patients on hormonal therapy every 1 to 3 months depending on symptoms.

  • Consider monitoring tumor markers, if abnormal, every 3 to 4 months in patients with metastatic disease to follow response to therapy and disease progression.

  • Monitor imaging tests, such as CT scans and bone scans, as needed based on the patient's specific disease and clinical presentation.

Evidence
  • Consensus.

Rationale
  • Early radiation therapy or orthopedic surgery may prevent paraplegia and bed-confining fractures.

  • Systemic chemotherapy or hormone therapy may delay cancer-related morbidity.

  • Although some chemotherapy drugs may prolong survival, the main treatment goal is palliation.

Table Grahic Jump Location
 Differential Diagnosis of Breast Mass

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DiseaseCharacteristics
Breast cancerFirm fixed mass with skin changes and possibly axillary lymphadenopathy. Skin thickening and erythema may be seen and may suggest inflammatory cancer. May be clinically indistinguishable from benign disease, so imaging (mammography, ultrasound) and biopsy are essential
Fibrocystic changes of the breastProminent nodularity and generalized lumpiness.
Pain may be exacerbated premenstrually
FibroadenomaDiscrete mass that is well circumscribed and mobile (may be tender on palpation).
If confirmed by ultrasound and needle biopsy, can be left alone
Breast cystLocalized pain often compatible with rapid expansion of a cyst.
Ultrasound usually diagnostic and is test of choice in women under 40
Breast hematomaTender mass, usually in association with breast trauma. May be followed by development of fat necrosis.
May occur after core biopsy (particularly with a larger gauge needle, e.g., size 11)
Breast abscessErythema of breast with possible tender fluctuant swelling, fever, more common in lactating breast with mastitis as initial presentation
Ductal papillomaUnilateral, spontaneous, single duct bloody discharge; mass usually not detectable
Referral to surgeon for duct exploration indicated (subareolar duct excision or microdochectomy)
Table Grahic Jump Location
 Drug Treatment for Breast Cancer

