Current Medical Diagnosis & Treatment 2015

17

Breast Disorders

Armando E. Giuliano, MD
Sara A. Hurvitz, MD

BENIGN BREAST DISORDERS

FIBROCYSTIC CONDITION

image ESSENTIAL INQUIRIES

image Painful, often multiple, usually bilateral masses in the breast.

image Rapid fluctuation in the size of the masses is common.

image Frequently, pain occurs or worsens and size increases during premenstrual phase of cycle.

image Most common age is 30–50. Rare in postmenopausal women not receiving hormonal replacement.

image General Considerations

Fibrocystic condition is the most frequent lesion of the breast. Although commonly referred to as “fibrocystic disease,” it does not, in fact, represent a pathologic or anatomic disorder. It is common in women 30–50 years of age but rare in postmenopausal women who are not taking hormonal replacement. Estrogen is considered a causative factor. There may be an increased risk in women who drink alcohol, especially women between 18 and 22 years of age. Fibrocystic condition encompasses a wide variety of benign histologic changes in the breast epithelium, some of which are found so commonly in normal breasts that they are probably variants of normal but have nonetheless been termed a “condition” or “disease.”

The microscopic findings of fibrocystic condition include cysts (gross and microscopic), papillomatosis, adenosis, fibrosis, and ductal epithelial hyperplasia. Although fibrocystic condition has generally been considered to increase the risk of subsequent breast cancer, only the variants with a component of epithelial proliferation (especially with atypia) or increased breast density on mammogram represent true risk factors.

image Clinical Findings

A. Symptoms and Signs

Fibrocystic condition may produce an asymptomatic mass in the breast that is discovered by accident, but pain or tenderness often calls attention to it. Discomfort often occurs or worsens during the premenstrual phase of the cycle, at which time the cysts tend to enlarge. Fluctuations in size and rapid appearance or disappearance of a breast mass are common with this condition as are multiple or bilateral masses and serous nipple discharge. Patients will give a history of a transient lump in the breast or cyclic breast pain.

B. Diagnostic Tests

Mammography and ultrasonography should be used to evaluate a mass in a patient with fibrocystic condition. Ultrasonography alone may be used in women under 30 years of age. Because a mass due to fibrocystic condition is difficult to distinguish from carcinoma on the basis of clinical findings, suspicious lesions should be biopsied. Fine-needle aspiration (FNA) cytology may be used, but if a suspicious mass that is nonmalignant on cytologic examination does not resolve over several months, it should be excised or biopsied by core needle. Surgery should be conservative, since the primary objective is to exclude cancer. Occasionally, FNA cytology will suffice. Simple mastectomy or extensive removal of breast tissue is rarely, if ever, indicated for fibrocystic condition.

image Differential Diagnosis

Pain, fluctuation in size, and multiplicity of lesions are the features most helpful in differentiating fibrocystic condition from carcinoma. If a dominant mass is present, the diagnosis of cancer should be assumed until disproven by biopsy. Mammography may be helpful, but the breast tissue in these young women is usually too radiodense to permit a worthwhile study. Sonography is useful in differentiating a cystic mass from a solid mass, especially in women with dense breasts. Final diagnosis, however, depends on analysis of the excisional biopsy specimen or needle biopsy.

$image Treatment

When the diagnosis of fibrocystic condition has been established by previous biopsy or is likely because the history is classic, aspiration of a discrete mass suggestive of a cyst is indicated to alleviate pain and, more importantly, to confirm the cystic nature of the mass. The patient is reexamined at intervals thereafter. If no fluid is obtained by aspiration, if fluid is bloody, if a mass persists after aspiration, or if at any time during follow-up a persistent or recurrent mass is noted, biopsy should be performed.

Breast pain associated with generalized fibrocystic condition is best treated by avoiding trauma and by wearing a good supportive brassiere during the night and day. Hormone therapy is not advisable, because it does not cure the condition and has undesirable side effects. Danazol (100–200 mg orally twice daily), a synthetic androgen, is the only treatment approved by the US Food and Drug Administration (FDA) for patients with severe pain. This treatment suppresses pituitary gonadotropins, but androgenic effects (acne, edema, hirsutism) usually make this treatment intolerable; in practice, it is rarely used. Similarly, tamoxifen reduces some symptoms of fibrocystic condition, but because of its side effects, it is not useful for young women unless it is given to reduce the risk of cancer. Postmenopausal women receiving hormone replacement therapy may stop or change doses of hormones to reduce pain. Oil of evening primrose (OEP), a natural form of gamolenic acid, has been shown to decrease pain in 44–58% of users. The dosage of gamolenic acid is six capsules of 500 mg orally twice daily. Studies have also demonstrated a low-fat diet or decreasing dietary fat intake may reduce the painful symptoms associated with fibrocystic condition. Further research is being done to determine the effects of topical treatments such as topical nonsteroidal anti-inflammatory drugs as well as topical hormonal drugs such as topical tamoxifen.

The role of caffeine consumption in the development and treatment of fibrocystic condition is controversial. Some studies suggest that eliminating caffeine from the diet is associated with improvement while other studies refute the benefit entirely. Many patients are aware of these studies and report relief of symptoms after giving up coffee, tea, and chocolate. Similarly, many women find vitamin E (400 international units daily) helpful; however, these observations remain anecdotal.

image Prognosis

Exacerbations of pain, tenderness, and cyst formation may occur at any time until menopause, when symptoms usually subside, except in patients receiving hormonal replacement. The patient should be advised to examine her own breasts regularly just after menstruation and to inform her practitioner if a mass appears. The risk of breast cancer developing in women with fibrocystic condition with a proliferative or atypical component in the epithelium or papillomatosis is higher than that of the general population. These women should be monitored carefully with physical examinations and imaging studies.

Liu Y et al. Intakes of alcohol and folate during adolescence and risk of proliferative benign breast disease. Pediatrics. 2012 May;129(5):e1192–8. [PMID: 22492774]

Salzman B et al. Common breast problems. Am Fam Physician. 2012 Aug 15;86(4):343–9. [PMID: 22963023]

FIBROADENOMA OF THE BREAST

This common benign neoplasm occurs most frequently in young women, usually within 20 years after puberty. It is somewhat more frequent and tends to occur at an earlier age in black women. Multiple tumors are found in 10–15% of patients.

The typical fibroadenoma is a round or ovoid, rubbery, discrete, relatively movable, nontender mass 1–5 cm in diameter. It is usually discovered accidentally. Clinical diagnosis in young patients is generally not difficult. In women over 30 years, fibrocystic condition of the breast and carcinoma of the breast must be considered. Cysts can be identified by aspiration or ultrasonography. Fibroadenoma does not normally occur after menopause but may occasionally develop after administration of hormones.

No treatment is usually necessary if the diagnosis can be made by needle biopsy or cytologic examination. Excision with pathologic examination of the specimen is performed if the diagnosis is uncertain. Cryoablation, or freezing of the fibroadenoma, appears to be a safe procedure if the lesion is consistent with fibroadenoma on histology prior to ablation. Cryoablation is not appropriate for all fibroadenomas because some are too large to freeze or the diagnosis may not be certain. There is no obvious advantage to cryoablation of a histologically proven fibroadenoma except that some patients may feel relief that a mass is gone. However, at times a mass of scar or fat necrosis replaces the mass of the fibroadenoma. Reassurance seems preferable. It is usually not possible to distinguish a large fibroadenoma from a phyllodes tumor on the basis of needle biopsy results or imaging alone and histology is usually required.

Phyllodes tumor is a fibroadenoma-like tumor with cellular stroma that grows rapidly. It may reach a large size and, if inadequately excised, will recur locally. The lesion can be benign or malignant. If benign, phyllodes tumor is treated by local excision with a margin of surrounding breast tissue. The treatment of malignant phyllodes tumor is more controversial, but complete removal of the tumor with a rim of normal tissue avoids recurrence. Because these tumors may be large, simple mastectomy is sometimes necessary. Lymph node dissection is not performed, since the sarcomatous portion of the tumor metastasizes to the lungs and not the lymph nodes.

Abe M et al. Malignant transformation of breast fibroadenoma to malignant phyllodes tumor: long-term outcome of 36 malignant phyllodes tumors. Breast Cancer. 2011 Oct;18(4):268–72. [PMID: 22121516]

Amin AL et al. Benign breast disease. Surg Clin North Am. 2013 Apr;93(2):299–308. [PMID: 23464687]

Gutwein LG et al. Utilization of minimally invasive breast biopsy for the evaluation of suspicious breast lesions. Am J Surg. 2011 Aug;202(2):127–32. [PMID: 21295284]

$NIPPLE DISCHARGE

In order of decreasing frequency, the following are the most common causes of nipple discharge in the nonlactating breast: duct ectasia, intraductal papilloma, and carcinoma. The important characteristics of the discharge and some other factors to be evaluated by history and physical examination are listed in Table 17–1.

Table 17–1. Characteristics of nipple discharge in the nonpregnant, nonlactating woman.

image

Spontaneous, unilateral, serous or serosanguineous discharge from a single duct is usually caused by an intraductal papilloma or, rarely, by an intraductal cancer. A mass may not be palpable. The involved duct may be identified by pressure at different sites around the nipple at the margin of the areola. Bloody discharge is suggestive of cancer but is more often caused by a benign papilloma in the duct. Cytologic examination may identify malignant cells, but negative findings do not rule out cancer, which is more likely in women over age 50 years. In any case, the involved bloody duct—and a mass if present—should be excised. A ductogram (a mammogram of a duct after radiopaque dye has been injected) is of limited value since excision of the suspicious ductal system is indicated regardless of findings. Ductoscopy, evaluation of the ductal system with a small scope inserted through the nipple, has been attempted but is not effective management.

In premenopausal women, spontaneous multiple duct discharge, unilateral or bilateral, most noticeable just before menstruation, is often due to fibrocystic condition. Discharge may be green or brownish. Papillomatosis and ductal ectasia are usually detected only by biopsy. If a mass is present, it should be removed.

A milky discharge from multiple ducts in the nonlactating breast may occur from hyperprolactinemia. Serum prolactin levels should be obtained to search for a pituitary tumor. Thyroid-stimulating hormone (TSH) helps exclude causative hypothyroidism. Numerous antipsychotic drugs and other drugs may also cause a milky discharge that ceases on discontinuance of the medication.

Oral contraceptive agents or estrogen replacement therapy may cause clear, serous, or milky discharge from a single duct, but multiple duct discharge is more common. In the premenopausal woman, the discharge is more evident just before menstruation and disappears on stopping the medication. If it does not stop, is from a single duct, and is copious, exploration should be performed since this may be a sign of cancer.

A purulent discharge may originate in a subareolar abscess and require removal of the abscess and the related lactiferous sinus.

When localization is not possible, no mass is palpable, and the discharge is nonbloody, the patient should be reexamined every 3 or 4 months for a year, and a mammogram and an ultrasound should be performed. Although most discharge is from a benign process, patients may find it annoying or disconcerting. To eliminate the discharge, proximal duct excision can be performed both for treatment and diagnosis.

Chen L et al. Bloody nipple discharge is a predictor of breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2012 Feb;132(1):9–14. [PMID: 21947751]

Huang W et al. Evaluation and management of galactorrhea. Am Fam Physician. 2012 Jun 1;85(11):1073–80. [PMID: 22962879]

Salzman B et al. Common breast problems. Am Fam Physician. 2012 Aug 15;86(4):343–9. [PMID: 22963023]

FAT NECROSIS

Fat necrosis is a rare lesion of the breast but is of clinical importance because it produces a mass (often accompanied by skin or nipple retraction) that is usually indistinguishable from carcinoma even with imaging studies. Trauma is presumed to be the cause, though only about 50% of patients give a history of injury. Ecchymosis is occasionally present. If untreated, the mass effect gradually disappears. The safest course is to obtain a biopsy. Needle biopsy is often adequate, but frequently the entire mass must be excised, primarily to exclude carcinoma. Fat necrosis is common after segmental resection, radiation therapy, or flap reconstruction after mastectomy.

BREAST ABSCESS

During nursing, an area of redness, tenderness, and induration may develop in the breast. The organism most commonly found in these abscesses is Staphylococcus aureus (see Puerperal Mastitis, Chapter 19).

Infection in the nonlactating breast is rare. A subareolar abscess may develop in young or middle-aged women who are not lactating (Figure 17–1). These infections tend to recur after incision and drainage unless the area is explored during a quiescent interval, with excision of the involved $lactiferous duct or ducts at the base of the nipple. In the nonlactating breast, inflammatory carcinoma must always be considered. Thus, incision and biopsy of any indurated tissue with a small piece of erythematous skin is indicated when suspected abscess or cellulitis in the nonlactating breast does not resolve promptly with antibiotics. Often needle or catheter drainage is adequate to treat an abscess, but surgical incision and drainage may be necessary.

image

image Figure 17–1. Breast abscess and cellulitis. (Reproduced with permission, from Richard P. Usatine, MD.)

Amin AL et al. Benign breast disease. Surg Clin North Am. 2013 Apr;93(2):299–308. [PMID: 23464687]

Trop I et al. Breast abscesses: evidence-based algorithms for diagnosis, management, and follow-up. Radiographics. 2011 Oct;31(6):1683–99. [PMID: 21997989]

Wang K et al. The Mammotome biopsy system is an effective treatment strategy for breast abscess. Am J Surg. 2013 Jan;205(1):35–8. [PMID: 23036601]

DISORDERS OF THE AUGMENTED BREAST

At least 4 million American women have had breast implants. Breast augmentation is performed by placing implants under the pectoralis muscle or, less desirably, in the subcutaneous tissue of the breast. Most implants are made of an outer silicone shell filled with a silicone gel, saline, or some combination of the two. Capsule contraction or scarring around the implant develops in about 15–25% of patients, leading to a firmness and distortion of the breast that can be painful. Some require removal of the implant and surrounding capsule.

Implant rupture may occur in as many as 5–10% of women, and bleeding of gel through the capsule is noted even more commonly. Although silicone gel may be an immunologic stimulant, there is no increase in autoimmune disorders in patients with such implants. The FDA has advised symptomatic women with ruptured silicone implants to discuss possible surgical removal with their clinicians. However, women who are asymptomatic and have no evidence of rupture of a silicone gel prosthesis should probably not undergo removal of the implant. Women with symptoms of autoimmune illnesses often undergo removal, but no benefit has been shown.

Studies have failed to show any association between implants and an increased incidence of breast cancer. However, breast cancer may develop in a patient with an augmentation prosthesis, as it does in women without them. Detection in patients with implants is more difficult because mammography is less able to detect early lesions. Mammography is better if the implant is subpectoral rather than subcutaneous. Prostheses should be placed retropectorally after mastectomy to facilitate detection of a local recurrence of cancer, which is usually cutaneous or subcutaneous and is easily detected by palpation. There is a possible association of lymphoma of the breast with silicone implants, but this has not been clearly established.

