Breast Cancer

Breast cancer accounts for approximately one third of all cancers in women and is second only to lung cancer as the leading cause of cancer deaths among women. Breast cancer, however, has the highest incidence rate of all cancers. According to statistics from the American Cancer Society, 213,000 new cases of invasive breast cancer, as well as nearly 62,000 cases of in situ cancers, will be diagnosed during 2006 in the United States, with 41,000 women succumbing to the disease during the same period (1). Over the past 50 years, the incidence of breast cancer in the United States has increased significantly; currently one in every seven women will develop the disease during her lifetime. Fortunately, the mortality rate has declined since 1990.

Predisposing Factors

Fewer than 1% of breast cancers occur in women younger than 25 years of age. After age 30, however, there is a sharp increase in the incidence of breast cancer. Except for a short plateau between the ages of 45 and 50 years, the incidence increases steadily with age (2).

Family History

Of women who develop breast cancer, 20% to 30% have a family history of the disease. Although any family history of breast cancer increases the overall relative risk (3), this risk is not significantly increased if the disease was diagnosed postmenopausally in a first degree or more distant relative. If a woman's mother or sister had unilateral breast cancer premenopausally, her lifetime risk of developing the disease approaches 30%, whereas a woman whose mother or sister had bilateral breast cancers premenopausally has at least a 40% to 50% lifetime risk. The increased incidence in these women is probably due to inherited oncogenes.

Approximately 5% to 10% of breast cancers have an inherited basis. All inherited genes are autosomal dominant but have variable penetrance. Men carry the gene 50% of the time. The most common mutations are the BRCA1 (chromosome 17q21) and BRCA2 (chromosome 13q12–13) gene deletions. Carriers of these germline mutations have up to a 4%-per-year risk of developing breast cancer and a lifetime risk that ranges from 35% to 85% (4). In addition, these individuals have up to a 65% risk of developing a contralateral breast cancer. The BRCA1 mutation also is associated with an increased risk of ovarian and prostate cancer, whereas BRCA2 carriers, although less common, demonstrate increased risks of male breast and prostate cancers. Both mutations are rare in the general public (0.1%) but are more commonly identified in Jews of Ashkenazi descent (1%–2.3%) (5). Genetic testing is available and should be considered if there is a high likelihood that results will be positive and will be used to influence decisions regarding the clinical management of the care of the patient and her family.

Diet, Obesity, and Alcohol

There are marked geographic differences in the incidence of breast cancer that may be related to diet. A recent meta-analysis demonstrated an association between higher intakes of total fat and an increased risk of breast cancer (6). Although a definitive relationship between total alcohol consumption and an increased risk of breast cancer has yet to be determined, high wine intake has been shown to be associated with elevated risk (7).

Reproductive and Hormonal Factors

The risk of breast cancer increases with the length of a woman's reproductive phase (8). Although early menarche has been reported among breast cancer patients, early menopause appears to protect against the development of the disease, with artificial menopause from oophorectomy lowering the risk more than early natural menopause (9). There is no clear association between the risk of breast cancer and menstrual irregularity and the duration of menses. Although lactation does not affect the incidence of breast cancer, women who have never been pregnant have a

1

higher risk of breast cancer than those who are multiparous. Also, women who give birth to their first child later in life have a higher incidence of breast cancer than do younger primigravida women (10).

An historic well-controlled study from the Centers for Disease Control and Prevention showed that oral contraceptive use does not increase the risk of breast cancer, regardless of duration of use, family history, or coexistence of benign breast disease (11). However, a more recent pooled analysis from 54 epidemiologic studies showed current users of oral contraceptives had a small but significant increased risk when compared with nonusers. Ten years after discontinuation, the risk of past users declined to that of the normal population (12).Although it was previously reported that short-term estrogen treatment for menopausal symptoms did not increase the risk of breast cancer, this belief was refuted by publication of the results of the Women's Health Initiative randomized trial. This prospective trial, involving 16,000 postmenopausal women randomly assigned to receive estrogen plus progesterone or placebo, revealed an association between hormone therapy use and the development of breast cancer. In addition, when invasive breast cancer did develop, it was diagnosed at a more advanced stage compared with tumors that developed among placebo users. Based on interim analysis, the trial was stopped early and the investigators concluded that even relatively short-term use of combined estrogen–progesterone therapy increases the development of invasive breast cancer (13). The risk demonstrated by this study must be considered when postmenopausal hormone therapy is used to treat conditions such as hot flashes and osteoporosis.

History of Cancer

Women with a history of breast cancer have a 50% risk of developing microscopic cancer and a 20% to 25% risk of developing clinically apparent cancer in the contralateral breast, which occurs at a rate of 1% to 2% per year (14). Lobular carcinoma has a higher incidence of bilaterality than does ductal carcinoma. A history of endometrial, ovarian, or colon cancer also is associated with an increased risk of subsequent breast cancer, as is a history of radiation therapy for Hodgkin's lymphoma.

Diagnosis

Breast cancer most commonly arises in the upper outer quadrant, where there is proportionally more breast tissue. Masses are most often discovered by the patient and less frequently by the physician during routine breast examination. The increasing use of screening mammography has enhanced the ability to detect nonpalpable breast abnormalities. Metastatic breast cancer is found as an axillary mass without obvious malignancy in less the 1% of cases.