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Drug or Drug ClassDosingSide EffectsPrecautionsClinical Use
Selective estrogen receptor modulatorsHot flushes, diaphoresis, GI side effects, menstrual irregularity, VTE, edema, CNS effects, strokeAvoid with pregnancy
blackboxiconTamoxifen20 mg PO qdVisual impairment, hepatotoxicity, pancytopeniablackboxicon Risk for uterine malignancy, stroke, PE. Substrate of CYPs 3A4, 1A2, 2C9, 2D6. Inhibitor of CYP3A4 and P-gpAdjuvant therapy for invasive disease. Also for primary prevention in DCIS, palliation of metastatic disease
blackboxiconRaloxifene (Evista)60 mg PO qdMuscle cramps, arthralgiasblackboxicon Risk for VTE, stroke. May increase risk for endometrial or uterine cancer Caution with moderate CKD, hepatic diseaseAlternative to tamoxifen for prevention
Aromatase inhibitorsHot flushes, diaphoresis, GI effects, menstrual irregularity, VTE, edema, hypertension, CNS effects, osteoporosis, arthralgiasCaution with hepatic disease. Avoid in pregnancyAdjuvant and neoadjuvant therapy in postmenopausal women with hormone receptor(+) disease. Also for metastatic disease
Letrozole (Femara)2.5 mg PO qdDyspnea, hypercholesterolemia, visual impairment, hepatotoxicityCaution with severe CKD. Inhibits CYPs 2A6, 2C19. Substrate of CYPs 3A4, 2A6, 2C19
Anastrozole (Arimidex)1 mg PO qdAnemia, leukopenia, lymphedema, hypercholesterolemia, hepatotoxicity, MICaution with ischemic cardiac disease. No data with severe hepatic disease
Exemestane (Aromasin)25 mg PO qdArthralgia, visual impairment, hepatotoxicityCaution with CKD, CYP3A4 inducers
Estrogen receptor antagonist
Fulvestrant (Faslodex)500 mg IM given as two 250 mg IM injections, one in each buttock. Given on days 1, 15, 29, and then once monthlyGI effects, headache, back pain, hot flushes, pharyngitis, injection-site reactionsUse 250 mg IM with moderate hepatic disease. No data with severe hepatic diseaseFor postmenopausal women. Alternative to aromatase inhibitors in metastatic disease
Antineoplastic agents: biologic response modifiersNausea, vomiting, stomatitisAvoid with pregnancy, especially in first trimesterMetastatic disease, aduvant and neoadjuvant setting
blackboxiconTrastuzumab (Herceptin)8 mg/kg IV on week 1, then 6 mg/kg IV every 3 weeks. Or, 4 mg/kg IV on week 1, then 2 mg/kg IV every weekDiarrhea, arthralgia, back pain, bone pain, depression, fatigueblackboxicon Cardiomyopathy, infusion reactions, pulmonary toxicity, teratogenicityAdjuvant therapy or treatment of metastatic disease in HER2(+) women
Bevacizumab (Avastin)10 mg/kg IV on days 1 and 15. Or, 15 mg/kg IV every 3 weeksHypertension, neutropenia, nephrotoxicity, cardiotoxicity, VTE, abdominal pain, constipation, asthenia, dizziness, fatigue, neuropathy, alopecia, ovarian failure, exfoliative dermatitis, proteinuriablackboxicon GI perforation, wound dehiscence, hemorrhageMetastatic disease
blackboxiconLapatinib (Tykerb)1000-1500 mg PO qdCardiotoxicity, anemia, neutropenia, fatigue, pneumonitis, diarrhea, rash, QT prolongationblackboxicon Hepatotoxicity. Decrease dose with severe hepatic disease. Adjust dose with potent CYP3A4 inhibitors or inducers. Inhibits CYPs 3A4 and 2C8. Substrate and inhibitor of P-gpAdd to trastuzumab or use as a single agent in trastuzumab-refractory metastatic disease. Sometimes used in neoadjuvant setting
blackboxiconPertuzumab (Perjeta)Initial dose of 840 mg IV over 60 minutes. In 3 weeks, 420 mg IV over 30-60 minutes, and repeat every 3 weeksHematologic toxicity, infection risk. Alopecia, rash, pruritus, headache, dizziness, infusion reactions, lacrimation, antibody formation, fatigue, cough, hepatotoxicityblackboxicon Cardiomyopathy, embryo-fetal toxicity
Everolimus (Afinitor)10 mg PO qdHematologic toxicity, risk for infection, malignancy. Rash, hypersensitivity reactions, nephrotoxicity, infertility, pneumonitis, dyspnea, angioedema, hyperglycemia, hyperlipidemia, hepatotoxicityAvoid potent CYP3A4 inhibitors or inducers. Caution with CKD. Decrease dose with hepatic disease, moderate CYP3A4 or P-gp inhibitors