If a cancer develops in a patient with implants, it should be treated in the same manner as in women without implants. Such women should be offered the option of mastectomy or breast-conserving therapy, which may require removal or replacement of the implant. Radiotherapy of the augmented breast often results in marked capsular contracture. Adjuvant treatments should be given for the same indications as for women who have no implants.

Jewell ML. Silicone gel breast implants at 50: the state of the science. Aesthet Surg J. 2012 Nov;32(8):1031–4. [PMID: 23012658]

Kim B et al. Anaplastic large cell lymphoma and breast implants: results from a structured expert consultation process. Plast Reconstr Surg. 2011 Sep;128(3):629–39. [PMID: 21502904]

Lavigne E et al. Breast cancer detection and survival among women with cosmetic breast implants: systematic review and meta-analysis of observational studies. BMJ. 2013 Apr 29;346:f2399. [PMID: 23637132]

Taylor CR et al. Anaplastic large cell lymphoma occurring in association with breast implants: review of pathologic and immunohistochemical features in 103 cases. Appl Immunohistochem Mol Morphol. 2013 Jan;21(1):13–20. [PMID: 23235342]

Vase MO et al. Breast implants and anaplastic large-cell lymphoma: a Danish population-based cohort study. Cancer Epidemiol Biomarkers Prev. 2013 Nov;22(11):2126–9. [PMID: 23956025]

Yang N et al. The augmented breast: a pictorial review of the abnormal and unusual. AJR Am J Roentgenol. 2011 Apr;196(4):W451–60. [PMID: 21427311]

CARCINOMA OF THE FEMALE BREAST

image ESSENTIAL INQUIRIES

image Risk factors include age, delayed childbearing, positive family history of breast cancer or genetic mutations (BRCA1, BRCA2), and personal history of breast cancer or some types of proliferative conditions.

image Early findings: Single, nontender, firm to hard mass with ill-defined margins; mammographic abnormalities and no palpable mass.

image Later findings: Skin or nipple retraction; axillary lymphadenopathy; breast enlargement, erythema, edema, pain; fixation of mass to skin or chest wall.

$image Incidence & Risk Factors

Breast cancer will develop in one of eight American women. Next to skin cancer, breast cancer is the most common cancer in women; it is second only to lung cancer as a cause of death. In 2013, there were approximately 232,340 new cases and 39,620 deaths from breast cancer in women in the United States. An additional 64,640 cases of breast carcinoma in situ were detected, principally by screening mammography. Worldwide, breast cancer is diagnosed in approximately 1.38 million women, and about 458,000 die of breast cancer each year, with the highest rates of diagnosis in Western and Northern Europe, Australia, New Zealand, and North America and lowest rates in Sub-Saharan Africa and Asia. These regional differences in incidence are likely due to the variable availability of screening mammography as well as differences in reproductive and hormonal factors. In western countries, incidence rates decreased with a reduced use of postmenopausal hormone therapy and mortality declined with increased use of screening and improved treatments. In contrast, incidence and mortality from breast cancer in many African and Asian countries has increased as reproductive factors have changed (such as delayed childbearing) and as the incidence of obesity has risen.

The most significant risk factor for the development of breast cancer is age. A woman’s risk of breast cancer rises rapidly until her early 60s, peaks in her 70s, and then declines. A significant family history of breast or ovarian cancer may also indicate a high risk of developing breast cancer. Germline mutations in the BRCA family of tumor suppressor genes accounts for approximately 5–10% of breast cancer diagnoses and tend to cluster in certain ethnic groups, including women of Ashkenazi Jewish descent. Women with a mutation in the BRCA1 gene, located on chromosome 17, have an estimated 85% chance of developing breast cancer in their lifetime. Other genes associated with an increased risk of breast and other cancers include BRCA2 (associated with a gene on chromosome 13); ataxia-telangiectasia mutation; and mutation of the tumor suppressor gene p53. If a woman has a compelling family history (such as breast cancer diagnosed in two first-degree relatives, especially if diagnosed younger than age 50; ovarian cancer; male breast cancer; or a first-degree relative with bilateral breast cancer), genetic testing may be appropriate. In general, it is best for a woman who has a strong family history to meet with a genetics counselor to undergo a risk assessment and decide whether genetic testing is indicated.

Even when genetic testing fails to reveal a predisposing genetic mutation, women with a strong family history of breast cancer are at higher risk for development of breast cancer. Women who are BRCA-negative but have mutation-affected women in their family also appear to be at increased risk. Compared with a woman with no affected family members, a woman who has one first-degree relative (mother, daughter, or sister) with breast cancer has double the risk of developing breast cancer and a woman with two first-degree relatives with breast cancer has triple the risk of developing breast cancer. The risk is further increased for a woman whose affected family member was premenopausal at the time of diagnosis or had bilateral breast cancer. Lifestyle and reproductive factors also contribute to risk of breast cancer. Nulliparous women and women whose first full-term pregnancy occurred after the age of 30 have an elevated risk. Late menarche and artificial menopause are associated with a lower incidence, whereas early menarche (under age 12) and late natural menopause (after age 55) are associated with an increase in risk. Combined oral contraceptive pills may increase the risk of breast cancer. Several studies show that concomitant administration of progesterone and estrogen to postmenopausal women may markedly increase the incidence of breast cancer, compared with the use of estrogen alone or with no hormone replacement treatment. The Women’s Health Initiative prospective randomized study of hormone replacement therapy stopped treatment with estrogen and progesterone early because of an increased risk of breast cancer compared with untreated women or women treated with estrogen alone. Alcohol consumption, high dietary intake of fat, and lack of exercise may also increase the risk of breast cancer. Fibrocystic breast condition, when accompanied by proliferative changes, papillomatosis, or atypical epithelial hyperplasia, and increased breast density on mammogram are also associated with an increased incidence. A woman who had cancer in one breast is at increased risk for cancer developing in the other breast. In these women, a contralateral cancer develops at the rate of 1% or 2% per year. Women with cancer of the uterine corpus have a risk of breast cancer significantly higher than that of the general population, and women with breast cancer have a comparably increased risk of endometrial cancer. Socioeconomic and racial factors have also been associated with breast cancer risk. Breast cancer tends to be diagnosed more frequently in women of higher socioeconomic status and is more frequent in white women than in black women.

Women at greater than average risk for developing breast cancer (Table 17–2) should be identified by their practitioners and monitored carefully. Risk assessment models have been developed and several have been $validated (most extensively the Gail 2 model) to evaluate a woman’s risk of developing cancer. Those with an exceptional family history should be counseled about the option of genetic testing. Some of these high-risk women may consider prophylactic mastectomy, oophorectomy, or tamoxifen, an FDA-approved preventive agent. The Prevention and Observation of Surgical Endpoints (PROSE) consortium monitored women with deleterious BRCA1/2 mutations from 1974 to 2008 and reported that 15% of women with a known BRCA mutation underwent bilateral prophylactic mastectomy, and none of them developed breast cancer during the 3 years of follow-up. In contrast, subsequent breast cancer developed in 98 (7%) of the 1372 women who did not have surgery. Moreover, women who underwent prophylactic salpingo-oophorectomy had a lower risk of ovarian cancer, all-cause mortality, as well as breast cancer- and ovarian cancer-specific mortality.

Table 17–2. Factors associated with increased risk of breast cancer.

image

Women with genetic mutations in whom breast cancer develops may be treated in the same way as women who do not have mutations (ie, lumpectomy), though there is an increased risk of ipsilateral and contralateral breast cancer after lumpectomy for these women. One study showed that of patients with a diagnosis of breast cancer who were found to be carriers of a BRCA mutation, approximately 50% chose to undergo bilateral mastectomy.

Evans et al. Increased rate of phenocopies in all age groups in BRCA1/BRCA2 mutation kindred, but increased prospective breast cancer risk is confined to BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev. 2013 Dec;22(12):2269–76. [PMID: 24285840]

Zheng JS et al. Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies. BMJ. 2013 Jun 27;346:f3706. [PMID: 23814120]

image Prevention

Several clinical trials have evaluated the use of selective estrogen receptor modulators (SERMs), including tamoxifen and raloxifene, for prevention of breast cancer in women with no personal history of breast cancer but at high risk for developing the disease. A meta-analysis of nine of these studies including 83,399 women with a median follow-up of 65 months demonstrated a 38% reduction in breast cancer incidence (hazard ratio [HR], 0.62; 95% CI, 0.56, 0.69) with a 10-year cumulative incidence of 6.3% in control groups and 4.2% in SERM-treated groups. An increased risk of endometrial cancer and venous thromboembolic events but a reduced risk of vertebral fractures was seen in SERM groups. While SERMs have been shown to be effective at reducing the risk of breast cancer, the uptake of this intervention by women has been relatively low, possibly due to the perceived risks and side effects of therapy. A cost-effectiveness study based on a meta-analysis of four randomized prevention trials showed that tamoxifen saves costs and improves life expectancy when higher risk (Gail 5-year risk at least 1.66%) women under the age of 55 years were treated.

Similar to SERMs, aromatase inhibitors (AIs), such as exemestane and anastrozole, have shown success in preventing breast cancer with a lower risk of uterine cancer and thromboembolic events, although bone loss is a significant side effect of this treatment.

Collaborative Group on Hormonal Factors in Breast Cancer. Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol. 2012 Nov;13(11):1141–51. [PMID: 23084519]

Cuzick J et al; IBIS-II investigators. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet. 2014 Mar 22;383(9922):1041–8. [PMID: 24333009]

Cuzick J et al; SERM Chemoprevention of Breast Cancer Overview Group. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet. 2013 May 25;381(9880):1827–34. [PMID: 23639488]

Desantis C et al. Breast Cancer Statistics, 2013. CA Cancer J Clin. 2014 Jan-Feb;64(1):52–62. [PMID: 24114568]

Eheman C et al. Annual Report to the Nation on the status of cancer, 1975–2008, featuring cancers associated with excess weight and lack of sufficient physical activity. Cancer. 2012 May 1;118(9):2338–66. [PMID: 22460733]

Goss PE et al; CTG MAP.3 Study Investigators. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011 Jun 23;364(25):2381–91. [PMID: 21639806]

Schwartz MD et al. Long-term outcomes of BRCA1/BRCA2 testing: risk reduction and surveillance. Cancer. 2012 Jan 15;118(2):510–7. [PMID: 21717445]

image Early Detection of Breast Cancer

A. Screening Programs

A number of large screening programs, consisting of physical and mammographic examination of asymptomatic women, have been conducted over the years. On average, these programs identify 10 cancers per 1000 women over the age of 50 and 2 cancers per 1000 women under the age of 50. Screening detects cancer before it has spread to the lymph nodes in about 80% of the women evaluated. This increases the chance of survival to about 85% at 5 years.

About one-third of the abnormalities detected on screening mammograms will be found to be malignant when biopsy is performed. The probability of cancer on a screening mammogram is directly related to the Breast Imaging Reporting and Data System (BIRADS) assessment, and work-up should be performed based on this classification. Women 20–40 years of age should have a breast examination as part of routine medical care every 2–3 years. Women over age 40 years should have annual breast examinations. The sensitivity of mammography varies from approximately 60% to 90%. This sensitivity depends on several factors, including patient age (breast density) and tumor size, location, and mammographic appearance. In young women with dense breasts, mammography is less sensitive than in older women with fatty breasts, in whom mammography can detect at least 90% of malignancies. Smaller tumors, particularly those without calcifications, are more difficult to detect, especially in dense breasts. The lack of sensitivity and the low incidence of breast cancer in young women have led to questions concerning the value of mammography for screening in $women 40–50 years of age. The specificity of mammography in women under 50 years varies from about 30% to 40% for nonpalpable mammographic abnormalities to 85% to 90% for clinically evident malignancies. In 2009, the US Preventive Services Task Force recommended against routine screening mammography in this age range, and also recommended mammography be performed every 2 years for women between the ages of 50 and 74. The change in recommendation for screening women age 40–50 were particularly controversial in light of several meta-analyses that included women in this age group and showed a 15–20% reduction in the relative risk of death from breast cancer with screening mammography. To add to the controversy, an analysis of the Surveillance, Epidemiology and End Results (SEER) database from 1976 to 2008 suggests that screening mammography has led to substantial increases in the number of breast cancer cases diagnosed but has only had a minor impact on the rate of women presenting with advanced disease. These data should all be taken into consideration when advising a patient about the usefulness of screening mammography. The American Cancer Society continues to recommend yearly mammography for women beginning at the age of 40, continuing as long as good health lasts.

B. Clinical Breast Examination and Self-Examination

Breast self-examination (BSE) has not been shown to improve survival. Because of the lack of strong evidence demonstrating value, the American Cancer Society no longer recommends monthly BSE. While BSE is not a recommended practice, patients should recognize and report any breast changes to their clinicians as it remains an important facet of proactive care. In contrast to BSE, the American Cancer Society recommends CBE every 3 years in women ages 20–39 and annually starting at the age of 40. Although studies have not consistently shown any additional benefit of CBE over routine screening mammography, CBE should be performed.

C. Imaging

Mammography is the most reliable means of detecting breast cancer before a mass can be palpated. Most slowly growing cancers can be identified by mammography at least 2 years before reaching a size detectable by palpation. Film screen mammography delivers < 0.4 cGy to the mid breast per view. Although full-field digital mammography provides an easier method to maintain and review mammograms, it has not been proven that it provides better images or increases detection rates more than film mammography. In subset analysis of a large study, digital mammography seemed slightly superior in women with dense breasts. Computer-assisted detection has not shown any increase in detection of cancers. Tomosynthesis creates tomographic “slices” of the breast volume with a single acquisition. This technique may improve the sensitivity of mammogram especially in patients with dense breast tissue.

Calcifications are the most easily recognized mammographic abnormality. The most common findings associated with carcinoma of the breast are clustered pleomorphic microcalcifications. Such calcifications are usually at least five to eight in number, aggregated in one part of the breast and differing from each other in size and shape, often including branched or V- or Y-shaped configurations. There may be an associated mammographic mass density or, at times, only a mass density with no calcifications. Such a density usually has irregular or ill-defined borders and may lead to architectural distortion within the breast but may be subtle and difficult to detect.

Indications for mammography are as follows: (1) to screen at regular intervals asymptomatic women at high risk for developing breast cancer (see above); (2) to evaluate each breast when a diagnosis of potentially curable breast cancer has been made, and at regular intervals thereafter; (3) to evaluate a questionable or ill-defined breast mass or other suspicious change in the breast; (4) to search for an occult breast cancer in a woman with metastatic disease in axillary nodes or elsewhere from an unknown primary; (5) to screen women prior to cosmetic operations or prior to biopsy of a mass, to examine for an unsuspected cancer; (6) to monitor those women with breast cancer who have been treated with breast-conserving surgery and radiation; and (7) to monitor the contralateral breast in those women with breast cancer treated with mastectomy.