The standard screening modalities of mammography and physical examination are complementary. Approximately 10% to 50% of cancers detected mammographically are not palpable, whereas physical examination detects 10% to 20% of cancers not seen radiographically (15). The purpose of screening is to detect tumors when they are small (less than 1 cm) and have the highest potential for surgical cure. Most trials have shown a 20% to 30% reduction in breast cancer mortality for women age 50 and older who undergo annual screening mammography. Data on screening women younger than 40 years have been more controversial. Results from the Gothenburg screening trial showed a 45% reduction in mortality for women screened between the ages of 40 and 49 (16). Because of these findings, it is recommended that all women undergo yearly screening mammography starting at age 40, along with clinical breast examination and breast self-examination. No other tests, including ultrasonography, computed tomography (CT) scans, sestamibi scans, positron emission tomography (PET) scans, or serum blood markers, have been shown to be effective screening modalities. Screening guidelines recommended by the American College of Radiology and the American Cancer Society are presented in Table 38.1. Recently, MRI was identified as a valuable adjunct to screening mammography for women with either a familial or genetic predisposition to breast cancer, although exact guidelines for its implementation have yet to be defined (17).

2

Unfortunately, although breast MRI is exceptionally sensitive in the detection of breast abnormalities, the technology is currently not specific enough for this imaging modality to be used for routine screening.Masses are easier to palpate in older women with fatty breasts than in younger women with dense, nodular breasts. An area of thickening amid normal nodularity may be the only clue to an underlying malignancy. Skin dimpling, nipple retraction, or skin erosion, while obvious, are later-stage disease signs. Algorithms for the evaluation of breast masses in premenopausal and postmenopausal women are presented in Chapter 19.

When a dominant breast mass is identified, the presence of a carcinoma must be considered, and biopsy should be performed to establish a tissue diagnosis. About 30% to 40% of lesions believed clinically to be malignant will be benign on histologic examination (18). Conversely, 25% of clinically benign-appearing lesions will be malignant when biopsied (19).

Biopsy Techniques

In rare cases, it may be reasonable to perform frozen section analysis on a biopsy specimen immediately before mastectomy or other definitive surgical treatment. It is preferable, however, for the patient to be involved in the planning of her therapy. In most instances, initial biopsy is better followed by definitive treatment at a later date. This approach allows the physician to discuss alternative forms of surgical therapy with the patient who has a malignancy. It also gives the patient an opportunity to obtain a second opinion before undergoing definitive treatment.

Fine-needle Aspiration Cytology

Fine-needle aspiration cytology (FNAC) is usually performed on palpable lesions or under ultrasound guidance using a 20- or 22-gauge needle. The technique has a high level of diagnostic accuracy, with low false-negative rates and rare, but persistent, false-positive results (20). In most reported series, false-negative rates range from 10% to 15%, and false-positive rates are generally less than 1%, whereas insufficient specimens account for about 15% of samples (21). If a mass appears to be malignant on physical examination, mammography, or both, FNAC cytology results can be used for definitive diagnosis. Negative FNAC results do not exclude malignancy and should be evaluated by either a core needle or traditional excisional biopsy for suspicious lesions. In younger women, it is prudent to monitor a benign-appearing mass for one or two menstrual cycles. Confirmation of a clinically apparent fibroadenoma with FNAC can serve as the basis for observational follow-up without excision.

3

Core Needle Biopsy

Core needle biopsy can be performed on both palpable and nonpalpable breast masses. Performing a core biopsy instead of FNAC on a palpable lesion has the advantage of obtaining more tissue for diagnostic purposes, including tests for estrogen and progesterone receptors and Her2/neu. Core biopsy of nonpalpable breast lesions usually is performed using mammographic or ultrasonographic guidance. Mammographic units with computerized stereotactic modifications can be used to localize abnormalities and perform CNB without surgery. Under mammographic guidance, a biopsy needle is inserted into the lesion and a core of tissue is removed for histologic examination. Devices with suction assistance are often used to increase the volume of tissue removed for evaluation. A titanium clip often is used to mark the biopsy site and serve as a guide should further excision be required. Ultrasonography may also be used to perform core biopsy on a nonpalpable lesion. Because it is less invasive and less expensive than open mammographic localization biopsy, CNB is preferred for accessible lesions. If a definitive diagnosis is not established, these procedures must also be followed by open biopsy.

Open Biopsy

Open biopsy may be performed if FNAC or CNB has not been performed or if needle biopsy results are negative, equivocal, or discordant with the clinical findings. An unequivocal histologic diagnosis of cancer should be obtained before treatment of breast cancer is undertaken. Cytologic diagnosis may be relied on if the mass clinically or mammographically appears to be malignant.

Open biopsy can be performed in the outpatient setting with local anesthesia in the following manner:

The patient is positioned and the location of the mass confirmed. Local anesthesia is used to infiltrate the skin and subcutaneous tissue surrounding the palpable mass. The skin in incised directly over the mass. Placement of this incision is critical. It should be situated in such a

way that it can be excised with an ellipse of skin should the patient require a subsequent mastectomy or placed cosmetically so that partial mastectomy can be performed through it successfully. Para-areolar incisions are appropriate only for lesions in proximity to the nipple–areolar complex.

The mass is gently grasped with Allis forceps or with a stay suture and moved into the operative field. The mass should be excised completely whenever possible. Larger lesions that are difficult to totally excise

can be incised for diagnostic purposes only. When an incisional biopsy is performed, a frozen section should be obtained to confirm that appropriate tissue for diagnosis is present. Such masses, however, are preferably sampled with FNAC or CNB, with incisional biopsy rarely indicated.

Once the mass is removed, hemostasis is achieved and the incision is closed. A cosmetically superior result will be achieved if the deep breast parenchyma is not reapproximated. The most superficial subcutaneous fat can be reapproximated with fine absorbable sutures, and the skin can be closed with a subcuticular suture and adhesive strips.