Other antineoplastic agentsHematologic toxicity, risk for infection or bleeding. Nausea, vomiting, alopeciaAvoid with pregnancy, especially in first trimesterMetastatic disease, aduvant and neoadjuvant setting
blackboxiconFluorouracil, 5-FUAs part of CMF regimen: 400-600 mg/m2 IV on days 1 and 8 of every cycle. Or 600 mg/m2 IV on day 1, every 21-28 daysDiarrhea, GI bleeding, stomatitis, hand and foot syndrome, neurotoxicity, lacrimation, cardiotoxicity, injection-site reactions, photosensitivityblackboxicon Hospitalize for first course due to severe toxic reactions. Consider dose reduction with hepatic disease
blackboxiconMethotrexateAs part of CMF regimen: 40-60 mg/m2 IV on day 1, every 21-28 daysNephrotoxicity, visual impairment, cardiotoxicity, TLSblackboxicon Avoid with pregnancy. Risk for malignancy. Monitor carefully. Significant toxicities: hematologic, GI, hepatic, pulmonary, dermatologic. Avoid with pleural or pericardial effusion, ascites, hepatic disease. Caution with CKD
CyclophosphamideAs part of CMF regimen: 100 mg/m2 PO on days 1-14. Or 500-1000 mg/m2 IV on day 1. As part of AC regimen: 600 mg/m2 on day 1 of every 14 daysHemorrhagic cystitis, infertility, SIADH, cardiotoxicity, interstitial pneumonitis, anaphylaxis, TLS, risk for malignancyConsider dose reduction if CrCl<55
blackboxiconDoxorubicinAs part of AC regimen: 60 mg/m2 IV on day 1, every 14 to 21 daysStomatitis, esophagitis, urine discoloration, excessive lacrimation, TLSblackboxicon Extravasation, cardiotoxicity, secondary malignancy, severe myelosuppression. Decrease dose with hepatic disease. Substrate of CYP3A4 and P-gp. Caution with obesityCheck echocardiograms periodically
blackboxiconEpirubicin (Ellence)60-100 mg/m2 IV every 21 daysStomatitis, esophagitis, urine discoloration, venous flare, radiation recall reaction, TLS, hot flushesblackboxicon Avoid extravasation. Cardiotoxicity, secondary AML, myelosuppression. Decrease dose with hepatic disease. Avoid with severe hepatic disease. Decrease dose with severe CKD
blackboxiconPaclitaxel175 mg/m2 IV every 3 weeksNeuropathy, edema, fever, asthenia, injection-site reactions, myalgia, arthralgia, hypotension, cardiotoxicity, diarrhea, stomatitis, radiation recall reaction, hepatotoxicityblackboxicon Treatment facility required. Anaphylaxis. Avoid with low neutrophil counts. Avoid extravasation. Must premedicate. Decrease dose with hepatic disease. Metabolized by CYPs 3A4, 2C8 and P-gp
blackboxiconDocetaxel (Taxotere, Docefrez)60-100 mg/m2 IV every 3 weeksNeuropathy, edema, rash, nail discoloration, dyspnea, injection-site reactions, diarrhea, stomatitis, radiation recall reaction, hepatotoxicityblackboxicon Increased mortality risk in certain patients. Risk for neutropenia, severe hypersensitivity reactions, fluid retention. Extreme caution with hepatic disease. Must premedicate. Metabolized by CYP3A
BisphosphonatesGI side effects, musculoskeletal pain, fever, hypocalcemia, hypophosphatemia, nephrotoxicity, injection-site reactions. Atypical bone fractures of femur with long-term useAvoid with pregnancy, severe CKD. Caution with CKDMetastatic bone disease
Pamidronate90 mg IV every 4 weeks. Administer over at least 2 hAnemia, fatigue, dyspnea, headacheNo data with severe hepatic disease
Zoledronic acid, zoledronate (Reclast)4 mg IV every 4 weeks. Administer over at least 15 minFlu-like syndrome
Ibandronate (Boniva)6 mg IV every 3-4 weeks. Or 50 mg PO qdHypertension, CNS effects, hypercholesterolemia, flu-like syndromeHypocalcemia. Anaphylaxis, including fatal events
RANK-ligand inhibitor
Denosumab
(Xgeva)
120 mg SC every 4 weeks. Calcium and vitamin D supplementation requiredSevere hypocalcemia, infection, nausea, flu-like syndrome, rashAvoid with pregnancy. Osteonecrosis of the jaw. Pancreatitis. Caution if CrCl <30. Monitor for secondary malignancyBone metastases, solid tumor. Limited long-term safety and efficacy data