Patients with a dominant or suspicious mass on examination must undergo biopsy despite mammographic findings. The mammogram should be obtained prior to biopsy so that other suspicious areas can be noted and the contralateral breast can be evaluated. Mammography is never a substitute for biopsy because it may not reveal clinical cancer, especially in a very dense breast, as may be seen in young women with fibrocystic changes, and may not reveal medullary cancers.

Communication and documentation among the patient, the referring practitioner, and the interpreting physician are critical for high-quality screening and diagnostic mammography. The patient should be told about how she will receive timely results of her mammogram; that mammography does not “rule out” cancer; and that she may receive a correlative examination such as ultrasound at the mammography facility if referred for a suspicious lesion. She should also be aware of the technique and need for breast compression and that this may be uncomfortable. The mammography facility should be informed in writing by the clinician of abnormal physical examination findings. The Agency for Health Care Policy and Research (AHCPR) Clinical Practice Guidelines strongly recommend that all mammography reports be communicated in writing to the patient and referring practitioner. Legislation has been passed in a number of US states that requires imaging facilities to report to patients the density of their breasts. This may prompt women with dense breasts to discuss with their clinician whether or not additional screening options would be appropriate in addition to mammogram.

MRI and ultrasound may be useful screening modalities in women who are at high risk for breast cancer but not for the general population. The sensitivity of MRI is much higher than mammography; however, the specificity is $significantly lower and this results in multiple unnecessary biopsies. The increased sensitivity despite decreased specificity may be considered a reasonable trade-off for those at increased risk for developing breast cancer but not for normal-risk population. In 2009, the National Comprehensive Cancer Network (NCCN) guidelines recommended MRI in addition to screening mammography for high-risk women, including those with BRCA1/2 mutations, those who have a lifetime risk of breast cancer of > 20%, and those with a personal history of LCIS. Women who received radiation therapy to the chest in their teens or twenties are also known to be at high risk for developing breast cancer and screening MRI may be considered in addition to mammography. MRI is useful in women with breast implants to determine the character of a lesion present in the breast and to search for implant rupture and at times is helpful in patients with prior lumpectomy and radiation.

Bleyer A et al. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med. 2012 Nov 22;367(21):1998–2005. [PMID: 23171096]

Drukteinis JS et al. Beyond mammography: new frontiers in breast cancer screening. Am J Med. 2013 Jun;126(6):472–9. [PMID: 23561631]

Gross CP et al. The cost of breast cancer screening in the Medicare population. JAMA Intern Med. 2013 Feb 11;173(3):220–6. [PMID: 23303200]

Hendrick RE et al. United States Preventive Services Task Force screening mammography recommendations: science ignored. AJR Am J Roentgenol. 2011 Feb;196(2):W112–6. [PMID: 21257850]

Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. Lancet. 2012 Nov 17;380(9855):1778–86. [PMID: 23117178]

Morrow M et al. MRI for breast cancer screening, diagnosis, and treatment. Lancet. 2011 Nov 19;378(9805):1804–11. [PMID: 22098853]

Plescia M et al. The National Prevention Strategy and breast cancer screening: scientific evidence for public health action. Am J Public Health. 2013 Sep;103(9):1545–8. [PMID: 23865665]

Tria Tirona M. Breast cancer screening update. Am Fam Physician. 2013 Feb 15;87(4):274–8. [PMID: 23418799]

Warner E. Clinical practice. Breast-cancer screening. N Engl J Med. 2011 Sep 15;365(11):1025–32. [PMID: 21916640]

image Clinical Findings Associated with Early Detection of Breast Cancer

A. Symptoms and Signs

The presenting complaint in about 70% of patients with breast cancer is a lump (usually painless) in the breast. About 90% of these breast masses are discovered by the patient. Less frequent symptoms are breast pain; nipple discharge; erosion, retraction, enlargement, or itching of the nipple; and redness, generalized hardness, enlargement, or shrinking of the breast. Rarely, an axillary mass or swelling of the arm may be the first symptom. Back or bone pain, jaundice, or weight loss may be the result of systemic metastases, but these symptoms are rarely seen on initial presentation.

The relative frequency of carcinoma in various anatomic sites in the breast is shown in Figure 17–2.

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image Figure 17–2. Frequency of breast carcinoma at various anatomic sites.

Inspection of the breast is the first step in physical examination and should be carried out with the patient sitting, arms at her sides and then overhead. Abnormal variations in breast size and contour, minimal nipple retraction, and slight edema, redness, or retraction of the skin can be identified (Figure 17–3). Asymmetry of the breasts and retraction or dimpling of the skin can often be accentuated by having the patient raise her arms overhead or press her hands on her hips to contract the pectoralis muscles. Axillary and supraclavicular areas should be thoroughly palpated for enlarged nodes with the patient sitting (Figure 17–4). Palpation of the breast for masses or other changes should be performed with the patient both seated and $supine with the arm abducted (Figure 17–5). Palpation with a rotary motion of the examiner’s fingers as well as a horizontal stripping motion has been recommended.

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image Figure 17–3. Peau d’orange sign (resemblance to the skin of an orange due to lymphedema) in advanced breast cancer. (Reproduced with permission, from Richard P. Usatine, MD.)

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image Figure 17–4. Palpation of axillary region for enlarged lymph nodes.

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image Figure 17–5. Palpation of breasts. Palpation is performed with the patient supine and arm abducted.

Breast cancer usually consists of a nontender, firm or hard mass with poorly delineated margins (caused by local infiltration). Very small (1–2 mm) erosions of the nipple epithelium may be the only manifestation of Paget disease of the breast. Watery, serous, or bloody discharge from the nipple is an occasional early sign but is more often associated with benign disease.

A small lesion, < 1 cm in diameter, may be difficult or impossible for the examiner to feel but may be discovered by the patient. She should always be asked to demonstrate the location of the mass; if the practitioner fails to confirm the patient’s suspicions and imaging studies are normal, the examination should be repeated in 2–3 months, preferably 1–2 weeks after the onset of menses. During the premenstrual phase of the cycle, increased innocuous nodularity may suggest neoplasm or may obscure an underlying lesion. If there is any question regarding the nature of an abnormality under these circumstances, the patient should be asked to return after her menses. Ultrasound is often valuable and mammography essential when an area is felt by the patient to be abnormal but the physician feels no mass. MRI may be considered, but the lack of specificity should be discussed by the clinician and the patient. MRI should not be used to rule out cancer because MRI has a false-negative rate of about 3–5%. Although lower than mammography, this false-negative rate cannot permit safe elimination of the possibility of cancer. False negatives are more likely seen in infiltrating lobular carcinomas and DCIS.

Metastases tend to involve regional lymph nodes, which may be palpable. One or two movable, nontender, not particularly firm axillary lymph nodes 5 mm or less in diameter are frequently present and are generally of no significance. Firm or hard nodes larger than 1 cm are typical of metastases. Axillary nodes that are matted or fixed to skin or deep structures indicate advanced disease (at least stage III). On the other hand, if the examiner thinks that the axillary nodes are involved, that impression will be borne out by histologic section in about 85% of cases. The incidence of positive axillary nodes increases with the size of the primary tumor. Noninvasive cancers (in situ) do not metastasize. Metastases are present in about 30% of patients with clinically negative nodes.

In most cases, no nodes are palpable in the supraclavicular fossa. Firm or hard nodes of any size in this location or just beneath the clavicle should be biopsied. Ipsilateral supraclavicular or infraclavicular nodes containing cancer indicate that the tumor is in an advanced stage (stage III or IV). Edema of the ipsilateral arm, commonly caused by metastatic infiltration of regional lymphatics, is also a sign of advanced cancer.

B. Laboratory Findings

Liver or bone metastases may be associated with elevation of serum alkaline phosphatase. Hypercalcemia is an occasional important finding in advanced cancer of the breast. Carcinoembryonic antigen (CEA) and CA 15-3 or CA 27-29 may be used as markers for recurrent breast cancer but are not helpful in diagnosing early lesions.

C. Imaging for Metastases

For patients with suspicious symptoms or signs (bone pain, abdominal symptoms, elevated liver biochemical tests) or locally advanced disease (clinically abnormal lymph nodes or large primary tumors), staging scans are indicated prior to surgery or systemic therapy. Chest imaging with CT or radiographs may be done to evaluate for pulmonary metastases. Abdominal imaging with CT or ultrasound may be obtained to evaluate for liver metastases. Bone scans using 99mTc-labeled phosphates or phosphonates are more sensitive than skeletal radiographs in detecting metastatic breast cancer. Bone scanning has not proved to be of clinical value as a routine preoperative test in the absence of symptoms, $physical findings, or abnormal alkaline phosphatase or calcium levels. The frequency of abnormal findings on bone scan parallels the status of the axillary lymph nodes on pathologic examination. Positron emission tomography (PET) scanning alone or combined with CT (PET-CT) is effective for detecting soft tissue or visceral metastases in patients with symptoms or signs of metastatic disease.

D. Diagnostic Tests

1. Biopsy—The diagnosis of breast cancer depends ultimately on examination of tissue or cells removed by biopsy. Treatment should never be undertaken without an unequivocal histologic or cytologic diagnosis of cancer. The safest course is biopsy examination of all suspicious lesions found on physical examination or mammography, or both. About 60% of lesions clinically thought to be cancer prove on biopsy to be benign, while about 30% of clinically benign lesions are found to be malignant. These findings demonstrate the fallibility of clinical judgment and the necessity for biopsy.

All breast masses require a histologic diagnosis with one probable exception, a nonsuspicious, presumably fibrocystic mass, in a premenopausal woman. Rather, these masses can be observed through one or two menstrual cycles. However, if the mass is not cystic and does not completely resolve during this time, it must be biopsied. Figures 17–6 and 17–7 present algorithms for management of breast masses in premenopausal and postmenopausal patients.

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image Figure 17–6. Evaluation of breast masses in premenopausal women. (Adapted, with permission, from Chang S, Haigh PI, Giuliano AE. Breast disease. In: Berek JS, Hacker NF [editors], Practical Gynecologic Oncology, 4th edition, LWW, 2004.)

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image Figure 17–7. Evaluation of breast masses in postmenopausal women. (Adapted, with permission, from Chang S, Haigh PI, Giuliano AE. Breast disease. In: Berek JS, Hacker NF [editors], Practical Gynecologic Oncology, 4th edition, LWW, 2004.)

$The simplest biopsy method is needle biopsy, either by aspiration of tumor cells (FNA cytology) or by obtaining a small core of tissue with a hollow needle (core biopsy).

FNA cytology is a useful technique whereby cells are aspirated with a small needle and examined cytologically. This technique can be performed easily with virtually no morbidity and is much less expensive than excisional or open biopsy. The main disadvantages are that it requires a pathologist skilled in the cytologic diagnosis of breast cancer and it is subject to sampling problems, particularly because deep lesions may be missed. Furthermore, noninvasive cancers usually cannot be distinguished from invasive cancers and immunohistochemical tests to determine expression of hormone receptors and the amplification of the HER2 oncogene cannot be reliably performed on FNA biopsies. The incidence of false-positive diagnoses is extremely low, perhaps 1–2%. The false-negative rate is as high as 10%. Most experienced clinicians would not leave a suspicious dominant mass in the breast even when FNA cytology is negative unless the clinical diagnosis, breast imaging studies, and cytologic studies were all in agreement, such as a fibrocystic lesion or fibroadenoma.

Large-needle (core needle) biopsy removes a core of tissue with a large cutting needle and is the diagnostic procedure of choice for both palpable and image-detected abnormalities. Hand-held biopsy devices make large-core needle biopsy of a palpable mass easy and cost effective in the office with local anesthesia. As in the case of any needle biopsy, the main problem is sampling error due to improper positioning of the needle, giving rise to a false-negative test result. This is extremely unusual with image-guided biopsies. Core biopsy allows the tumor to be tested for the expression of biological markers, such as estrogen receptor (ER), progesterone receptor (PR) and HER2.

Open biopsy under local anesthesia as a separate procedure prior to deciding upon definitive treatment is becoming less common with the increasing use of core needle biopsy. Needle biopsy, when positive, offers a more rapid approach with less expense and morbidity, but when nondiagnostic it must be followed by open biopsy. It generally consists of an excisional biopsy, which is done through an incision with the intent to remove the entire abnormality, not simply a sample. Additional evaluation for metastatic disease and therapeutic options can be discussed with the patient after the histologic or cytologic diagnosis of cancer has been established. As an alternative in highly suspicious circumstances, the diagnosis may be made on frozen section of tissue obtained by open biopsy under general anesthesia. If the frozen section is positive, the surgeon can proceed immediately with the definitive operation. This one-step method is rarely used today except when a cytologic study has suggested cancer but is not diagnostic and there is a high clinical suspicion of malignancy in a patient well prepared for the diagnosis of cancer and its treatment options.

In general, the two-step approach—outpatient biopsy followed by definitive operation at a later date—is preferred in the diagnosis and treatment of breast cancer, because patients can be given time to adjust to the diagnosis of cancer, can consider alternative forms of therapy, and can seek a second opinion if they wish. There is no adverse effect from the few week delay of the two-step procedure.

2. Ultrasonography—Ultrasonography is performed primarily to differentiate cystic from solid lesions but may show signs suggestive of carcinoma. Ultrasonography may show an irregular mass within a cyst in the rare case of intracystic carcinoma. If a tumor is palpable and feels like a cyst, an 18-gauge needle can be used to aspirate the fluid and make the diagnosis of cyst. If a cyst is aspirated and the fluid is nonbloody, it does not have to be examined cytologically. If the mass does not recur, no further diagnostic test is necessary. Nonpalpable mammographic densities that appear benign should be investigated with ultrasound to determine whether the lesion is cystic or solid. These may even be needle biopsied with ultrasound guidance.

3. Mammography—When a suspicious abnormality is identified by mammography alone and cannot be palpated by the clinician, the lesion should be biopsied under mammographic guidance. In thecomputerized stereotactic guided core needle technique, a biopsy needle is inserted into the lesion with mammographic guidance, and a core of tissue for histologic examination can then be examined. Vacuum assistance increases the amount of tissue obtained and improves diagnosis.