Image-Guided Localization Biopsy

Biopsy of nonpalpable lesions is a potentially difficult procedure that requires close cooperation between the surgeon and radiologist. Using ultrasonographic or mammographic guidance, a needle or specialized wire is placed into the breast parenchyma at or near the site of the suspected abnormality. Some mammographers will also inject a biologic dye into the breast parenchyma to assist localization further. The surgeon reviews the films and localizes the abnormality with respect to the tip of the wire or needle. Alternatively, the surgeon will perform ultrasonography intraoperatively to directly localize the lesion. An incision is made directly over the abnormality, and a small portion of the breast tissue suspected of containing the abnormality is excised. For mammographically detected lesions, a specimen radiograph is obtained to ensure that the abnormality has been recovered. Often, the radiologist can place a

4

needle in the specimen at the site of the abnormality to facilitate histologic evaluation and ensure that the pathologist examines the site of the abnormality.

Pathology and Natural History

Breast cancer may arise in the intermediate-sized ducts, terminal ducts, or lobules. In most cases, the diagnosis of lobular and intraductal carcinoma is based more on histologic appearance than site of origin. The cancer may be either in situ (ductal carcinoma in situ or lobular carcinoma in situ) or invasive (infiltrating ductal carcinoma, infiltrating lobular carcinoma). Morphologic subtypes of infiltrating ductal carcinoma include scirrhous, tubular, medullary, and mucinous carcinoma.

True invasive ductal carcinoma accounts for 80% of all invasive tumors, with the final 20% split evenly between lobular carcinoma and special variants of infiltrating ductal carcinoma (22). Mammographically, invasive ductal cancers are characterized by a stellate density or microcalcifications. Macroscopically, gritty, chalky streaks are present within the tumor that most likely represent a desmoplastic response. Finally, invasion of the surrounding stroma and fat, with a fibrotic, desmoplastic reaction surrounding the invasive carcinoma, generally are present.Special types of infiltrating ductal carcinoma are uncommon and typically account for nearly 10% of all invasive cancers. Medullary carcinoma, which accounts for 5% to 8% of breast carcinomas, arises from larger ducts within the breast and has a dense lymphocytic infiltrate. The tumor appears to be a slower growing and less–aggressive malignancy than other forms of carcinoma. Even when axillary disease is present, the prognosis with medullary carcinoma is better than that of other variants of invasive ductal carcinoma. Mucinous (colloid) carcinoma accounts for 5% of all breast cancers. Grossly, areas of the tumor may appear mucinous or gelatinous, whereas microscopically they are relatively acellular. Infiltrating comedo carcinoma accounts for less than 1% of all breast malignancies and is an invasive cancer characterized by foci of necrosis that exude a comedonecrosislike substance when biopsied. Usually, comedocarcinomas are in situ malignancies. Papillary carcinoma is predominantly a noninvasive ductal carcinoma; when invasive components are present, it should be specified as invasive papillary carcinoma. Tubular carcinoma, a well-differentiated breast cancer that accounts for 1% to 2% of all malignant breast neoplasms, tends to have a better prognosis than infiltrating ductal carcinoma and rarely metastasizes to axillary lymph nodes. Finally, adenoid cystic carcinomas are extremely rare breast tumors that histologically are similar to those seen in the salivary glands. They generally are well differentiated cancers that are slow to metastasize.

Growth Patterns

The growth potential of breast cancer and the patient's resistance to malignancy vary widely with the individual and the stage of disease. The doubling time of breast cancer ranges from several weeks for rapidly growing tumors to months or years for slowly growing lesions. If the doubling time of a breast tumor was constant and a tumor originated from one cell, a doubling time of 100 days would result in a 1-cm tumor in about 8 years (Fig. 38.1) (23). During the preclinical phase, tumor cells may be circulating throughout the body. Because of the long preclinical tumor growth phase and the tendency of infiltrating lesions to metastasize early, many clinicians view breast cancer as a systemic disease at the time of diagnosis. Although cancer cells may be released from the tumor before diagnosis, variations in the tumor's ability to grow in other organs and the host's response to tumor cells may inhibit dissemination of the disease. Many women with breast cancer can be treated successfully with surgery alone, and some patients have been cured even in the presence of palpable axillary disease. Thus, a pessimistic attitude that breast cancer is systemic and incurable at diagnosis is unwarranted.

5

Figure 38.1 Growth rate of breast cancer indicating long preclinical phase. (From Gullino PM. Natural history of breast cancer: progression from hyperplasia to neoplasia as predicted by angiogenesis. Cancer 1977;39:2699. with permission.)

6

7

8

A more realistic approach may be to view breast cancer as a two-component disease involving the breast and the body as a whole. Although the primary breast tumor and issues of local control must be managed, the possibility of systemic metastases with their life-threatening consequences should not be overlooked.

Although breast cancer can metastasize to any organ, involvement of bone, lungs, or liver occurs in up to 85% of women who develop distant disease (24,25). In addition to these sites, invasive lobular carcinoma is known to disseminate to the abdominal viscera, uterus, ovaries, and peritoneal surfaces.

Staging

After the diagnosis of breast cancer has been definitively established, the clinical stage of the disease should be determined. The Columbia Clinical Staging System was used historically (26) but has been replaced by the tumor–nodes–metastases (TNM) system of the American Joint Committee on Cancer (27). The TNM system allows both preoperative clinical staging and postoperative pathologic staging to be determined (Tables 38.2 and 38.3).