blackboxicon = black box warning; AC = Adriamycin (doxorubicin), cyclophosphamide; AML = acute myelogenous leukemia; bid = twice daily; CKD = chronic kidney disease; CMF = cyclophosphamide, methotrexate and fluorouracil; CNS = central nervous system; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P450 isoenzyme; DCIS = ductal carcinoma in situ; GI = gastrointestinal; HER2 = human epidermal growth factor receptor 2; IM = intramuscular; IV = intravenous; MI = myocardial infarction; PE = pulmonary embolism; P-gp = P-glycoprotein; PO = oral; qd = once daily; RANK = receptor activator of nuclear factor κβ; SC = subcutaneous; SCr = serum creatinine; SIADH = syndrome of inappropriate secretion of antidiuretic hormone; TLS = tumor lysis syndrome; VTE = venous thromboembolism.

ACP Smart Medicine provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.

Table Grahic Jump Location
 Evaluation of Clinical Breast Abnormalities

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Breast AbnormalityDiagnostic Test
Palpable lump or mass
Age <30Ultrasound:
  Consider ultrasound, tissue diagnosis, or optional observation to assess resolution within 1 or 2 menstrual cycles.
  If cystic, observe or aspirate (if symptomatic or indeterminate). If fluid is bloody or a mass persists, consider biopsy or excision for diagnosis.
  If solid and indeterminate or suspicious, consider mammogram and tissue diagnosis (FNA, core biopsy, or surgical excision) to rule out benign process vs. atypical hyperplasia vs. LCIS vs. DCIS/invasive cancer. If results suggest fibroadenoma, consider observation (if <2 cm) or tissue diagnosis.
  If not visualized, obtain mammogram and consider tissue diagnosis
Needle biopsy:
  If no fluid and fibroadenoma, observe or excise; if indeterminate, obtain imaging study and tissue diagnosis.
  If fluid retrieved and mass resolves, reevaluate in 2-4 months; if bloody or mass persists, obtain imaging study and tissue diagnosis
Observation for 1-2 cycles:
  If resolves, do routine screening; if persists, obtain ultrasound or tissue diagnosis
Age ≥30Mammogram:
  BI-RADS category 1-3*
  Obtain ultrasound (see above)
  BI-RADS category 4-5†
  Obtain tissue diagnosis
Nipple discharge, no mass
Bilateral, milkyPregnancy test (if negative, endocrine evaluation)
Nonspontaneous,
  multiple ducts
Educate to stop compression of the breasts, also do mammogram if age ≥40
Persistent, spontaneous, unilateral, one duct, or serous/bloodyCytology optional, obtain imaging study and consider surgical referral for duct exploration
Thickening or asymmetry
Age <30Consider unilateral imaging study; if normal, reassess in 3-6 months; if abnormal, obtain tissue diagnosis
Age ≥30Obtain bilateral imaging study; if normal, reassess in 3-6 months; if abnormal, obtain tissue diagnosis
Skin changes (e.g., erythema, peau d’orange, scaling, nipple excoriation, eczema)Obtain bilateral imaging study; if normal, consider skin biopsy; if abnormal or indeterminate, needle biopsy or excision (also consider skin punch biopsy)

DCIS = ductal carcinoma in situ; FNA = fine-needle aspiration; LCIS = lobular carcinoma in situ.

* Breast Imaging Reporting and Data System: BI-RADS 1: negative; BI-RADS 2: benign finding; BI-RADS 3: probably benign finding and short interval follow-up suggested.

Breast Imaging Reporting and Data System: BI-RADS 4: suspicious abnormality, consider biopsy; BI-RADS 5: highly suggests malignancy, take appropriate action.