Mammographic localization biopsy is performed by obtaining a mammogram in two perpendicular views and placing a needle or hook-wire near the abnormality so that the surgeon can use the metal needle or wire as a guide during operation to locate the lesion. After mammography confirms the position of the needle in relation to the lesion, $an incision is made and the subcutaneous tissue is dissected until the needle is identified. Often, the abnormality cannot even be palpated through the incision—as is the case with microcalcifications—and thus it is essential to obtain a mammogram of the specimen to document that the lesion was excised. At that time, a second marker needle can further localize the lesion for the pathologist. Stereotactic core needle biopsies have proved equivalent to mammographic localization biopsies. Core biopsy is preferable to mammographic localization for accessible lesions since an operation can be avoided. A metal clip should be placed after any image-guided core biopsy to facilitate finding the site of the lesion if subsequent treatment is necessary.

4. Other imaging modalities—Other modalities of breast imaging have been investigated for diagnostic purposes. Automated breast ultrasonography is useful in distinguishing cystic from solid lesions but should be used only as a supplement to physical examination and mammography. Ductography may be useful to define the site of a lesion causing a bloody discharge, but since biopsy is almost always indicated, ductography may be omitted and the blood-filled nipple system excised. Ductoscopy has shown some promise in identifying intraductal lesions, especially in the case of pathologic nipple discharge, but in practice, this technique is rarely used. MRI is highly sensitive but not specific and should not be used for screening except in highly selective cases. For example, MRI is useful in differentiating scar from recurrence postlumpectomy and may be valuable to screen high-risk women (eg, women with BRCA mutations). It may also be of value to examine for multicentricity when there is a known primary cancer; to examine the contralateral breast in women with cancer; to examine the extent of cancer, especially lobular carcinomas; or to determine the response to neoadjuvant chemotherapy. Moreover, MRI-detected suspicious findings that are not seen on mammogram or ultrasound may be biopsied under MRI-guidance. PET scanning does not appear useful in evaluating the breast itself but is useful to examine for distant metastases.

5. Cytology—Cytologic examination of nipple discharge or cyst fluid may be helpful on rare occasions. As a rule, mammography (or ductography) and breast biopsy are required when nipple discharge or cyst fluid is bloody or cytologically questionable.

image Differential Diagnosis

The lesions to be considered most often in the differential diagnosis of breast cancer are the following, in descending order of frequency: fibrocystic condition of the breast, fibroadenoma, intraductal papilloma, lipoma, and fat necrosis.

image Staging

The American Joint Committee on Cancer and the International Union Against Cancer have agreed on a TNM (tumor, regional lymph nodes, distant metastases) staging system for breast cancer. Using the TNM staging system enhances communication between researchers and clinicians. Table 17–3 outlines the TNM classification.

Table 17–3. TNM staging for breast cancer.

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image Pathologic Types

Numerous pathologic subtypes of breast cancer can be identified histologically (Table 17–4).

Table 17–4. Histologic types of breast cancer.

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Except for the in situ cancers, the histologic subtypes have only a slight bearing on prognosis when outcomes are compared after accurate staging. The noninvasive cancers by definition are confined by the basement membrane of the ducts and lack the ability to spread. Histologic parameters for invasive cancers, including lymphovascular invasion and tumor grade, have been shown to be of prognostic value. Immunohistochemical analysis for expression of hormone receptors and for overexpression of HER2 in the primary tumor offers prognostic and therapeutic information.

image Special Clinical Forms of Breast Cancer

A. Paget Carcinoma

Paget carcinoma is not common (about 1% of all breast cancers). Over 85% of cases are associated with an underlying invasive or noninvasive cancer, usually a well differentiated infiltrating ductal carcinoma or a DCIS. The ducts of the nipple epithelium are infiltrated, but gross nipple changes are often minimal, and a tumor mass may not be palpable.

Because the nipple changes appear innocuous, the diagnosis is frequently missed. The first symptom is often itching or burning of the nipple, with superficial erosion or ulceration. These are often diagnosed and treated as dermatitis or bacterial infection, leading to delay or failure in detection. The diagnosis is established by biopsy of the area of erosion. When the lesion consists of nipple changes only, the incidence of axillary metastases is < 5%, and the prognosis is excellent. When a breast mass is also present, the incidence of axillary metastases rises, with an associated marked decrease in prospects for cure by surgical or other treatment.

B. Inflammatory Carcinoma

This is the most malignant form of breast cancer and constitutes < 3% of all cases. The clinical findings consist of a rapidly growing, sometimes painful mass that enlarges the breast. The overlying skin becomes erythematous, edematous, and warm. Often there is no distinct mass, since the tumor infiltrates the involved breast diffusely. The inflammatory changes, often mistaken for an infection, are caused by carcinomatous invasion of the subdermal lymphatics, with resulting edema and hyperemia. If the clinician suspects infection but the lesion does not respond rapidly (1–2 weeks) to antibiotics, biopsy should be performed. The diagnosis should be made when the redness involves more than one-third of the skin over the breast and biopsy shows infiltrating carcinoma with invasion of the subdermal lymphatics. Metastases tend to occur early and widely, and for this reason inflammatory carcinoma is rarely curable. Radiation, hormone therapy (if hormone $$receptor positive), anti-HER2 therapy (if HER2 overexpressing or amplified), and chemotherapy are the measures most likely to be of value initially rather than operation. Mastectomy is indicated when chemotherapy and radiation have resulted in clinical remission with no evidence of distant metastases. In these cases, residual disease in the breast may be eradicated.

image Breast Cancer Occurring during Pregnancy or Lactation

Breast cancer complicates approximately one in 3000 pregnancies. The diagnosis is frequently delayed, because physiologic changes in the breast may obscure the lesion and screening mammography is not done in young or pregnant women. When the cancer is confined to the breast, the 5-year survival rate is about 70%. In 60–70% of patients, axillary metastases are already present, conferring a 5-year survival rate of 30–40%. A retrospective analysis of women who were younger than 36 years when breast cancer was diagnosed showed that while women with pregnancy-associated breast cancer were more frequently diagnosed with later stage breast cancer, they had similar rates of local regional recurrence, distant metastases and overall survival as women with nonpregnancy-associated breast cancer. It is thus important for primary care and reproductive specialists to aggressively work up any breast abnormality discovered in a pregnant woman. Pregnancy (or lactation) is not a contraindication to operation or treatment, and therapy should be based on the stage of the disease as in the nonpregnant (or nonlactating) woman. Overall survival rates have improved, since cancers are now diagnosed in pregnant women earlier than in the past and treatment has improved. Breast-conserving surgery may be performed—and chemotherapy given—even during the pregnancy.

$image Bilateral Breast Cancer

Bilateral breast cancer occurs in < 5% of cases, but there is as high as a 20–25% incidence of later occurrence of cancer in the second breast. Bilaterality occurs more often in familial breast cancer, in women under age 50 years, and when the tumor in the primary breast is lobular. The incidence of second breast cancers increases directly with the length of time the patient is alive after her first cancer—about 1–2% per year.

In patients with breast cancer, mammography should be performed before primary treatment and at regular intervals thereafter, to search for occult cancer in the opposite breast or conserved ipsilateral breast. MRI may be useful in this high-risk group.

image Noninvasive Cancer

Noninvasive cancer can occur within the ducts (DCIS) or lobules (LCIS). DCIS tends to be unilateral and most often progresses to invasive cancer if untreated. In approximately 40–60% of women who have DCIS treated with biopsy alone, invasive cancer develops within the same breast. LCIS is generally agreed to be a marker of an increased risk of breast cancer rather than a direct precursor of breast cancer itself. The probability of breast cancer (DCIS or invasive in either breast) in a woman in whom LCIS has been diagnosed is estimated to be 1% per year. If LCIS is detected on core needle biopsy, an excisional biopsy without lymph node sampling should be performed to rule out malignancy, since DCIS or invasive cancer is found in 10–20% of patients. The incidence of LCIS is rising, likely due to increased use of screening mammography. In addition, the rate of mastectomy after the diagnosis of LCIS is increasing in spite of the fact that mastectomy is only recommended in those patients who otherwise have an increased risk of breast cancer through family history, genetic mutation, or past exposure to thoracic radiation. Pleomorphic LCIS may behave more like DCIS and may be associated with invasive carcinoma. For this reason, pleomorphic LCIS should be surgically removed with clear margins.

The treatment of intraductal lesions is controversial. DCIS can be treated by wide excision with or without radiation therapy or with total mastectomy. Conservative management is advised in patients with small lesions amenable to lumpectomy. Patients in whom LCIS is diagnosed or who have received lumpectomy for DCIS may discuss chemoprevention (using a SERM) with their clinician, which is effective in preventing invasive breast cancer in both LCIS and DCIS that has been completely excised by breast conserving surgery. Axillary metastases from in situ cancers should not occur unless there is an occult invasive cancer. Sentinel node biopsy may be indicated in DCIS treated with mastectomy.

Bagaria SP et al. The florid subtype of lobular carcinoma in situ: marker or precursor for invasive lobular carcinoma? Ann Surg Oncol. 2011 Jul;18(7):1845–51. [PMID: 21287281]

Chavez-Macgregor M et al. Male breast cancer according to tumor subtype and race: a population-based study. Cancer. 2013 May 1;119(9):1611–7. [PMID: 23341341]

Colfry AJ 3rd. Miscellaneous syndromes and their management: occult breast cancer, breast cancer in pregnancy, male breast cancer, surgery in stage IV disease. Surg Clin North Am. 2013 Apr;93(2):519–31. [PMID: 23464700]

Portschy PR et al. Trends in incidence and management of lobular carcinoma in situ: a population-based analysis. Ann Surg Oncol. 2013 Oct;20(10):3240–6. [PMID: 23846782]

Rakha EA et al. The prognostic significance of lymphovascular invasion in invasive breast carcinoma. Cancer. 2012 Aug 1; 118(15):3670–80. [PMID: 22180017]

image Biomarkers & Gene Expression Profiling

Determining the ER, PR, and HER2 status of the tumor at the time of diagnosis of early breast cancer and, if possible, at the time of recurrence is critical, both to gauge a patient’s prognosis and to determine the best treatment regimen. In addition to ER status and PR status, the rate at which tumor divides (assessed by an immunohistochemical stain for Ki-67) and the grade and differentiation of the cells are also important prognostic factors. These markers may be obtained on core biopsy or surgical specimens, but not reliably on FNA cytology. Patients whose tumors are hormone receptor-positive tend to have a more indolent disease course than those whose tumors are receptor-negative. Moreover, treatment with an anti-hormonal agent is an essential component of therapy for hormone-receptor positive breast cancer at any stage. While up to 60% of patients with metastatic breast cancer will respond to hormonal manipulation if their tumors are ER-positive, < 5% of patients with metastatic, ER-negative tumors will respond.

Another key element in determining treatment and prognosis is the amount of the HER2 oncogene present in the cancer. HER2 overexpression is measured by an immunohistochemical assay that is scored using a numerical $system: 0 and 1+ are considered negative for overexpression, 2+ is borderline/indeterminate, and 3+ is over expression. In the case of 2+ expression, fluorescence in situ hybridization (FISH) is recommended to more accurately assess HER2 amplification. Guidelines for the interpretation of HER2 results by IHC and FISH have been published by the College of American Pathologists. According to these guidelines, a tumor is positive for HER2 amplification if one of the criteria is met: (1) the single-probe average HER2 copy number is ≥ 6.0 signals/cell or (2) dual-probe HER2/CEP17 ratio is ≥ 2.0 with an average HER2 copy number ≥ 4.0 signals per cell or (3) dual-probe HER2/CEP17 ratio ≥ 2.0 with an average HER2 copy number < 4.0 signals per cell or (4) dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number ≥ 6.0 signals/cell. The presence of HER2 amplification and overexpression is of prognostic significance and predicts the response to trastuzumab.

Individually these biomarkers are predictive and thus provide insight to guide appropriate therapy. Moreover, when combined they provide useful information regarding risk of recurrence and prognosis. In general, tumors that lack expression of HER2, ER, and PR (“triple negative”) have a higher risk of recurrence and metastases and are associated with a worse survival compared with other types. Neither endocrine therapy nor HER2–targeted agents are useful for this type of breast cancer, leaving chemotherapy as the only treatment option. In contrast, patients with early stage, hormone receptor-positive breast cancer may not benefit from the addition of chemotherapy to hormonal treatments. Several molecular tests have been developed to assess risk of recurrence and to predict which patients are most likely to benefit from chemotherapy.

Cuzick J et al. Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4273–8. [PMID: 21990413]

Galanina N et al. Molecular predictors of response to therapy for breast cancer. Cancer J. 2011 Mar–Apr;17(2):96–103. [PMID: 21427553]

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Ghoussaini M et al. Inherited genetic susceptibility to breast cancer: the beginning of the end or the end of the beginning? Am J Pathol. 2013 Oct;183(4):1038–51. [PMID: 23973388]

Sgroi DC et al. Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC 4 in the TransATAC study population. Lancet Oncol. 2013 Oct;14(11):1067–76. [PMID: 24035531]

Stefansson OA et al. Epigenetic modifications in breast cancer and their role in personalized medicine. Am J Pathol. 2013 Oct;183(4):1052–63. [PMID: 23899662]

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image Treatment: Curative

Clearly, not all breast cancer is systemic at the time of diagnosis. For this reason, a pessimistic attitude concerning the management of breast cancer is unwarranted. Most patients with early breast cancer can be cured. Treatment with a curative intent is advised for clinical stage I, II, and III disease (see Tables 17–3, 39–4). Patients with locally advanced (T3, T4) and even inflammatory tumors may be cured with multimodality therapy, but metastatic disease will be diagnosed in most patients and at that point palliation is all that can be expected. Treatment with palliative intent is appropriate for all patients with stage IV disease and for patients with unresectable local cancers.

A. Choice and Timing of Primary Therapy

The extent of disease and its biologic aggressiveness are the principal determinants of the outcome of primary therapy. Clinical and pathologic staging help in assessing extent of disease (see Table 17–3), but each is to some extent imprecise. Other factors such as tumor grade, hormone receptor assays, and HER2 oncogene amplification are of prognostic value and are key to determining systemic therapy, but are not as relevant in determining the type of local therapy.

Controversy has surrounded the choice of primary therapy of stage I, II, and III breast carcinoma. Currently, the standard of care for stage I, stage II, and most stage III cancer is surgical resection followed by adjuvant radiation or systemic therapy, or both, when indicated. Neoadjuvant therapy is becoming more popular since large tumors may be shrunk by chemotherapy prior to surgery, making some patients who require mastectomy candidates for lumpectomy. It is important for patients to understand all of the surgical options, including reconstructive options, prior to having surgery. Patients with large primary tumors, inflammatory cancer, or palpably enlarged lymph nodes should have staging scans performed to rule out distant metastatic disease prior to definitive surgery. In general, adjuvant systemic therapy is started when the breast has adequately healed, usually within 4–8 weeks after surgery. While no prospective studies have defined the appropriate timing of adjuvant chemotherapy, one retrospective population-based study has suggested that chemotherapy should be initiated within 12 weeks of surgery to avoid a compromise in relapse-free and overall survival.