9

Treatment

Preoperative Evaluation

The extent of the preoperative workup varies with the initial stage of the disease (28). For most patients with small tumors, clinically negative lymph nodes, and no evidence of metastasis (TNM stage I), the preoperative evaluation should consist of bilateral mammography, chest radiography, complete blood count, and screening blood chemistry tests. Bone, CT, and MRI scanning are unnecessary unless there are symptoms or abnormal blood chemistry levels to suggest the existence of bone or intra-abdominal involvement. For patients with clinical stage II, node-positive disease, a bone scan is recommended, but CT scan of the abdomen is not necessary unless symptoms or laboratories suggest liver disease. Patients with clinical stage III or stage IV disease should undergo both bone and liver scanning.

Radical Mastectomy

Traditionally, the treatment of breast cancer has been surgical, but the type of procedure has remained a controversial and highly emotional issue. During the nineteenth century, surgical treatment of breast cancer was haphazard, varying from local excision alone to total mastectomy. The radical mastectomy was based on the principle that breast carcinoma was a locally infiltrative process that spread in a stepwise fashion from breast, to nodes, to distant sites (29). Thus, radical mastectomy removes the entire breast, the underlying pectoral muscles, and the contiguous axillary lymph nodes in continuity (30) (Fig. 38.2A). A report of 51 years of experience with radical mastectomy, which included 1,036 patients with a follow-up of 47 years, is thus far unequaled in evaluating any single method of treating breast cancer (31).

During the twentieth century, extensions and modifications of the radical mastectomy were devised that involved removal of more local and regional tissue. At one time, supraclavicular lymph node dissections were considered a routine component of surgical treatment (32). In addition, supraclavicular, mediastinal, and internal mammary lymph node dissections were performed (33).

An en bloc internal mammary lymph node dissection was added to the standard radical mastectomy in the 1960s (34). This technique became popular and is the operation commonly referred to as the extended radical mastectomy. Unfortunately, extended radical mastectomy did not enhance overall survival rates (35), because only 3% to 5% of patients with negative axillary nodes will have involvement of internal mammary nodes. Locally destructive surgery is not justified, however, based on current understanding of the biologic behavior of breast cancer.

Modified Radical Mastectomy

In contrast to radical mastectomy, modified radical mastectomy preserves the pectoralis major muscle (36,37) (Fig. 38.2B). The breast is removed in a manner similar to that of radical mastectomy, but neither the axillary lymph node dissection nor the skin excision is as extensive. Consequently, there is no need for skin grafting. Although there are no differences in survival rates between radical and modified radical mastectomy, the latter procedure has a better functional outcome and a superior cosmetic result (38). Modified radical mastectomy has therefore replaced radical mastectomy in the United States.

Total Mastectomy

Total mastectomy involves removal of the entire breast, nipple, and areolar complex without resection of the underlying muscles or intentional excision of axillary lymph nodes. Low-lying lymph nodes, however, in the upper outer portion of the breast and low axilla often are excised. Total mastectomy has local control rates comparable

10

with those of radical or modified radical mastectomy but has a higher risk of axillary recurrence. Regional recurrence will occur in at least 15% to 20% of patients treated with total mastectomy alone.

Postmastectomy Radiation Therapy

McWhirther developed the combination of total mastectomy followed by radiation (39). Many have advocated adjuvant radiation therapy used in combination with various operative procedures. Unfortunately, studies claiming improvements in overall survival usually are flawed by the use of historical controls and inaccurate preoperative staging. Classic trials, both prospective randomized and historical control studies, have showed that adjuvant radiation therapy improves local control but not overall survival rates (40,41,42,43). In a prospective randomized trial performed by the National Surgical Adjuvant Breast Project (NSABP), the roles of postoperative radiation therapy and axillary treatment were examined. Patients were randomly assigned to either total mastectomy, radical mastectomy, or total mastectomy with radiation therapy. This trial showed no difference in survival among the three treatment arms, whereas radiation therapy and axillary treatment improved local and regional control.

Twenty-five-year follow-up data continue to support these conclusions (44).

Three randomized control studies from the 1990s showed that postmastectomy radiation therapy reduced the risk of local-regional failure by 20% and produced an absolute survival benefit of 10% at 10 years among women with stage II to III breast cancer, regardless of menopausal status (45,46,47). More recently, additional trials challenged the need for postmastectomy radiation among women with only one to three involved axillary nodes and T1 or T2 primary tumors. These studies showed adequate local-regional control rates with mastectomy and chemotherapy alone (48,49,50). Current guidelines from the American Society of Clinical Oncology recommend postmastectomy radiation therapy for women with T3 (>5 cm) primary tumors and four or more positive axillary lymph nodes (51).

Breast Conservation Therapy with or without Radiation Therapy

Radiation therapy alone, without excision of the tumor, is associated with a high local failure rate (52,53,54,55), as is local excision without radiation. Throughout the last quarter of the twentieth century, a paradigm shift occurred in the surgical management of breast cancer. Data from the NSABP B-04 trial, for which 25-year follow-up exists, established the equivalency of radical versus total mastectomy with regards to overall survival (56). Shortly after initiation of the B-04 trial, a number of studies were designed to evaluate the efficacy of breast preservation among women with early-stage breast cancers. The Milan trial, a major prospective randomized trial that began accruing patients in 1973, compared treatment with either radical mastectomy or a combination of quadrantectomy, axillary lymph node dissection, and postoperative radiation therapy. In total, 701 clinically node-negative patients with noncentrally located, small tumors (<2 cm) (T1 N0 M0) were enrolled. After 20 years of follow-up, there continues to be no statistically significant difference between the two groups in either local control or overall survival rates (57).