Table Grahic Jump Location
 Information on Breast Cancer Screening Guidelines

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The recommendations of the U.S. Preventive Services Task Force (2009) are as follows:
Recommends against routine screening mammography in women aged 40 to 49 years. In this age group the decision to start screening mammography should be an individual one and take into account patient context, including the patient's values regarding specific benefits and harms (Grade C recommendations)
Recommends biennial screening mammography for women aged 50 to 74 years (Grade B recommendation)
The evidence is insufficient to assess the additional benefits and harms of screening mammography in women aged 75 years or older (Grade I statement)
Recommends against teaching breast self-examination (Grade D recommendation)
The evidence is insufficient to assess the additional benefits and harms of clinical breast examination beyond screening mammography in women aged 40 or older (Grade I statement)
The evidence is insufficient to assess the additional benefits and harms of either digital mammography or magnetic resonance imaging instead of film mammography as screening modalities for breast cancer (Grade I statement)
The recommendations of the American College of Physicians (2007) regarding screening mammography for women aged 40 to 49 years are as follows:
Clinicians should periodically perform individualized assessment of the risk for breast cancer to help guide decisions about screening mammography
Clinicians should inform about the potential benefits and harms of screening mammography
Clinicians should base screening mammography decisions on the benefits and harms of screening, as well as on a woman's preferences and breast cancer risk profile
Further research on the net benefits and harms of breast cancer screening modalities is recommended
The recommendations of the Canadian Task Force on Preventive Health Care (2011) are as follows:
Upon reaching age 40, women should be informed of the potential benefits and risks of screening mammography and be assisted in deciding at what age to initiate screening
For women aged 40 to 49 years: recommendation is not to routinely screen (Grade C recommendation)
For women aged 50 to 69 years: Routine screening with mammography every 2 to 3 years is recommended (Weak recommendation; moderate-quality evidence)
For women aged 70 to 74: Routine screening with mammography every 2 to 3 years is recommended (Weak recommendation; low-quality evidence)
The recommendations of the American Cancer Society (reviewed 2013) are as follows:
All women should start annual screening mammography at age 40
All women should have yearly clinical breast examinations by a health care professional close to the time of mammography beginning at age 40
All women should receive clinical breast examinations from a health care professional every 3 years between the ages of 20 and 39
All women should be informed of the benefits and limitations of breast self-examinations beginning at age 20
The recommendations of the American College of Obstetricians and Gynecologists (2011) are as follows:
All women should begin annual screening mammography at age 40
All women should receive a clinical breast examination every 1 to 3 years between the ages of 20 and 39 and annually beginning at age 40
All women aged 20 and older should be educated regarding breast self-awareness
Table Grahic Jump Location
 Hazards of Screening Younger Women

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Harmful EffectConsequences
CostIncreased expenditure on intervention of no proven value
Radiation exposurePossible harm from radiation exposure
False-positive resultsUnnecessary breast biopsies; additional imaging studies; transient increases in general anxiety and depression
OverdiagnosisTreatment of a cancer that would otherwise not have become clinically apparent during a woman's lifetime; unnecessarily early treatment of a breast cancer that would have become apparent but would not have shortened the patient's life; financial and emotional consequences of being labeled a cancer patient
False-negative resultsFalse reassurance
PainPain associated with a procedure may be a disincentive from future screening
  • Inflammatory Breast Cancer Note that the right breast is larger than the left, is associated with an inverted nipple, and the inferior portion of the breast is erythematous. These findings are characteristic of inflammatory breast cancer, accounting for approximately 3% of all breast cancers. Figure courtesy of the Inflammatory Breast Cancer Research Foundation.
  • Peau d’orange Patients with primary inflammatory breast cancer often present with an enlarged, painful breast with thickened, sometimes discolored overlying skin, and enlarged pores that resemble the skin of an orange (peau d’orange).
  • Axillary Vein Thrombosis Axillary vein thrombosis associated with inflammatory breast cancer.
Moyer VA. Medications for Risk Reduction of Primary Breast Cancer in Women: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2013 Sep 24 [Epub ahead of print]. (PMID: 24061472)
 
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Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-88. (PMID: 9747868)
 
Wickerham DL, Costantino JP, Vogel V, Cronin W, Cecchini R, Atkins J, et al. The study of tamoxifen and raloxifene (STAR): initial findings from the NSABP P-2 breast cancer prevention study [Abstract]. J Clin Oncol. 2006;24(Suppl):LBA5.
 