B. Surgical Resection

1. Breast-conserving therapy—Multiple, large, randomized studies including the Milan and NSABP trials show that disease-free and overall survival rates are similar for patients with stage I and stage II breast cancer treated with partial mastectomy (breast-conserving lumpectomy or “breast conservation”) plus axillary dissection followed by radiation therapy and for those treated by modified radical mastectomy (total mastectomy plus axillary dissection).

Tumor size is a major consideration in determining the feasibility of breast conservation. The NSABP lumpectomy trial randomized patients with tumors as large as 4 cm. To achieve an acceptable cosmetic result, the patient must $have a breast of sufficient size to enable excision of a 4-cm tumor without considerable deformity. Therefore, large tumor size is only a relative contraindication. Subareolar tumors, also difficult to excise without deformity, are not contraindications to breast conservation. Clinically detectable multifocality is a relative contraindication to breast-conserving surgery, as is fixation to the chest wall or skin or involvement of the nipple or overlying skin. The patient—not the surgeon—should be the judge of what is cosmetically acceptable. Given the relatively high risk of poor outcome after radiation, concomitant scleroderma is a contraindication to breast-conserving surgery. A history of prior therapeutic radiation to the ipsilateral breast or chest wall (or both) is also a contraindication for breast conservation.

Axillary dissection is primarily used to properly stage cancer and plan radiation and systemic therapy. Intraoperative lymphatic mapping and sentinel node biopsy identify lymph nodes most likely to harbor metastases if present (Figure 17–8). Sentinel node biopsy is a reasonable alternative to axillary dissection in patients without clinical evidence of axillary lymph node metastases. If sentinel node biopsy reveals no evidence of axillary metastases, it is highly likely that the remaining lymph nodes are free of disease and axillary dissection may be omitted. An important study from the American College of Surgeons Oncology group randomized women with sentinel node metastases to undergo completion of axillary dissection or to receive no further axillary treatment after lumpectomy; no difference in survival was found, showing that axillary dissection for selected node-positive women is not necessary for patients treated with lumpectomy, whole breast irradiation, and adjuvant systemic therapy. These results challenged standard treatment regimens. Omission of axillary dissection is now accepted at many major cancer institutions.

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imageFigure 17–8. Sentinel node. (Reproduced with permission, from Giuliano AE.)

Breast-conserving surgery with radiation is the preferred form of treatment for patients with early-stage breast cancer. Despite the numerous randomized trials showing no survival benefit of mastectomy over breast-conserving partial mastectomy and irradiation, breast-conserving surgery still appears to be underutilized.

2. Mastectomy—Modified radical mastectomy was the standard therapy for most patients with early-stage breast cancer. This operation removes the entire breast, overlying skin, nipple, and areolar complex as well as the underlying pectoralis fascia with the axillary lymph nodes in continuity. The major advantage of modified radical mastectomy is that radiation therapy may not be necessary, although radiation may be used when lymph nodes are involved with cancer or when the primary tumor is large (≥ 5 cm). The disadvantage of mastectomy is the cosmetic and psychological impact associated with breast loss. Radical mastectomy, which removes the underlying pectoralis muscle, should be performed rarely, if at all. Axillary node dissection is not indicated for noninvasive cancers because nodal metastases are rarely present. Skin-sparing and nipple-sparing mastectomy is currently gaining favor but is not appropriate for all patients. Breast-conserving surgery and radiation should be offered whenever possible given the lower risk of surgical complications and the smaller emotional impact on the patient. Breast reconstruction, immediate or delayed, should be discussed with patients who choose or require mastectomy. Patients should have an interview with a reconstructive plastic surgeon to discuss options prior to making a decision regarding reconstruction. Time is well spent preoperatively in educating the patient and family about these matters.

C. Radiotherapy

Radiotherapy after partial mastectomy consists of 5–7 weeks of five daily fractions to a total dose of 5000–6000 cGy. Most radiation oncologists use a boost dose to the cancer location. Shorter fractionation schedules may be reasonable for women over the age of 50 with early stage, lymph node–negative breast cancer. Accelerated partial breast irradiation, in which only the portion of the breast from which the tumor was resected is irradiated for 1–2 weeks, appears effective in achieving local control for selected patients; however, the results of prospective randomized trials, such as the NSABP B-39/RTOG 0413, are awaited. In women over the age of 70 with small (< 2 cm), lymph node–negative, hormone receptor–positive cancers, radiation therapy may be avoided. The recurrence rates after intraoperative radiation, while low, appear significantly higher than postoperative whole breast radiation therapy. However, in all of these situations, a balanced discussion with a radiation oncologist to weigh the risks and benefits of each approach is warranted.

Current studies suggest that radiotherapy after mastectomy may improve recurrence rates and survival in patients with tumors ≥ 5 cm or positive lymph nodes. Researchers are also examining the utility of axillary irradiation as an alternative to axillary dissection in the clinically node-negative patient with sentinel node micrometastases (metastasis > 0.2 mm or more than 200 cells, but none > 2.0 mm). An ACOSOG study (Z0010) and large NSABP trial (B-32) showed no adverse impact of micrometastases on survival and support no alteration in treatment when found. A Canadian trial (MA20) of postoperative nodal irradiation after lumpectomy and axillary dissection shows improved survival with nodal irradiation.

$D. Adjuvant Systemic Therapy

The goal of systemic therapy, including hormone modulating drugs (endocrine therapy), cytotoxic chemotherapy, and the HER2-targeted agent trastuzumab, is to kill cancer cells that have escaped the breast and axillary lymph nodes as micrometastases before they become macrometastases (ie, stage IV cancer). Systemic therapy improves survival and is advocated for most patients with curable breast cancer. In practice, most medical oncologists are currently using adjuvant chemotherapy for patients with either node-positive or higher-risk (eg, hormone receptor-negative or HER2-positive) node-negative breast cancer and using endocrine therapy for all hormone receptor–positive invasive breast cancer unless contraindicated. Prognostic factors other than nodal status that are used to determine the patient’s risks of recurrence are tumor size, ER and PR status, nuclear grade, histologic type, proliferative rate, oncogene expression (Table 17–5), and patient’s age and menopausal status. In general, systemic chemotherapy decreases the chance of recurrence by about 30% and hormonal modulation decreases the relative risk of recurrence by 40–50% (for hormone receptor–positive cancer). Systemic chemotherapy is usually given sequentially, rather than concurrently with radiation. In terms of sequencing, typically chemotherapy is given before radiation and endocrine therapy is started concurrent with or after radiation therapy.

Table 17–5. Prognostic factors in node-negative breast cancer.

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The long-term advantage of systemic therapy has been well established. All patients with invasive hormone receptor–positive tumors should consider the use of hormone-modulating therapy. Most patients with HER2-positive tumors should receive trastuzumab-containing chemotherapy regimens. In general, adjuvant systemic chemotherapy should not be given to women who have small node-negative breast cancers with favorable histologic findings and tumor markers. The ability to predict more accurately which patients with HER2-negative, hormone receptor-positive, lymph node-negative tumors should receive chemotherapy is improving with the advent of prognostic tools, such as Oncotype DX and Mammaprint. These tests are undergoing prospective evaluation in two clinical trials (TAILORx and MINDACT).

1. Chemotherapy—The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis involving over 28,000 women enrolled in 60 trials of adjuvant polychemotherapy versus no chemotherapy demonstrated a significant beneficial impact of chemotherapy on clinical outcome in non–stage IV breast cancer. This study showed that adjuvant chemotherapy reduces the risk of recurrence and breast cancer–specific mortality in all women but also showed that women under the age of 50 derive the greatest benefit. On the basis of the superiority of anthracycline-containing regimens in metastatic breast cancer, both doxorubicin and epirubicin have been studied extensively in the adjuvant setting. Studies comparing Adriamycin (doxorubicin) and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC) to cyclophosphamide-methotrexate-5-fluorouracil (CMF) have shown that treatments with anthracycline-containing regimens are at least as effective as treatment with CMF. The EBCTCG analysis including over 14,000 patients enrolled in trials comparing anthracycline-based regimens to CMF, showed a small but statistically significant improved disease-free and overall survival with the use of anthracycline-based regimens. It should be noted, however, that most of these studies included a mixed population of patients with HER2-positive and HER2-negative breast cancer and were performed before the introduction of trastuzumab. Retrospective analyses of a number of these studies suggest that anthracyclines may be primarily effective in tumors with HER2 overexpression or alteration in the expression of topoisomerase IIa (the target of anthracyclines and close to the HER2 gene). Given this, for HER2-negative, node-negative breast cancer, four cycles of AC or six cycles of CMF are probably equally effective.

When taxanes (T = paclitaxel and docetaxel) emerged in the 1990s, multiple trials were conducted to evaluate their use in combination with anthracycline-based regimens. The majority of these trials showed an improvement in disease-free survival and at least one showed an improvement in overall survival with the taxane-based regimen. A meta-analysis of taxane versus non-taxane anthracycline-based regimen trials showed an improvement in disease-free and overall survival for the taxane-based regimens.

Several regimens have been reported including AC followed by paclitaxel or docetaxel (AC-T), TAC (docetaxel concurrent with AC), 5-fluorouracil (F)EC-docetaxel and FEC-paclitaxel. Results from CALGB 9741 showed that compared with a standard dose regimen, administration of “dose-dense” AC-P chemotherapy (that is, in an accelerated fashion, in which the frequency of administration is increased without changing total dose or duration) with granulocyte colony stimulating factor (G-CSF) support led to improved both disease-free (82% vs 75% at 4 years) and overall survival (92% vs 90%). Exploratory subset analysis suggested that patients with hormone receptor–negative tumors derived the most benefit from the dose-dense approach.

$The US Oncology trial 9735 compared four cycles of AC with four cycles of Taxotere (docetaxel) and cyclophosphamide (TC). With a median of 7 years follow-up, this study showed a statistically significantly improved disease-free survival and overall survival in the patients who received TC. Until this, no trial had compared a non-anthracycline, taxane-based regimen to an anthracycline-based regimen.

An important ongoing study (US Oncology 06090) is prospectively evaluating whether anthracyclines add any incremental benefit to a taxane-based regimen by comparing six cycles of TAC to six cycles of TC in HER2-negative breast cancer patients. A third arm was added to evaluate the benefit of adding bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor (VEGF), to TC. While awaiting the results of this trial, oncologists are faced with choosing from among the above treatment regimens for HER2-negative breast cancer. It is interesting to note a sharp decline in the use of anthracyclines has been observed since 2006. Given the benefits described above, taxanes are now used for most patients receiving chemotherapy for early breast cancer.

The overall duration of adjuvant chemotherapy still remains uncertain. However, based on the meta-analysis performed in the Oxford Overview (EBCTCG), the current recommendation is for 3–6 months of the commonly used regimens. Although it is clear that dose intensity to a specific threshold is essential, there is no evidence to support the long-term survival benefit of high-dose chemotherapy with stem cell support.

Chemotherapy side effects are now generally well controlled. Nausea and vomiting are abated with drugs that directly affect the central nervous system, such as ondansetron and granisetron. Infertility and premature ovarian failure are common side effects of chemotherapy and should be discussed with patients prior to starting treatment. The risk of life-threatening neutropenia associated with chemotherapy can be reduced by use of growth factors such as pegfilgrastim and filgrastim (G-CSF), which stimulate proliferation and differentiation of hematopoietic cells. Long-term toxicities from chemotherapy, including cardiomyopathy (anthracyclines), peripheral neuropathy (taxanes), and leukemia/myelodysplasia (anthracyclines and alkylating agents), remain a small but significant risk.

2. Targeted therapy—Targeted therapy refers to agents that are directed specifically against a protein or molecule expressed uniquely on tumor cells or in the tumor microenvironment.

A. HER2 OVEREXPRESSIONApproximately 20% of breast cancers are characterized by amplification of the HER2 oncogene leading to overexpression of the HER2 oncoprotein. The poor prognosis associated with HER2 overexpression has been drastically improved with the development of HER2-targeted therapy. Trastuzumab (Herceptin [H]), a monoclonal antibody that binds to HER2, has proved effective in combination with chemotherapy in patients with HER2 overexpressing metastatic and early breast cancer. In the adjuvant setting, the first and most commonly studied chemotherapy backbone used with trastuzumab is AC-T. Subsequently, the BCIRG006 study showed similar efficacy for AC-TH and a nonanthracycline-containing regimen, TCH (docetaxel, carboplatin, trastuzumab). Both were significantly better than AC-T in terms of disease-free and overall survival and TCH had a lower risk of cardiac toxicity. Both AC-TH and TCH are FDA-approved for nonmetastatic, HER2-positive breast cancer. In these regimens, trastuzumab is given with chemotherapy and then continues beyond the course of chemotherapy to complete a full year. The reporting of two trials in 2012 (the Herceptin Adjuvant [HERA] evaluating 1 versus 2 years of trastuzumab and the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure [PHARE] study evaluating 6 versus 12 months of trastuzumab) have confirmed that 1 year of trastuzumab should remain the standard of care. At least one study (N9831) suggests that concurrent, rather than sequential, delivery of trastuzumab with chemotherapy may be more beneficial. Neoadjuvant chemotherapy plus dual HER2-targeted therapy with trastuzumab and pertuzumab (also a HER2-targeted monoclonal antibody that prevents dimerization of HER2 with HER3 and has been shown to be synergistic in combination with trastuzumab) was FDA approved in 2013 and is now a standard of care option available to patients with nonmetastatic HER2-Another question being addressed in trials is whether to treat small (< 1 cm), node-negative tumors with trastuzumab plus chemotherapy. Retrospective studies have shown that even small (stage T1a,b) HER2-positive tumors have a worse prognosis compared with same-sized HER2-negative tumors. The NSABP B43 study is also ongoing to evaluate whether the addition of trastuzumab to radiation therapy is warranted for DCIS.

Cardiomyopathy develops in a small but significant percent (1–4%) of patients who receive trastuzumab-based regimens. For this reason, anthracyclines and trastuzumab are rarely given concurrently and cardiac function is monitored periodically throughout therapy.