At nearly the same time, in the NSABP B-06 trial, patients with early breast cancer (stage I or stage II, T1 or T2, and N0 or N1) were randomized to modified radical mastectomy, segmental mastectomy (lumpectomy), and axillary lymph node dissection, or segmental mastectomy, axillary lymph node dissection, and postoperative radiation therapy. Unlike the quadrantectomy performed in the Milan study, segmental mastectomy consists of removing only the tumor and a small rim of normal surrounding tissue, yielding cosmetically superior results (Fig. 38.3). A total of 1,843 women were enrolled, with the lowest local recurrence rate seen among patients treated with segmental mastectomy and postoperative radiation therapy. Although the addition of radiation clearly improved the local control rate, no significant differences in overall survival or disease-free survival rates were detected among the three treatment arms; there was a trend, however, in favor of patients who received radiation. This NSABP study established, now with 25-year follow-up, that the combination of segmental mastectomy (with negative surgical margins), axillary lymph node dissection, and postoperative radiation therapy is as effective as modified radical mastectomy for the management of patients with stage I and II breast cancer (58). A number of

11

additional studies also demonstrated no decrease in overall survival among women being treated with breast preservation therapy (59,60,61).

Axillary lymph node status and the number of involved nodes is the most important prognostic indicator for patients with primary breast cancer (62). For these reasons, axillary lymphadenectomy traditionally was used to detect and quantify the extent of nodal metastasis (63). Before the introduction of sentinel lymph node dissection in the 1990s, axillary lymph node dissection was performed routinely on all patients with early breast cancer. Although axillary dissection is associated with a very low risk of regional recurrence (1%–3%), the rate of acute complications is as high as 30% (64). Similarly, the risk of chronic lymphedema ranges from 6% to as high 30% (65). Limiting the dissection to level I nodes or random sampling is associated with unacceptably high false-negative rates and should not be done (66). Only one third of patients with a clinically negative axilla will be found to have nodal metastasis after histopathologic examination of all harvested lymph nodes (67). This means that two thirds of patients will be exposed to the morbidity of axillary lymph note dissection without proven benefit when performed routinely in the presence of invasive breast cancer.

In 1991, intraoperative lymphatic mapping and sentinel lymph node dissection were introduced to address these problems (68). The concept behind sentinel lymph node dissection is best described by the definition of a sentinel node. The sentinel note is the lymph node that has the greatest potential to harbor metastasis if axillary disease is present. The sentinel lymph node dissection thus accurately predicts the status of the entire nodal basin. Removing only one or two lymph nodes can accurately stage the axilla with minimal morbidity. Numerous investigators have demonstrated that, with proper training, sentinel lymph node dissection identification rates range from 90% to 99%, with false-negative rates of less than 5% found in most large studies (69). In one study of 107 patients with T1 and T2

breast cancer who underwent sentinel lymph node dissection followed by axillary lymph note dissection, the sentinel note was successfully identified in 100 patients (93.5%). There were no false-negative results, and the sentinel node accurately predicted axillary status in all 100 patients.

The technique of sentinel lymph node dissection has been validated by a number of authors using a variety of techniques (70,71). The information obtained from sentinel lymph node dissection appears to be equivalent to that of axillary lymph note dissection in the trials conducted to date. One prospective study demonstrated that in node-negative patients undergoing sentinel lymph node dissection, only the recurrence rate in the axilla was zero at a median follow-up of 39 months (72). An additional randomized trial demonstrated sentinel node biopsy to be both safe and accurate when compared with axillary dissection, with fewer complications and no axillary recurrences among the sentinel node trial arm (73). This degree of accuracy in predicting axillary metastasis, combined with its very low morbidity rate, makes sentinel lymph node dissection the preferred procedure for staging the axilla in breast cancer today.

Adjuvant Systemic Therapy

For many patients, local and regional control of breast cancer is achieved with surgery and radiation therapy alone. About 90% of patients will never experience an in-breast recurrence; these patients, however, may still develop metastatic disease. The goal of adjuvant systemic therapy is to eliminate occult metastases during the early postoperative period and thus reduce the risk of local and distant recurrence (74).

Adjuvant systemic therapy will prolong survival in selected breast cancer patients. In patients with favorable tumors and a low risk of recurrence and subsequent death, however, such as those with node-negative cancers smaller than 1 cm or node-negative cancers smaller than 2 cm with grade 1 histology, this benefit is small and may not justify the risks of systemic therapy. Adjuvant systemic therapy reduces the odds of death by 25% per year in both node-negative and node-positive patients (75). Because this risk reduction is relatively constant, patients with favorable, node-negative disease have a much smaller absolute benefit compared with patients who have higher-risk, node-

12

positive disease. For patients with node-negative disease, the absolute benefit may be minimal versus 10% to 20% for those with nodal involvement.

Cytotoxic chemotherapy and hormonal therapy have inherent risks that must be considered when treatment decisions are made. Although there are many known acute side effects with current standard regimens, there is growing evidence that patients who undergo chemotherapy report more frequent chronic neurocognitive deficits than do untreated controls (76). The impact of these deficits remains undefined. Similarly, systemic therapy with tamoxifen has been associated with an increased incidence of uterine cancer, vaginal dryness, and hot flashes, whereas aromatase inhibitors have been linked to osteoporosis and musculoskeletal symptoms. Choosing those patients who should receive adjuvant therapy can be a difficult decision that often entails analyzing a variety of prognostic and predictive factors, identifying patients at risk for recurrence, and quantifying that risk. Based on available data, adjuvant chemotherapy is currently recommended for women with greater than a 10% chance of relapse within 10 years. The choice of therapy generally depends on an evaluation of specific risk factors.