Visvanathan K, Chlebowski RT, Hurley P, Col NF, Ropka M, Collyar D, et al; American Society of Clinical Oncology. American Society of Clinical Oncology clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol. 2009;27:3235-58. (PMID: 19470930)
 
Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, et al.; National Surgical Adjuvant Breast and Bowel Project. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prev Res (Phila). 2010;3:696-706. (PMID: 20404000)
 
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Land SR, Wickerham DL, Costantino JP, Ritter MW, Vogel VG, Lee M, et al. Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2742-51. (PMID: 16754728)
 
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Willett LR. ACP Journal Club. Exemestane prevented invasive breast cancer in postmenopausal women at moderately increased risk. Ann Intern Med. 2011;155:JC4-3. [Full Text] (PMID: 22007062)
 
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AC

doxorubicin (Adriamycin) and cyclophosphamide (drug regimen)

AJCC

American Joint Committee on Cancer

ASCO

American Society of Clinical Oncology

ATAC

Arimidex, Tamoxifen, Alone or in Combination trial

ATLAS

Adjuvant Tamoxifen: Longer Against Shorter (trial)

BMI

body mass index

CI

confidence interval

CISH

chromogenic in situ hybridization

CMF

cyclophosphamide, methotrexate and fluorouracil

CT

computed tomography

DCIS

ductal carcinoma in situ

DEXA

dual-energy x-ray absorptiometry

DIEAP

deep inferior epigastric artery perfortor flap

ER

estrogen receptor

FDG-PET

fludeoxyglucose positron emission tomography

FISH

fluorescent in situ hybridization

FNA

fine-needle aspiration

HER2

human epidermal growth factor receptor 2

HR

hazard ratio

ICSI

Institute for Clinical Systems Improvement

iv

intravenous

LCIS

lobular carcinoma in situ

LHRH

luteinizing hormone-releasing hormone

MRI

magnetic resonance imaging

NOAH

Neo-Adjuvant Herceptin (trial)

NSABP

National Surgical Adjuvant Breast and Bowel Project

OR

odds ratio

PCR

polymerase chain reaction

PET

positron emission tomography

po

oral

qd

once daily

RR

relative risk

SABRE

Study of Anastrozole with the Bisphosphonate Risedronate

SEER

Surveillance, Epidemiology, and End Results

sc

subcutaneous

SNRI

serotonin-norepinephrine reuptake inhibitor

SSRI

selective serotonin reuptake inhibitor

STAR

Study of Tamoxifen and Raloxifene (National Surgical Adjuvant Breast and Bowel Project P-2 trial)

TACT

Taxotere as Adjuvant Chemotherapy (trial)

TAnDEM

Trastuzumab and Anastrozole Directed Against ER-Positive HER2-Positive Mammary Carcinoma (study)

T-DM1

trastuzumab emtansine

TEAM

Tamoxifen and Exemestane Adjuvant Multinational (trial)

TNM

tumor, node, metastasis

TRAM

transverse rectus abdominis myocutaneous


Terms
Founder effect

In population genetics, the loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population, leading to an increased prevalence of a genetic characteristic in a specific patient population that can trace its ancestors to a small group of individuals, in part to either geographic (e.g., Iceland) or ethnic isolation (e.g., Ashkenazi Jews)

Gail Model

A method to estimate the chance that a woman with given age and risk factors will develop breast cancer over a specified interval. It was developed from case-control data from the Breast Cancer Detection Demonstration Project

Postlumpectomy radiation therapy

The use of radiation therapy following lumpectomy to complete the so-called breast-conservation procedure in patients who opt not to have a modified radical mastectomy. This is typically recommended in patients diagnosed with breast cancer of an early stage, involving a localized lesion of ≤4 cm that has been removed with clear margins

Postmastectomy radiation therapy

The use of radiation therapy after mastectomy in patients who are felt to be at increased risk for chest wall recurrence. Such patients include those with positive margins after resection, dermal invasion with locally advanced or inflammatory breast cancer, tumors >5 cm (T3 lesion), four or more involved axillary lymph nodes, or, in premenopausal women, at least one involved lymph node

Adjuvant (chemo)therapy

Cancer chemotherapy employed after the primary tumor has been removed by some other method

Neoadjuvant (chemo)therapy

Initial use of chemotherapy in patients with localized cancer in order to decrease the tumor burden before treatment with other modalities