B. ENDOCRINE THERAPYAdjuvant hormone modulation therapy is highly effective in decreasing relative risk of recurrence by 40–50% and mortality by 25% in women with hormone receptor–positive tumors regardless of menopausal status. The traditional regimen has been 5 years of the estrogen-receptor antagonist/agonist tamoxifen until the 2012 reporting of the Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trial in which 5 versus 10 years of adjuvant tamoxifen were compared. In this study, disease-free and overall survival were significantly improved in women who received 10 years of tamoxifen, particularly after year 10. Though these results are impressive and potentially practice changing, the clinical application of long-term tamoxifen use must be discussed with patients individually, taking into consideration risks of tamoxifen such as secondary uterine cancers, venous thromboembolic events as well as side effects that impact quality of life. Ovarian ablation in premenopausal patients with ER-positive tumors may produce a benefit similar to that of adjuvant systemic chemotherapy. Whether the use of ovarian ablation plus tamoxifen (or an AI) is more effective than either measure alone is still unclear. In the $Stockholm subset of the Zoladex in Premenopausal Patients (ZIPP) study, 927 premenopausal women were randomly assigned to goserelin, tamoxifen, the combination of both, or to no endocrine therapy for 2 years. With a median follow-up of 12.3 years, this substudy showed that goserelin and tamoxifen each significantly reduce the risk of recurrence of hormone receptor–positive breast cancer compared to control (goserelin 32%, [P = 0.005] and tamoxifen 27% [P = 0.018]), yet the combination of goserelin and tamoxifen was not superior to either treatment alone. This issue is still not settled and is being addressed in ongoing clinical trials (Suppression of Ovarian Function Trial [SOFT] and Tamoxifen and Exemestane Trial [TEXT]) that have not yet reported. AIs, including anastrozole, letrozole, and exemestane, reduce estrogen production and are also effective in the adjuvant setting for postmenopausal women. Approximately seven large randomized trials enrolling more than 24,000 patients have compared the use of AIs with tamoxifen or placebo as adjuvant therapy. All of these studies have shown small but statistically significant improvements in disease-free survival (absolute benefits of 2–6%) with the use of AIs. In addition, AIs have been shown to reduce the risk of contralateral breast cancers and to have fewer associated serious side effects (such as endometrial cancers and thromboembolic events) than tamoxifen. However, they are associated with accelerated bone loss and an increased risk of fractures as well as a musculoskeletal syndrome characterized by arthralgias or myalgias (or both) in up to 50% of patients. The American Society of Clinical Oncology and the NCCN have recommended that postmenopausal women with hormone receptor–positive breast cancer be offered an AI either initially or after tamoxifen therapy. HER2 status should not affect the use or choice of hormone therapy.

3. Bisphosphonates—Two randomized studies (ZO-FAST and ABCSG-12) have evaluated the use of an adjuvant intravenous bisphosphonate (zoledronic acid) in addition to standard local and systemic therapy. The results showed a 32–40% relative reduction in the risk of cancer recurrence for hormone receptor–positive nonmetastatic breast cancer. Conflicting results have been reported from the AZURE study. In this randomized study that enrolled premenopausal and postmenopausal patients, there was no disease-free or overall survival benefits associated with the addition of zoledronic acid to endocrine therapy for the overall study population. However, a prespecified subset analysis in patients who were postmenopausal for at least 5 years did demonstrate a significant disease-free and overall survival benefit with the addition of the bisphosphonate. A meta-analysis of 15 studies evaluating adjuvant therapy with zoledronic acid showed a significant improvement in overall survival and a reduced fracture rate but no significant difference in disease-free survival outcome or bone metastases. Side effects associated with intravenous bisphosphonate therapy include bone pain, fever, osteonecrosis of the jaw (rare, < 1%), and renal failure. The adjuvant use of bisphosphonates and other bone stabilizing drugs, such as inhibitors of receptor activator of nuclear factor kappa B ligand (RANK-B) (eg denosumab), remains investigational.

4. Adjuvant therapy in older women—Data relating to the optimal use of adjuvant systemic treatment for women over the age of 65 are limited. Results from the EBCTCG overview indicates that while adjuvant chemotherapy yields a smaller benefit for older women compared with younger women, it still improves clinical outcomes. Moreover, individual studies do show that older women with higher risk disease derive benefits from chemotherapy. One study compared the use of oral chemotherapy (capecitabine) to standard chemotherapy in older women and concluded that standard chemotherapy is preferred. Another study (USO TC vs AC) showed that women over the age of 65 derive similar benefits from the taxane-based regimen as women who are younger. The benefits of endocrine therapy for hormone receptor-positive disease appear to be independent of age. In general, decisions relating to the use of systemic therapy should take into account a patient’s comorbidities and physiological age, more so than chronologic age.

E. Neoadjuvant Therapy

The use of chemotherapy or endocrine therapy prior to resection of the primary tumor (neoadjuvant) is gaining popularity. This enables the assessment of in vivo chemosensitivity. Patients with hormone receptor–negative, triple negative, or HER2-positive breast cancer are more likely to have a pathologic complete response to neoadjuvant chemotherapy than those with hormone receptor–positive breast cancer. A complete pathologic response at the time of surgery is associated with improvement in event-free and overall survival. Neoadjuvant chemotherapy also increases the chance of breast conservation by shrinking the primary tumor in women who would otherwise need mastectomy for local control. Survival after neoadjuvant chemotherapy is similar to that seen with postoperative adjuvant chemotherapy.

1. HER2-positive breast cancer—Dual targeting of HER2 with two monoclonal antibodies, trastuzumab and pertuzumab, has been evaluated in two clinical trials in the neoadjuvant setting. TRYPHAENA was a phase II, open-label study in which 225 patients with operable HER2-positive breast cancer were randomly assigned to six neoadjuvant cycles every 3 weeks of either 5-fluorouracil, epirubicin, cyclophosphamide [FEC] plus trastuzumab [H] and pertuzumab [P] for three cycles followed by docetaxel [T] plus HP for three cycles (Arm A) or FEC for three cycles followed by THP for three cycles (Arm B) or TCHP for six cycles (Arm C). Pathologic complete response (in breast and lymph nodes) was seen in 50.7% of patients in Arm A, 45.3% in Arm B, and 51.9% in Arm C. Symptomatic left ventricular systolic dysfunction developed in two patients in this study, both in Arm B. Declines in left ventricular ejection fraction ≥ 10% from baseline to < 50% was observed in 4 patients in Arm A (5.6%), 4 patients in Arm B (5.3%) and 3 patients in Arm C (3.9%).

The NEOSPHERE study randomly assigned 417 patients with HER2-positive breast cancer to four cycles of trastuzumab (H) plus docetaxel (T) (group A), pertuzumab (P) plus TH (group B), PH (group C) or PT (group D). $Pathologic complete response in the breast and lymph nodes was seen in 21.5% in group A, 39.3% in group B, 11.2% in group C and 17.7% in group D. Studies indicate that those patients who achieve a pathologic complete response have improved disease-free survival and may have better overall survival. In 2013, given the results of these two studies, the FDA granted accelerated approval for neoadjuvant pertuzumab. This is the first medication to receive regulatory approval in the neoadjuvant setting for breast cancer. Based on the above clinical trials, three regimens have received approval in the HER2-positive neoadjuvant setting: TCHP for six cycles; FEC for 3 cycles followed by THP for 3 cycles; or THP for 4 cycles (followed by three cycles of postoperative FEC). Pertuzumab is not approved for the adjuvant setting. Postoperatively all patients should continue to receive trastuzumab to complete a full year.

2. Hormone receptor–positive, HER2-negative breast cancer—Patients with hormone receptor-positive breast cancer have a lower chance of achieving a pathologic complete response with neoadjuvant therapy than those patients with triple negative or HER2-positive breast cancers. Studies are ongoing to evaluate hormonally targeted regimens in the neoadjuvant setting. Outside of the clinical trial setting, the use of neoadjuvant hormonal therapy is generally restricted to postmenopausal patients who are unwilling or unable to tolerate chemotherapy.

3. Triple negative breast cancer—No targeted therapy has been identified for patients with breast cancer that is lacking in HER2 amplification or hormone receptor expression. Neoadjuvant chemotherapy leads to pathologic complete response in approximately 25–45% of patients with triple negative breast cancer. Patients who achieve a pathologic complete response seem to have a similar prognosis to other breast cancer subtypes with pathologic complete response. However, those patients with residual disease at the time of surgery have a poor prognosis. Based on the theory that triple negative breast cancers may be more vulnerable to DNA damaging agents, several studies are evaluating whether the addition of platinum salts to a neoadjuvant chemotherapy regimen is beneficial in this disease subtype. A randomized phase II trial (GeparSixto) randomly assigned 595 patients with triple negative or HER2-positive breast cancer to weekly paclitaxel plus weekly liposomal doxorubicin (18 weeks) alone or with weekly carboplatin. Patients with triple negative disease also received bevacizumab. Those patients with triple negative disease who received carboplatin had a pathologic complete response rate of 58.7% compared to those who did not receive carboplatin (37.9%; P < 0.05). Similarly designed studies are ongoing to evaluate the pathologic complete response rates and long-term outcomes associated with incorporating platinums into standard chemotherapy regimens.

4. Timing of lymph node biopsy in neoadjuvant setting—There is considerable concern about the timing of sentinel lymph node biopsy, since the chemotherapy may affect any cancer present in the lymph nodes. Several studies have shown that sentinel node biopsy can be done after neoadjuvant therapy. However, a large multicenter study, ACOSOG 1071, demonstrated a false-negative rate of 10.7%, well above the false-negative rate outside the neoadjuvant setting (< 1–5%). Many physicians recommend performing sentinel lymph node biopsy before administering the chemotherapy in order to avoid a false-negative result and to aid in planning subsequent radiation therapy. Others prefer to perform sentinel lymph node biopsy after neoadjuvant therapy to avoid a second operation and assess post-chemotherapy nodal status. If a complete dissection is desired, this can be performed at the time of the definitive breast surgery.

Important questions remaining to be answered are the timing and duration of adjuvant and neoadjuvant chemotherapy, which chemotherapeutic agents should be applied for which subgroups of patients, the use of combinations of hormonal therapy and chemotherapy as well as possibly targeted therapy, and the value of prognostic factors other than hormone receptors in predicting response to therapy.

image Treatment: Palliative

Palliative treatments are those to manage symptoms, improve quality of life, and even prolong survival, without the expectation of achieving cure. Only 10% of patients have de novo metastatic breast cancer at the time of diagnosis. However, in most patients who have a breast cancer recurrence after initial local and adjuvant therapy, the recurrence presents as metastatic rather than local (in breast) disease. Breast cancer most commonly metastasizes to the liver, lungs and bone, causing symptoms such as fatigue, change in appetite, abdominal pain, respiratory symptoms, or bone pain. Headaches, imbalance, vision changes, vertigo, and other neurologic symptoms may be signs of brain metastases. Triple negative (ER-, PR-, HER2-negative) and HER2-positive tumors have a higher rate of brain metastases than hormone-receptor positive, HER2-negative tumors.

A. Radiotherapy and Bisphosphonates

Palliative radiotherapy may be advised for primary treatment of locally advanced cancers with distant metastases to control ulceration, pain, and other manifestations in the breast and regional nodes. Irradiation of the breast and chest wall and the axillary, internal mammary, and supraclavicular nodes should be undertaken in an attempt to cure locally advanced and inoperable lesions when there is no evidence of distant metastases. A small number of patients in this group are cured in spite of extensive breast and regional node involvement.

Palliative irradiation is of value also in the treatment of certain bone or soft-tissue metastases to control pain or avoid fracture. Radiotherapy is especially useful in the treatment of isolated bony metastases, chest wall recurrences, brain metastases, and acute spinal cord compression.

In addition to radiotherapy, bisphosphonate therapy has shown excellent results in delaying and reducing skeletal events in women with bony metastases. Pamidronate and zoledronic acid are FDA-approved intravenous $bisphosphonates given for bone metastases or hypercalcemia of malignancy from breast cancer. Denosumab, a fully human monoclonal antibody that targets RANK-ligand, is approved by the FDA for the treatment of advanced breast cancer causing bone metastases, with data showing that it reduced the time to first skeletal-related event (eg, pathologic fracture) compared to zoledronic acid.

Caution should be exercised when combining radiation therapy with chemotherapy because toxicity of either or both may be augmented by their concurrent administration. In general, only one type of therapy should be given at a time unless it is necessary to irradiate a destructive lesion of weight-bearing bone while the patient is receiving chemotherapy. The regimen should be changed only if the disease is clearly progressing. This is especially difficult to determine for patients with destructive bone metastases, since changes in the status of these lesions are difficult to determine radiographically.

B. Targeted Therapy

1. Endocrine therapy for metastatic disease—The first targeted therapy was the use of antiestrogen therapy in hormone receptor–positive breast cancer. The following therapies have all been shown to be effective in hormone receptor–positive metastatic breast cancer: administration of drugs that block hormone receptors (such as tamoxifen) or drugs that block the synthesis of hormones (such as AIs); ablation of the ovaries, adrenals, or pituitary; and the administration of hormones (eg, estrogens, androgens, progestins); see Table 17–6. Palliative treatment of metastatic cancer should be based on the ER status of the primary tumor or the metastases. Because only 5–10% of women with ER-negative tumors respond, they should not receive endocrine therapy except in unusual circumstances, eg, in an older patient who cannot tolerate chemotherapy. The rate of response is nearly equal in premenopausal and postmenopausal women with ER-positive tumors. A favorable response to hormonal manipulation occurs in about one-third of patients with metastatic breast cancer. Of those whose tumors contain ER, the response is about 60% and perhaps as high as 80% for patients whose tumors contain PR as well. The choice of endocrine therapy depends on the menopausal status of the patient. Women within 1 year of their last menstrual period are arbitrarily considered to be premenopausal and should receive tamoxifen therapy or rarely ovarian ablation, whereas women whose menses ceased more than a year before are postmenopausal and may receive tamoxifen or an AI. Women with ER-positive tumors who do not respond to first-line endocrine therapy or experience progression should be given a different form of hormonal manipulation. Because the quality of life during endocrine manipulation is usually superior to that during cytotoxic chemotherapy, it is best to try endocrine manipulation whenever possible. However, when receptor status is unknown, disease is progressing rapidly or involves visceral organs, chemotherapy should be used as first-line treatment.

Table 17–6. Agents commonly used for hormonal management of metastatic breast cancer.

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A. THE PREMENOPAUSAL PATIENT

(1) Primary hormonal therapy—The potent SERM tamoxifen is by far the most common and preferred method of hormonal manipulation in the premenopausal patient, in large part because it can be given with less morbidity and fewer side effects than cytotoxic chemotherapy $and does not require oophorectomy. Tamoxifen is given orally in a dose of 20 mg daily. The average remission associated with tamoxifen lasts about 12 months.

There is no significant difference in survival or response between tamoxifen therapy and bilateral oophorectomy. Bilateral oophorectomy is less desirable than tamoxifen in premenopausal women because tamoxifen is so well tolerated. However, oophorectomy can be achieved rapidly and safely either by surgery, by irradiation of the ovaries if the patient is a poor surgical candidate, or by chemical ovarian ablation using a gonadotropin-releasing hormone (GnRH) analog. Oophorectomy presumably works by eliminating estrogens, progestins, and androgens, which stimulate growth of the tumor. AIs should not be used in a patient with functioning ovaries since they do not block ovarian production of estrogen.