Recently, gene assays such as the Oncotype DX have been introduced to help identify those estrogen receptor–positive, lymph node–negative patients who will benefit most from systemic chemotherapy. This test, which calculates a recurrence risk score for each individual, allows the treating physician to determine the average rate of distant disease at 10 years and make treatment recommendations based on this risk (77).

Prognostic Indicators

Factors that determine each patient's risk of recurrence include nodal involvement, tumor size, estrogen and progesterone receptor status, nuclear grade, histologic type, proliferative rate, and biologic markers such as Her2/neu status. These prognostic factors and their effects on recurrence are summarized in Table 38.4. Patients with high-risk prognostic factors are more likely to benefit from adjuvant cytotoxic or hormonal therapy and usually are offered such treatment.

Patients with lymph node metastasis have a higher risk of recurrence than patients with node-negative disease. The 10-year survival rate for women with palpable metastatic axillary lymph nodes who fail to receive systemic therapy is only about 50% to 60%. The number of lymph nodes involved and the presence of extracapsular invasion are important indicators of poor prognosis.

Another prognostic indicator of relapse is primary tumor size. In an evaluation of 767 patients with node-negative disease who underwent radical or modified radical mastectomy without adjuvant chemotherapy, the relapse rate in patients with tumors larger than 1 cm or special tumor types larger than 3 cm (tubular, mucinous, or papillary) was 27% at 10 years, compared with 9% for tumors smaller than 1 cm (78).

Hormone receptor status is an important predictor not only of long-term prognosis but also of response to endocrine therapy. Several studies demonstrated that patients with positive estrogen and progesterone receptor status have improved overall survival (79,80). Receptor status should be known when determining the need for and choice of adjuvant therapy. Histologic grade also appears to predict overall survival. Patients with well-differentiated tumors tend to have more favorable outcomes than those with poorly differentiated ones (Table 38.5). In a British study of 1,168 women, histologic grade, along with tumor size and lymph node status, was an independent predictor of overall survival at 10 years (81).

Finally, the possible roles of specific tumor markers in predicting which patients will respond to chemotherapy regimens have been investigated. The most thoroughly researched of these markers is HER-2/neu. In an NSABP study, patients with HER-2/neu overexpression who were not treated with anthracycline-based regimens fared worse (82). Another study showed that the addition of trastuzumab (Herceptin), an antibody directed against the HER-2/neu receptor, significantly increased the response rate to therapy over standard chemotherapy alone in the

13

presence of metastatic disease (83). At the 2005 meeting of the American Society of Clinical Oncology, data were reported from trials investigating the adjuvant use of Herceptin for women with early-stage Her2/neu breast cancers. Significant improvements in disease-free survival were reported for those women receiving Herceptin (84), suggesting that its routine use as an adjuvant therapy is inevitable.

Systemic Regimens

Based on the results of more than 100 prospective, randomized trials examining the role of adjuvant chemotherapy in breast cancer, a variety of systemic regimens have emerged. Systemic therapy includes cytotoxic agents and hormonal agents, used alone or in combination. Following is a brief description of the more commonly used regimens. Initially, trials involved a single perioperative course of chemotherapy aimed at eradicating circulating tumor cells. The Nissen-Meyer study from Norway showed that a single course of cyclophosphamide improved overall survival rates (85). Subsequently, numerous trials demonstrated the benefit of adjuvant chemotherapy for certain subgroups of patients (86). In the initial NSABP adjuvant trial, a 2-year course of melphalan was shown to be superior to no treatment (87), and further trials demonstrated enhanced beneficial effect with the use of multiple drugs as well as with the combination of hormonal manipulation with chemotherapy (88).

14

Historically, the most frequently used adjuvant combination chemotherapy has been CMF: cyclophosphamide (C), methotrexate (M), and 5-fluorouracil (5-FU). In the original study by Bonadonna et al., patients with positive axillary lymph nodes were randomized to receive either 12 monthly cycles of CMF or no therapy after radical mastectomy (89). A statistically significant benefit was found with CMF treatment for premenopausal patients, especially those with one to three positive nodes. A subsequent study showed six cycles of CMF to be as effective as 12 cycles (90). Interestingly, no significant effect was seen for postmenopausal women, which was probably related in part to the fact that these women were less likely to tolerate the full course of therapy (91). After 20 years of follow-up, this trial demonstrated a persistent survival advantage for premenopausal women receiving CMF adjuvant therapy (92). In a later study involving node-negative, estrogen receptor–negative breast cancer patients, after 12 years of follow-up, 71% of patients treated with adjuvant CMF remained disease free compared with 48% in the control group, regardless of menopausal status (93).

Currently, anthracylines (A) are more commonly used in the adjuvant and metastatic treatment of breast cancer than any other agents. A large randomized NSABP study compared CMF with AC regimens in node-positive patients and found similar treatment outcomes among both groups. The AC regimen, however, was preferred because of its shorter duration (four cycles for 3 months versus six cycles for 6 months) and better tolerance (94).Taxanes are also being used in a variety of multiple-agent chemotherapy regimens because of their demonstrated activity in metastatic breast cancer patients (95). In a randomized trial of 3,170 node-positive patients who received four cycles of AC followed by four cycles of paclitaxel for 4 weeks or no additional therapy, survival rates improved from 84% to 87% in the treated group after 36 months of follow-up. Benefits were similar in both premenopausal and postmenopausal women (96). Although the role of taxanes in the adjuvant setting for women with node-negative disease has yet to be definitively defined, early results suggest an improvement in overall survival when taxanes are used in the treatment of women with early-stage breast cancer (97).