Combination (chemo)therapy

The combination of several different agents or modalities simultaneously in order to enhance their effectiveness

Induction (chemo)therapy

The use of drug therapy as the initial treatment for patients presenting with advanced cancer that cannot be treated by other means

Regional (chemo)therapy

(Chemo)therapy administered as a regional perfusion


Guidelines

ACOG Committee Opinion No. 593: Management of Women With Dense Breasts Diagnosed by Mammography

ACOG Committee Opinion. No. 601: Tamoxifen and Uterine Cancer

ACOG Practice bulletin no. 122: Breast cancer screening

ACR–ACS–CAP–SSO Practice guideline for the breast conservation therapy in the management of invasive breast carcinoma

Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update

American Cancer Society recommendations for early breast cancer detection in women without breast symptoms

American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer.

American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer

American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer.

American Society of Clinical Oncology endorsement of the cancer care Ontario practice guideline on adjuvant ovarian ablation in the treatment of premenopausal women with early-stage invasive breast cancer

American Society of Clinical Oncology: Sentinel lymph node biopsy for patients with early-stage breast cancer

Breast cancer follow-up and management after primary treatment: American Society of Clinical Oncology clinical practice guideline update

Canadian Medical Association: Baseline staging tests in primary breast cancer: a practice guideline

Health Canada: Clinical practice guidelines for the care and treatment of breast cancer: 15. Treatment for women with stage III or locally advanced breast cancer

Institute for Clinical Systems Improvement: Diagnosis of Breast Disease

International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment

Medications for Risk Reduction of Primary Breast Cancer in Women: U.S. Preventive Services Task Force Recommendation Statement.

NICE guidelines: Advanced breast cancer (update): Diagnosis and treatment

NICE guidelines: Early and locally advanced breast cancer: diagnosis and treatment

Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology

Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update

Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement.

Screening mammography for women 40 to 49 years of age: a clinical practice guideline from the American College of Physicians

Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American society of Clinical Oncology clinical practice guideline

Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline.

Systematic Reviews

A systematic review of FDG-PET in breast cancer

A systematic review of the effectiveness of magnetic resonance imaging (MRI) as an addition to mammography and ultrasound in screening young women at high risk of breast cancer

Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer

Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer: patient-level meta-analysis of randomised trials

Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women (Cochrane review)

Axillary recurrence after a tumour-negative sentinel node biopsy in breast cancer patients: A systematic review and meta-analysis of the literature

Bisphosphonates and other bone agents for breast cancer (Cochrane review)

Breast MRI in clinically and mammographically occult breast cancer presenting with an axillary metastasis: a systematic review.

Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer (Cochrane review)

Early detection of breast cancer: benefits and risks of supplemental breast ultrasound in asymptomatic women with mammographically dense breast tissue. A systematic review

Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials

Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials

Effects of omega-3 fatty acids on cancer risk: a systematic review

Evaluation of abnormal mammography results and palpable breast abnormalities

Follow-up strategies for women treated for early breast cancer (Cochrane review)

High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer (Cochrane review)

Immediate versus delayed reconstruction following surgery for breast cancer (Cochrane review)

Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen

Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers

Non-hormonal interventions for hot flushes in women with a history of breast cancer (Cochrane review)

Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review

Post-operative radiotherapy for ductal carcinoma in situ of the breast (Cochrane review)

Postoperative tamoxifen for ductal carcinoma in situ (Cochrane review)

Preoperative chemotherapy for women with operable breast cancer (Cochrane review)

Preoperative ultrasound-guided needle biopsy of axillary nodes in invasive breast cancer: meta-analysis of its accuracy and utility in staging the axilla

Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials

Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis.