(2) Secondary or tertiary hormonal therapy—Patients who do not respond to tamoxifen or ovarian ablation may be treated with chemotherapy or may try a second endocrine regimen, such as GnRH analog plus AI. Whether to opt for chemotherapy or another endocrine measure depends largely on the sites of metastatic disease (visceral being more serious than bone-only, thus sometimes warranting the use of chemotherapy), the disease burden, the rate of growth of disease, and patient preference. Patients who take chemotherapy and then later have progressive disease may subsequently respond to another form of endocrine treatment (Table 17–6). The optimal choice for secondary endocrine manipulation has not been clearly defined for the premenopausal patient.

Patients who improve after oophorectomy but subsequently relapse should receive tamoxifen or an AI; if one fails, the other may be tried. Megestrol acetate, a progesterone agent, may also be considered. Adrenalectomy or hypophysectomy, procedures rarely done today, induced regression in 30–50% of patients who previously responded to oophorectomy. Pharmacologic hormonal manipulation has replaced these invasive procedures.

B. THE POSTMENOPAUSAL PATIENT

(1) Primary hormonal therapy—For postmenopausal women with metastatic breast cancer amenable to endocrine manipulation, tamoxifen or an AI is the initial therapy of choice. AIs may be more effective. The side effect profile of AIs differs from tamoxifen. The main side effects of tamoxifen are nausea, skin rash, and hot flushes. Rarely, tamoxifen induces hypercalcemia in patients with bony metastases. Tamoxifen also increases the risk of venous thromboembolic events and uterine hyperplasia and cancer. The main side effects of AIs include hot flushes, vaginal dryness, and joint stiffness; however, osteoporosis and bone fractures are significantly higher than with tamoxifen. Phase 2 data from the randomized Fulvestrant fIRst line Study comparing endocrine Treatments (FIRST) suggest that the pure estrogen antagonist, fulvestrant may be even more effective than front-line anastrozole in terms of time to progression. The combination of fulvestrant plus anastrozole may also be more effective than anastrozole alone, although two studies evaluating this question have yielded conflicting results.

(2) Secondary or tertiary hormonal therapy—AIs are also used for the treatment of advanced breast cancer in postmenopausal women after tamoxifen treatment. In the event that the patient responds to AI but then has progression of disease, fulvestrant has shown efficacy with about 20–30% of women benefiting from use. Postmenopausal women who respond initially to a SERM or AI but later manifest progressive disease may be crossed over to another hormonal therapy. Until recently, patients who experienced disease progression during or after treatment with a SERM or AI were routinely offered chemotherapy. This standard practice changed in 2012 with the approval of everolimus (Afinitor), an oral inhibitor of the mammalian target of rapamycin (MTOR)—a protein whose activation has been associated with the development of endocrine resistance. A phase III, placebo-controlled trial (BOLERO-2) evaluated exemestane with or without everolimus in 724 patients with AI-resistant, hormone receptor–positive metastatic breast cancer, and at interim analysis found that patients treated with everolimus had a significantly improved progression-free survival (10.6 months vs 4.1 months; HR, 0.36; 95% CI, 0.27–0.47; P < 0.001). Androgens (such as testosterone) have many toxicities and should be used infrequently. As in premenopausal patients, neither hypophysectomy nor adrenalectomy should be performed. Estrogen therapy has also paradoxically been shown to induce responses in advanced breast cancer. A study that evaluated the use of low-dose (6 mg) versus high-dose (30 mg) estradiol daily orally for postmenopausal women with metastatic AI-resistant breast cancer showed that the two doses yielded similar clinical benefit rates (29% and 28%, respectively) and, as expected, the higher dose was associated with more adverse events than the low dose.

(3) Newer agents in development—Although endocrine therapy can lead to disease control for months to years in some patients, de novo and acquired resistance to hormonal manipulation remains an enormous barrier to the effective treatment of these patients. Thus, molecularly targeted agents are still needed to circumvent signaling pathways that lead to drug resistance. A randomized phase II study evaluating letrozole with or without an oral cyclin-D kinase (cdk) 4/6 inhibitor for the first-line treatment of postmenopausal women with hormone receptor–positive advanced breast cancer demonstrated a striking and highly significant 18.6 month improvement in progression-free survival with the cdk4/6-inhibitor (26.1 months with cdk 4/6 inhibitor vs 7.5 months in control arm). Phase III evaluation of this promising molecule is ongoing.

2. HER2-targeted agents—For patients with HER2 overexpressing or amplified tumors, trastuzumab plus chemotherapy has been shown to significantly improve clinical outcomes, including survival compared to chemotherapy alone. Trastuzumab plus chemotherapy alone was therefore the standard first-line treatment for HER2-positive metastatic breast cancer until 2012 when pertuzumab was granted FDA approval. Pertuzumab is a monoclonal antibody that targets the extracellular domain of HER2 at a different epitope than targeted by trastuzumab and inhibits receptor dimerization. A phase III placebo-controlled $randomized study (CLEOPATRA) showed that patients treated with the combination of pertuzumab, trastuzumab, and docetaxel had a significantly longer progression-free survival (18.5 months vs 12.4 months; HR, 0.62; 95% CI, 0.51–0.75; P < 0.001) compared with those treated with docetaxel and trastuzumab. Longer follow-up revealed a significant overall survival benefit associated with pertuzumab as well.

Lapatinib, an oral targeted drug that inhibits the intracellular tyrosine kinases of the epidermal growth factor and HER2 receptors, is FDA-approved for the treatment of trastuzumab-resistant HER2-positive metastatic breast cancer in combination with capecitabine, thus, a completely oral regimen. The combination of trastuzumab plus lapatinib has been shown to be more effective than lapatinib alone for trastuzumab-resistant metastatic breast cancer. Moreover, several trials have shown a significant clinical benefit for continuing HER2-targeted agents beyond progression. T-DM1 (trastuzumab emtansine) is a novel antibody drug conjugate in which trastuzumab is stably linked to a derivative of maytansine, enabling targeted delivery of the cytotoxic chemotherapy to HER2-overexpressing cells. The phase III trial (EMILIA) that evaluated T-DM1 in patients with HER2-positive, trastuzumab-pretreated advanced disease showed that T-DM1 is associated with improved progression-free and overall survival compared to lapatinib plus capecitabine (EMILIA). Regulatory approval of T-DM1 (Kadcyla [ado-trastuzumab emtansine]) was received in February 2013. Evaluation of T-DM1 in combination with pertuzumab for the first-line treatment of advanced breast cancer is ongoing in the phase III MARIANNE study, and trials evaluating the use of these agents in early breast cancer are ongoing. Several other drugs targeting the HER2 pathway are in development, including everolimus, afatinib, neratinib, and HER2-targeted vaccines.

3. Targeting “triple-negative” breast cancer—Until very recently, breast cancers lacking expression of the hormone receptors, ER and PR, and HER2 have only been amenable to therapy with cytotoxic chemotherapy. This type of “triple-negative” breast cancer, while heterogeneous, generally behaves aggressively and is associated with a poor prognosis. Newer classes of targeted agents are being evaluated specifically for triple-negative breast cancer. Some triple-negative breast cancers may be characterized by an inability to repair double-strand DNA breaks (due to mutation or epigenetic silencing of the BRCA gene). Poly-ADP ribose-polymerase (PARP) inhibitors are a class of agents that prevent the repair of single strand DNA breaks and are showing promise in BRCA-mutated and triple-negative breast cancer. Research in this area is rapidly expanding with multiple clinical trials of PARP inhibitors and other molecularly targeted agents ongoing.

C. Palliative Chemotherapy

Cytotoxic drugs should be considered for the treatment of metastatic breast cancer (1) if visceral metastases are present (especially brain, liver, or lymphangitic pulmonary), (2) if hormonal treatment is unsuccessful or the disease has progressed after an initial response to hormonal manipulation, or (3) if the tumor is ER-negative or HER2-positive. Prior adjuvant chemotherapy does not seem to alter response rates in patients who relapse. A number of chemotherapy drugs (including vinorelbine, paclitaxel, docetaxel, gemcitabine, ixabepilone, carboplatin, cisplatin, capecitabine, albumin-bound paclitaxel, eribulin, and liposomal doxorubicin) may be used as single agents with first-line objective response rates ranging from 30% to 50%.

Combination chemotherapy yields statistically significantly higher response rates and progression-free survival rates, but has not been conclusively shown to improve overall survival rates compared with sequential single-agent therapy. Combinations that have been tested in phase III studies and have proven efficacy compared with single-agent therapy include capecitabine/docetaxel, gemcitabine/paclitaxel, and capecitabine/ixabepilone (see Tables 39–11 and 39–12). Various other combinations of drugs have been tested in phase II studies, and a number of clinical trials are ongoing to identify effective combinations. Patients should be encouraged to participate in clinical trials given the number of promising targeted therapies in development. It is generally appropriate to treat willing patients with multiple sequential lines of therapy as long as they tolerate the treatment and as long as their performance status is good (eg, at least ambulatory and able to care for self, up out of bed more than 50% of waking hours).

Baselga J et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109–19. [PMID: 22149875]

Baselga J et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9;366(6):520–9. [PMID: 22149876]

Davies C et al; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013 Mar 9;381(9869): 805–16. Erratum in: Lancet. 2013 Mar 9;381(9869):804. [PMID: 23219286]

Dengel LT et al. Axillary dissection can be avoided in the majority of clinically node-negative patients undergoing breast-conserving therapy. Ann Surg Oncol. 2014 Jan;21(1):22–7. [PMID: 23975314]

Gianni L et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25–32. [PMID: 22153890]

Giuliano AE et al. Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer. JAMA. 2011 Jul 27;306(4)385–93. [PMID: 21791687]

Giuliano AE et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011 Feb 9; 305(6):569–75. [PMID: 21304082]

Goldhirsch A et al; Herceptin Adjuvant (HERA) Trial Study Team. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013 Sep 21;382(9897):1021–8. [PMID: 23871490]

$Haviland JS et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013 Oct;14(11):1086–94. [PMID: 24055415]

Mohamed A et al. Targeted therapy for breast cancer. Am J Pathol. 2013 Oct;183(4):1096–112. [PMID: 23988612]

National Comprehensive Cancer Network. NCCN Guidelines: Breast Cancer. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp

Pivot X et al; PHARE trial investigators. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 2013 Jul;14(8):741–8. [PMID: 23764181]

Roberston JF et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized ‘FIRST’ study. Breast Cancer Re2s Treat. 2012 Nov;136(2):503–11. [PMID: 23065000]

Schneeweiss A et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278–84. [PMID: 23704196]

Slamon D et al; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273–83. [PMID: 21991949]

Valachis A et al. Adjuvant therapy with zoledronic acid in patients with breast cancer: a systematic review and meta-analysis. Oncologist. 2013;18(4):353–61. [PMID: 23404816]

Verma S et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012 Nov 8;367(19):1783–91. [PMID: 23020162]

Veronesi U et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol. 2013 Dec;14(13):1269–77. [PMID: 24225155]

Von Minckwitz G et al. A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). 2013 ASCO Annual Meeting. Abstract 1004. Presented June 3, 2013.

Weaver DL et al. Effect of occult metastases on survival in node-negative breast cancer. N Engl J Med. 2011 Feb 3;364(5): 412–21. [PMID: 21247310]

image Prognosis

Stage of breast cancer is the most reliable indicator of prognosis (Table 17–7). Axillary lymph node status is the best-analyzed prognostic factor and correlates with survival at all tumor sizes. When cancer is localized to the breast with no evidence of regional spread after pathologic examination, the clinical cure rate with most accepted methods of therapy is 75% to > 90%. In fact, patients with small mammographically detected biologically favorable tumors and no evidence of axillary spread have a 5-year survival rate > 95%. When the axillary lymph nodes are involved with tumor, the survival rate drops to 50–70% at 5 years and probably around 25–40% at 10 years. Increasingly, the use of biologic markers, such as ER, PR, grade, and HER2, is helping to identify high-risk tumor types as well as direct treatment used (see Biomarkers & Gene Expression Profiling). Tumors with marked aneuploidy have a poor prognosis (see Table 17–5). Gene analysis studies, such as Oncotype Dx, can predict disease-free survival for some subsets of patients.

Table 17–7. Approximate survival (%) of patients with breast cancer by TNM stage.

image

Five-year statistics do not accurately reflect the final outcome of therapy. The mortality rate of breast cancer patients exceeds that of age-matched normal controls for nearly 20 years. Thereafter, the mortality rates are equal, though deaths that occur among breast cancer patients are often directly the result of tumor.

In general, breast cancer appears to be somewhat more aggressive and associated with worse outcomes in younger than in older women, and this may be related to the fact that fewer younger women have ER-positive tumors. Adjuvant systemic chemotherapy, in general, improves survival by about 30% and adjuvant hormonal therapy by about 25%.

For those patients whose disease progresses despite treatment, studies suggest supportive group therapy may improve survival. As they approach the end of life, such patients will require meticulous palliative care (see Chapter 5).

Manson JE et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013 Oct 2;310(13):1353–68. [PMID: 24084921]

Parmeshwar R et al. Patient surveillance after initial breast cancer therapy: variation by physician specialty. Am J Surg. 2013 Aug;206(2):218–22. [PMID: 23870392]

Rakha EA. Pitfalls in outcome prediction of breast cancer. J Clin Pathol. 2013 Jun;66(6):458–64. [PMID: 23618694]

image Follow-up Care

After primary therapy, patients with breast cancer should be monitored long-term in order to detect recurrences and to observe the opposite breast for a second primary carcinoma. Local and distant recurrences occur most frequently within the first 2–5 years. During the first 2 years, most patients should be examined every 6 months (with mammogram every 6 months on the affected $breast), then annually thereafter. Special attention is paid to the contralateral breast because a new primary breast malignancy will develop in 20–25% of patients. In some cases, metastases are dormant for long periods and may appear 10–15 years or longer after removal of the primary tumor. Although studies have failed to show an adverse effect of hormonal replacement in disease-free patients, it is rarely used after breast cancer treatment, particularly if the tumor was hormone receptor–positive. Even pregnancy has not been associated with shortened survival of patients rendered disease free—yet many oncologists are reluctant to advise a young patient with breast cancer that it is safe to become pregnant, and most will not support prescribing hormone replacement for the postmenopausal breast cancer patient. The use of estrogen replacement for conditions such as osteoporosis, vaginal dryness and hot flushes may be considered for a woman with a history of breast cancer after discussion of the benefits and risks; however, it is not routinely recommended, especially given the availability of nonhormonal agents for these conditions (such as bisphosphonates and denosumab for osteoporosis). Vaginal estrogen is frequently used to treat vaginal atrophy with no obvious ill effects.