Neoadjuvant Systemic Therapy

The use of neoadjuvant chemotherapy traditionally was limited to those individuals with either inoperable locally advanced or inflammatory breast cancers. The goal of preoperative systemic therapy was to convert inoperable patients into resectable candidates on the basis of pathologic and clinical responses (98). More recently, indications for neoadjuvant chemotherapy have been broadened to include individuals presenting with large operable tumors who desire to attempt breast preservation instead of mastectomy. Recent reports indicate that breast conservation therapy is possible and that low rates of in-breast or local-regional recurrences occur when neoadjuvant chemotherapy results in clinical and pathological tumor downstaging (99). In addition to large, operable tumors, neoadjuvant therapy continues to have a role in the treatment of inflammatory breast cancers and those presenting in a locally advanced state.

Hormonal Therapy

Hormonal manipulation with tamoxifen or an aromatase inhibitor, used alone or in combination with a cytotoxic regimen, is beneficial in select groups of women. Tamoxifen, an estrogen analogue, offers substantial benefits in both premenopausal and postmenopausal women. Taken at a dose of 20 mg per day for 5 years, tamoxifen reduces the annual risk of recurrence by about 50% and the annual risk of death by about 25%. These benefits were seen in women with estrogen receptor–positive disease regardless of chemotherapy treatment (100).

Tamoxifen, when used in combination with cytotoxic chemotherapy, improves survival in women with positive axillary lymph nodes and positive estrogen receptor expression (101). In patients with node-negative, estrogen receptor–positive disease, the addition of tamoxifen to chemotherapy improved disease-free survival rates after 5 years of follow-up (102). In NSABP study B-14, 2,644 patients with estrogen receptor–positive tumors and no axillary metastases were randomized to either tamoxifen (10 mg orally twice daily for 5 years) or a placebo control. After a 4-year median follow-up, the disease-free survival rate for the 1,318 patients treated with tamoxifen was

15

82% compared with 77% for the 1,326 patients treated with placebo (P = 0.00001), again regardless of menopausal status.

The Early Breast Cancer Trialists' Collaborative Group performed a meta-analysis of adjuvant systemic therapy for breast cancer. They analyzed randomized trials involving adjuvant systemic hormonal, cytotoxic, or immune therapy administered to more than 75,000 women with stage I or II carcinoma. The investigators concluded that for postmenopausal women with estrogen receptor–positive tumors, tamoxifen daily for at least 2 years had a significant beneficial effect on disease-free survival rates, with these effects lasting up to 10 years. The incidence of both carcinoma in the contralateral breast and death rate from heart disease decreased.

In addition to tamoxifen, aromatase inhibitors have been approved for use in the adjuvant treatment of patients with estrogen-receptor positive cancers. Aromatase inhibitors act by inhibiting the aromatase enzyme, thus blocking the conversion of androgens into estrogens. These drugs should be used only in postmenopausal patients or premenopausal women who have undergone chemical ovarian suppression or oophorectomy. Although aromatase inhibitors cause fewer episodes of thrombotic events, hot flashes, and endometrial cancers, musculoskeletal symptoms and osteoporosis are more commonly encountered among aromatase inhibitor users than those taking tamoxifen. Results from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial showed overall lower recurrence rates, as well as fewer contralateral tumors, among women treated with Arimidex alone after 68 months of follow up (103). Based on these results, aromatase inhibitors are now often offered as a first-line treatment option for adjuvant therapy. In addition, recent research suggests that conversion of patients from tamoxifen to an aromatase inhibitor, such as Femara, after 2.5 or 5 years may improve survival, although concurrent use of the two agents offers no benefit (103,104).

General Recommendations

Adjuvant systemic therapy lowers the incidence of recurrence by 25% to 30%. It is important to understand that the proportional reduction in risk of relapse is relatively constant regardless of absolute risk (105) (Table 38.6). As mentioned earlier, adjuvant cytotoxic chemotherapy appears to affect the natural history of patients with either axillary node-negative or node-positive breast cancer. All high-risk patients with node-negative disease are now considered candidates for adjuvant cytotoxic therapy.

Table 38.6 Effect of Systemic Therapy on Recurrence and Survival from Breast Cancer

In postmenopausal, estrogen receptor–positive women, chemotherapy is about one half as effective as tamoxifen in the adjuvant setting (106). For most postmenopausal women with hormone-responsive disease (estrogen- and progesterone-responsive positivity), including node-positive patients, hormonal therapy alone may be adequate

16

treatment. High-risk patients with hormone-resistant disease benefit from cytotoxic systemic therapy. Caution should be exercised when using chemotherapeutic agents. Patients in whom the risk of recurrence is low are likely to derive little overall benefit from the use of adjuvant systemic therapy, whereas those with a high risk of recurrence are likely to receive the greatest benefit. Regardless, comorbidities must always be considered on an individual basis.

The current recommendations for adjuvant systemic therapy in breast cancer are summarized as follows:

Premenopausal women with lymph node involvement should be treated with adjuvant combination chemotherapy. Tamoxifen should be added for patients with estrogen receptor–positive tumors following cytotoxic therapy.

Premenopausal women without evidence of axillary lymph node involvement but with large (>1 cm) size, aneuploid, or estrogen receptor–negative tumors should be treated with combination chemotherapy. Tamoxifen should be given to patients with estrogen receptor–positive tumors.

Postmenopausal patients with negative lymph nodes who are hormone receptor positive should receive adjuvant tamoxifen or aromatase inhibitor therapy. Those with positive lymph nodes may receive tamoxifen or an aromatase inhibitor alone, multidrug cytotoxic therapy, or a combination thereof.