Screening for breast cancer: an update for the U.S. Preventive Services Task Force

Screening for breast cancer with mammography (Cochrane review)

Single agent versus combination chemotherapy for metastatic breast cancer (Cochrane review)

Surgery versus primary endocrine therapy for operable primary breast cancer in elderly women (70 years plus) (Cochrane review)

Systematic review: comparative effectiveness of core-needle and open surgical biopsy to diagnose breast lesions

Systematic review: gene expression profiling assays in early-stage breast cancer

Systematic review: using magnetic resonance imaging to screen women at high risk for breast cancer

The clinical effectiveness and cost-effectiveness of different surveillance mammography regimens after the treatment for primary breast cancer: systematic reviews registry database analyses and economic evaluation

The clinical efficacy of cytotoxic agents in locally advanced or metastatic breast cancer patients pretreated with an anthracycline and a taxane: a systematic review

The nature and severity of cognitive impairment associated with adjuvant chemotherapy in women with breast cancer: a meta-analysis of the current literature

The rational clinical examination. Does this patient have breast cancer? The screening clinical breast examination: should it be done? How?

Trastuzumab containing regimens for early breast cancer (Cochrane review)

Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials

Use of medications to reduce risk for primary breast cancer: a systematic review for the U.S. Preventive Services Task Force

Volume-controlled vs no/short-term drainage after axillary lymph node dissection in breast cancer surgery: a meta-analysis.

Systematic Reviews

ASCO Guideline Update Recommends Aromatase Inhibitors Alone or with Tamoxifen as Adjuvant Therapy for Post-Menopausal Women with Hormone-Receptor Positive Breast Cancer

Agency for Healthcare Research and Quality: Having a Breast Biopsy: A Guide for Women and Their Families

Agency for Healthcare Research and Quality: Reducing the Risk of Breast Cancer With Medicine: A Guide for Women

American Cancer Society: Can Breast Cancer Be Found Early?

American Cancer Society: How Is Breast Cancer Staged?

American Cancer Society: What Happens After Treatment for Breast Cancer?

American Cancer Society: What is Breast Cancer?

American College of Physicians: Awareness is Power: Cancer and the African American

Consumer Reports: Breast Health: Your Questions Answered

Consumer Reports Best Buy Drugs: Evaluating Prescription Drugs Used to Treat the Symptoms of Menopause

National Cancer Institute: Adjuvant and Neoadjuvant Therapy for Breast Cancer: Questions and Answers: Fact Sheet

National Cancer Institute: Breast Cancer Prevention (PDQ®)

National Cancer Institute: Breast Cancer Screening (PDQ®)

National Cancer Institute: Breast Cancer Treatment (PDQ®)

National Cancer Institute: Male Breast Cancer Treatment (PDQ®)

National Cancer Institute: Understanding Breast Changes: A Health Guide for All Women

National Cancer Institute: What You Need To Know About Breast Cancer

Agency for Healthcare Research and Quality: Having a Breast Biopsy: A Guide for Women and Their Families (Spanish)

Agency for Healthcare Research and Quality: Reducing the Risk of Breast Cancer With Medicine: A Guide for Women (Spanish)

National Cancer Institute: Adjuvant and Neoadjuvant Therapy for Breast Cancer: Questions and Answers: Fact Sheet (Spanish)

National Cancer Institute: Breast Cancer Treatment (PDQ®) (Spanish)

National Cancer Institute: Male Breast Cancer Treatment (PDQ®) (Spanish)

DOI: 10.7326/d192
The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.
Author(s) and Disclosures:
Antonio C. Wolff, MD is a consultant for Pfizer, received honorarium from AstraZeneca, Pfizer, received grants from Roche, Pfizer, Wyeth. John Benson, MA, DM, FRCS(Eng), FRCS(Ed) has nothing to disclose. Tara Tomlin Barnett, MD has nothing to disclose. Shannon M. Haenel, DO has nothing to disclose. Courtney S. Yau, MD has nothing to disclose. Ashwini Bhat, MBBS has nothing to disclose.

One or more of the present or past ACP Smart Medicine physician editors worked on this module and had nothing to disclose: Davoren Chick, MD, FACP; Deborah Korenstein, MD, FACP; Marjorie Lazoff, MD, FACP; Richard Lynn, MD, FACP.

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