A. Local Recurrence

The incidence of local recurrence correlates with tumor size, the presence and number of involved axillary nodes, the histologic type of tumor, the presence of skin edema or skin and fascia fixation with the primary tumor, and the type of definitive surgery and local irradiation. Local recurrence on the chest wall after total mastectomy and axillary dissection develops in as many as 8% of patients. When the axillary nodes are not involved, the local recurrence rate is < 5%, but the rate is as high as 25% when they are heavily involved. A similar difference in local recurrence rate was noted between small and large tumors. Factors such as multifocal cancer, in situ tumors, positive resection margins, chemotherapy, and radiotherapy have an effect on local recurrence in patients treated with breast-conserving surgery. Adjuvant systemic therapy greatly decreases the rate of local recurrence.

Chest wall recurrences usually appear within the first several years but may occur as late as 15 or more years after mastectomy. All suspicious nodules and skin lesions should be biopsied. Local excision or localized radiotherapy may be feasible if an isolated nodule is present. If lesions are multiple or accompanied by evidence of regional involvement in the internal mammary or supraclavicular nodes, the disease is best managed by radiation treatment of the entire chest wall including the parasternal, supraclavicular, and axillary areas and usually by systemic therapy.

Local recurrence after mastectomy usually signals the presence of widespread disease and is an indication for studies to search for evidence of metastases. Distant metastases will develop within a few years in most patients with locally recurrent tumor after mastectomy. When there is no evidence of metastases beyond the chest wall and regional nodes, irradiation for cure after complete local excision should be attempted. After partial mastectomy, local recurrence does not have as serious a prognostic significance as after mastectomy. However, those patients in whom a recurrence develops have a worse prognosis than those who do not. It is speculated that the ability of a cancer to recur locally after radiotherapy is a sign of aggressiveness and resistance to therapy. Completion of the mastectomy should be done for local recurrence after partial mastectomy; some of these patients will survive for prolonged periods, especially if the breast recurrence is DCIS or occurs more than 5 years after initial treatment. Systemic chemotherapy or hormonal treatment should be used for women in whom disseminated disease develops or those in whom local recurrence occurs.

B. Breast Cancer Survivorship Issues

Given that most women with non-metastatic breast cancer will be cured, a significant number of women face survivorship issues stemming from either the diagnosis or the treatment of the breast cancer. These challenges include psychological struggles, upper extremity lymphedema, cognitive decline (also called “chemo brain”), weight management problems, cardiovascular issues, bone loss, postmenopausal side effects, and fatigue. One randomized study reported that survivors who received psychological intervention from the time of diagnosis had a lower risk of recurrence and breast cancer–related mortality. A randomized study in older, overweight cancer survivors showed that diet and exercise reduced the rate of self-reported functional decline compared with no intervention. Cognitive dysfunction is a commonly reported symptom experienced by women who have undergone systemic treatment for early breast cancer. Studies are ongoing to understand the pathophysiology leading to this syndrome. An interesting study reported that 200 mg of modafinil daily improved speed and quality of memory as well as attention for breast cancer survivors dealing with cognitive dysfunction. This promising study requires validation in a larger clinical trial.

1. Edema of the arm—Significant edema of the arm occurs in about 10–30% of patients after axillary dissection with or without mastectomy. It occurs more commonly if radiotherapy has been given or if there was postoperative infection. Partial mastectomy with radiation to the axillary lymph nodes is followed by chronic edema of the arm in 10–20% of patients. Sentinel lymph node dissection has proved to be a more accurate form of axillary staging without the side effects of edema or infection. Judicious use of radiotherapy, with treatment fields carefully planned to spare the axilla as much as possible, can greatly diminish the incidence of edema, which will occur in only 5% of patients if no radiotherapy is given to the axilla after a partial mastectomy and lymph node dissection.

Late or secondary edema of the arm may develop years after treatment, as a result of axillary recurrence or infection in the hand or arm, with obliteration of $lymphatic channels. When edema develops, a careful examination of the axilla for recurrence or infection is performed. Infection in the arm or hand on the dissected side should be treated with antibiotics, rest, and elevation. If there is no sign of recurrence or infection, the swollen extremity should be treated with rest and elevation. A mild diuretic may be helpful. If there is no improvement, a compressor pump or manual compression decreases the swelling, and the patient is then fitted with an elastic glove or sleeve. Most patients are not bothered enough by mild edema to wear an uncomfortable glove or sleeve and will treat themselves with elevation or manual compression alone. Benzopyrones have been reported to decrease lymphedema but are not approved for this use in the United States. Rarely, edema may be severe enough to interfere with use of the limb. Previously, patients were advised to avoid weight lifting with the ipsilateral arm to prevent a worsening in lymphedema. However, a prospective randomized study has shown that twice weekly progressive weight lifting improves lymphedema symptoms and exacerbations and improves extremity strength.

2. Breast reconstruction—Breast reconstruction is usually feasible after total or modified radical mastectomy. Reconstruction should be discussed with patients prior to mastectomy, because it offers an important psychological focal point for recovery. Reconstruction is not an obstacle to the diagnosis of recurrent cancer. The most common breast reconstruction has been implantation of a silicone gel or saline prosthesis in the subpectoral plane between the pectoralis minor and pectoralis major muscles. Alternatively, autologous tissue can be used for reconstruction.

Autologous tissue flaps are aesthetically superior to implant reconstruction in most patients. They also have the advantage of not feeling like a foreign body to the patient. The most popular autologous technique currently is the transrectus abdominis muscle flap (TRAM flap), which is done by rotating the rectus abdominis muscle with attached fat and skin cephalad to make a breast mound. The free TRAM flap is done by completely removing a small portion of the rectus with overlying fat and skin and using microvascular surgical techniques to reconstruct the vascular supply on the chest wall. A latissimus dorsi flap can be swung from the back but offers less fullness than the TRAM flap and is therefore less acceptable cosmetically. An implant often is used to increase the fullness with a latissimus dorsi flap. Reconstruction may be performed immediately (at the time of initial mastectomy) or may be delayed until later, usually when the patient has completed adjuvant therapy. When considering reconstructive options, concomitant illnesses should be considered, since the ability of an autologous flap to survive depends on medical comorbidities. In addition, the need for radiotherapy may affect the choice of reconstruction as radiation may increase fibrosis around an implant or decrease the volume of a flap.

3. Risks of pregnancy—Data are insufficient to determine whether interruption of pregnancy improves the prognosis of patients who are identified to have potentially curable breast cancer and who receive definitive treatment during pregnancy. Theoretically, the high levels of estrogen produced by the placenta as the pregnancy progresses could be detrimental to the patient with occult metastases of hormone-sensitive breast cancer. However, retrospective studies have not shown a worse prognosis for women with gestational breast cancer. The decision whether or not to terminate the pregnancy must be made on an individual basis, taking into account the clinical stage of the cancer, the overall prognosis for the patient, the gestational age of the fetus, the potential for premature ovarian failure in the future with systemic therapy, and the patient’s wishes. Women with early-stage gestational breast cancer who choose to continue their pregnancy should undergo surgery to remove the tumor and systemic therapy if indicated. Retrospective reviews of patients treated with anthracycline-containing regimens for gestational cancers (including leukemia and lymphomas) have established the relative safety of these regimens during pregnancy for both the patient and the fetus. Taxane-based and trastuzumab-based regimens have not been evaluated extensively, however. Radiation therapy should be delayed until the pregnant patient has delivered.

Equally important is the advice regarding future pregnancy (or abortion in case of pregnancy) to be given to women of child-bearing age who have had definitive treatment for breast cancer. To date, no adverse effect of pregnancy on survival of women who have had breast cancer has been demonstrated. When counseling patients, oncologists must take into consideration the patients’ overall prognosis, age, comorbidities, and life goals.

In patients with inoperable or metastatic cancer (stage IV disease), induced abortion is usually advisable because of the possible adverse effects of hormonal treatment, radiotherapy, or chemotherapy upon the fetus in addition to the expectant mother’s poor prognosis.

Berger AM et al. Cancer-related fatigue: implications for breast cancer survivors. Cancer. 2012 Apr 15;118(8 Suppl):2261–9. [PMID: 22488700]

Colfry AJ 3rd. Miscellaneous syndromes and their management: occult breast cancer, breast cancer in pregnancy, male breast cancer, surgery in stage IV disease. Surg Clin North Am. 2013 Apr;93(2):519–31. [PMID: 23464700]

Del Mastro L et al. Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial. JAMA. 2011 Jul 20;306(3):269–76. [PMID: 21771987]

Fong DY et al. Physical activity for cancer survivors: meta-analysis of randomized controlled trials. BMJ. 2012 Jan30:344:e70. [PMID: 22294757]

Hermelink K. Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. Cancer. 2011 Mar 1;117(5):1103. [PMID: 20960507]

Lee ES et al. Health-related quality of life in survivors with breast cancer 1 year after diagnosis compared with the general population: a prospective cohort study. Ann Surg. 2011 Jan;253(1):101–8. [PMID: 21294288]

$Siegel R et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012 Jul–Aug;62(4):220–41. [PMID: 22700443]

Thong MS et al. Population-based cancer registries for quality-of-life research: a work-in-progress resource for survivorship studies? Cancer. 2013 Jun 1;119(Suppl 11):2109–23. [PMID: 23695923]

CARCINOMA OF THE MALE BREAST

image ESSENTIAL INQUIRIES

image A painless lump beneath the areola in a man usually over 50 years of age.

image Nipple discharge, retraction, or ulceration may be present.

image Generally poorer prognosis than in women.

image General Considerations

Breast cancer in men is a rare disease; the incidence is only about 1% of that in women. The average age at occurrence is about 70 years and there may be an increased incidence of breast cancer in men with prostate cancer. As in women, hormonal influences are probably related to the development of male breast cancer. There is a high incidence of both breast cancer and gynecomastia in Bantu men, theoretically owing to failure of estrogen inactivation by a liver damaged by associated liver disease. It is important to note that first-degree relatives of men with breast cancer are considered to be at high risk. This risk should be taken into account when discussing options with the patient and family. In addition, BRCA2 mutations are common in men with breast cancer. Men with breast cancer, especially with a history of prostate cancer, should receive genetic counseling. The prognosis, even in stage I cases, is worse in men than in women. Blood-borne metastases are commonly present when the male patient appears for initial treatment. These metastases may be latent and may not become manifest for many years.

image Clinical Findings

A painless lump, occasionally associated with nipple discharge, retraction, erosion, or ulceration, is the primary complaint. Examination usually shows a hard, ill-defined, nontender mass beneath the nipple or areola. Gynecomastia not uncommonly precedes or accompanies breast cancer in men. Nipple discharge is an uncommon presentation for breast cancer in men but is an ominous finding associated with carcinoma in nearly 75% of cases.

Breast cancer staging is the same in men as in women. Gynecomastia and metastatic cancer from another site (eg, prostate) must be considered in the differential diagnosis. Benign tumors are rare, and biopsy should be performed on all males with a defined breast mass.

image Treatment

Treatment consists of modified radical mastectomy in operable patients, who should be chosen by the same criteria as women with the disease. Breast conserving therapy is rarely performed. Irradiation is the first step in treating localized metastases in the skin, lymph nodes, or skeleton that are causing symptoms. Examination of the cancer for hormone receptor proteins and HER2 overexpression is of value in determining adjuvant therapy. Men commonly have ER-positive tumors and rarely have overexpression of HER2. Adjuvant systemic therapy and radiation is used for the same indications as in breast cancer in women.

Because breast cancer in men is frequently a disseminated disease, endocrine therapy is of considerable importance in its management. Tamoxifen is the main drug for management of advanced breast cancer in men. Tamoxifen (20 mg orally daily) should be the initial treatment. There is little experience with AIs though they should be effective. Castration in advanced breast cancer is a successful measure and more beneficial than the same procedure in women but is rarely used. Objective evidence of regression may be seen in 60–70% of men with hormonal therapy for metastatic disease—approximately twice the proportion in women. The average duration of tumor growth remission is about 30 months, and life is prolonged. Bone is the most frequent site of metastases from breast cancer in men (as in women), and hormonal therapy relieves bone pain in most patients so treated. The longer the interval between mastectomy and recurrence, the longer the remission following treatment is likely. As in women, there is correlation between ERs of the tumor and the likelihood of remission following hormonal therapy.

AIs should replace adrenalectomy in men as they have in women. Corticosteroid therapy alone has been considered to be efficacious but probably has no value when compared with major endocrine ablation. Either tamoxifen or AIs may be primary or secondary hormonal manipulation.

Estrogen therapy—5 mg of diethylstilbestrol three times daily orally—may be effective hormonal manipulation after others have been successful and failed, just as in women. Androgen therapy may exacerbate bone pain. Chemotherapy should be administered for the same indications and using the same dosage schedules as for women with metastatic disease or for adjuvant treatment.

image Prognosis

Men with breast cancer seem to have a worse prognosis than women with breast cancer because breast cancer is diagnosed in men at a later stage. However, a large population based, international study reported that after adjustment for prognostic features (age, stage, treatment), men had a significantly improved relative survival from breast cancer compared to women. For node-positive disease, 5-year survival is approximately 69%, and for node-negative disease, it is 88%. A practice-patterns database study reported that based on NCCN guidelines, only $59% of patients received the recommended chemotherapy, 82% received the recommended hormonal therapy, and 71% received the recommended post-mastectomy radiation, indicating a relatively low adherence to NCCN guidelines for men.

For those patients whose disease progresses despite treatment, meticulous efforts at palliative care are essential (see Chapter 5).

Bird ST et al. Male breast cancer and 5α-reductase inhibitors finasteride and dutasteride. J Urol. 2013 Nov;190(5):1811–4. [PMID: 23665270]

Colfry AJ 3rd. Miscellaneous syndromes and their management: occult breast cancer, breast cancer in pregnancy, male breast cancer, surgery in stage IV disease. Surg Clin North Am. 2013 Apr;93(2):519–31. [PMID: 23464700]

Kiluk JV et al. Male breast cancer: management and follow-up recommendations. Breast J. 2011 Sep–Oct;17(5):503–9. [PMID: 21883641]

Miao H et al. Incidence and outcome of male breast cancer: an international population-based study. J Clin Oncol. 2011 Nov 20;29(33):4381–6. [PMID: 21969512]

Ravi A et al. Breast cancer in men: prognostic factors, treatment patterns, and outcome. Am J Mens Health. 2012 Jan;6(1):51–8. [PMID: 21831929]