Postmenopausal women with lymph node metastases who are hormone receptor negative may be treated with adjuvant chemotherapy.

Adjuvant systemic therapy is not recommended for patients with favorable tumors smaller than 1 cm. Hormonal therapy may be considered if the patient is estrogen receptor positive.

Prognosis

The treatment of advanced, metastatic breast cancer is largely palliative. For most physicians, quality-of-life issues are paramount when choosing which type of therapy is offered. In patients with locally advanced disease in conjunction with distant metastasis, palliative radiotherapy may be advised to control pain or avoid pathologic fractures. This approach is best exemplified in the treatment of isolated bone metastases, chest wall recurrences, brain metastases, and spinal cord compression.

Systemic disease may be controlled by hormonal or cytotoxic therapy. Because the quality of life during an endocrine-induced remission is usually superior to one following cytotoxic chemotherapy, it is preferable to try endocrine manipulation first. As many as one third of patients with disseminated disease respond favorably to either functional end-organ ablation (ovary, pituitary, adrenal glands) or administration of drugs that block hormonal function. For patients with estrogen receptor–positive tumors, this response rate may be as high as 60%. Because only 5% to 10% of women with estrogen receptor–negative cancers respond to endocrine treatment, they should not routinely receive hormonal therapy except in unusual cases, such as elderly women who are intolerant of cytotoxic therapy (107).

Cytotoxic chemotherapy should be considered for the treatment of metastatic breast cancer if organ involvement is potentially life-threatening (brain, lung, or liver), if hormonal treatment is unsuccessful, if the disease has progressed after an initial response to endocrine manipulation, or if the tumor is estrogen receptor negative. The most useful single chemotherapeutic agent is an anthracycline such as doxorubicin, which has an estimated response rate of 40% to 50%. Combination therapy using multiple agents has response rates as high as 60% to 80% (108). Clinical trials, including those investigating the use of Herceptin for Her-2/neu-positive women with metastases, are under way to examine a variety of combinations for stage IV disease. The historically prominent side effects of debilitating nausea and vomiting are now well controlled with central-acting antiemetics. The importance of controlling these potentially devastating symptoms cannot be overemphasized.

Special Breast Cancers17

Paget Disease

In the 1870s, Sir James Paget first described a nipple lesion similar to eczema and recognized that this nipple change was associated with an underlying breast malignancy (109). The erosion results from invasion of the nipple and surrounding areola by characteristic large cells with irregular nuclei, now called Paget cells. Although the origin of these cells has been much debated by pathologists, they are probably extensions of an underlying carcinoma into the major ducts of the nipple–areolar complex. There may be no visible changes associated with the initial invasion of the nipple. Often, the patient's presenting symptom will be nipple discharge, which is actually a combination of serum and blood from the involved ducts.

The overall prognosis for patients with this rare form of breast cancer depends on the stage of the underlying malignancy. When an intraductal carcinoma alone is identified, the prognosis remains favorable, whereas patients with infiltrating ductal carcinoma metastatic to the regional lymph nodes have worse outcomes. Traditionally, treatment has almost always been total mastectomy and lymph node dissection, although breast conservation therapy with resection of the tumor and nipple–areolar complex, followed by whole breast radiation, is being performed in appropriately identified patients (110).

Inflammatory Carcinoma

Patients presenting with inflammatory carcinoma initially appear to have acute inflammation of the breast with corresponding redness and edema. Additional clinical findings are variable and range from complete absence of a dominant mass to the presence of either satellite skin nodules or a large palpable abnormality.

Inflammatory cancer, rather than infiltrating ductal carcinoma, should be diagnosed when more than one third of the breast is involved with erythema and edema and when biopsy of the involved area, including the skin, demonstrates metastatic cancer in the subdermal lymphatics. Most of these tumors are poorly differentiated. Mammographically, the breast shows skin thickening with an infiltrative process and may or may not identify a mass or calcifications.

Except for biopsy of the lesion to establish the diagnosis, surgery is not part of the initial management of inflammatory carcinoma. Mastectomy usually fails locally within 2 years of the initial diagnosis and does not improve overall or disease-free survival rates. Better results are achieved with a combination of chemotherapy and radiation therapy. Mastectomy may be indicated for patients who remain free of distant metastatic disease after initial chemotherapy and radiation (111).

In Situ Carcinomas

Both lobular and ductal carcinoma may be confined by the basement membrane of the ducts. These carcinomas do not invade the surrounding tissue and, theoretically, lack the ability to spread.

Lobular Carcinoma In Situ

Lobular carcinoma in situshould not be considered a true malignancy but rather a risk factor for the subsequent development of invasive ductal or lobular carcinoma in either breast (112). A more appropriate nomenclature for lobular carcinoma in situ may be lobular neoplasia. Most women with lobular carcinoma in situ are premenopausal and have neither clinical nor mammographic signs of an abnormality. The lesion typically is not a discrete mass, but rather a multifocal entity within one or both breasts incidentally discovered by the pathologist during the evaluation of a completely unrelated issue. Lobular carcinoma in situ usually is managed with an excisional biopsy followed by careful surveillance with clinical breast examinations and mammography. Occasionally, a patient may request either

18

bilateral prophylactic mastectomy or tamoxifen for chemoprevention. Women with lobular carcinoma in situ have a 1% per year and up to a 30% lifetime risk of developing an invasive cancer.

Ductal Carcinoma In Situ

Ductal carcinoma in situ is more common in postmenopausal women. It may manifest as a palpable mass but usually is detected mammographically as a cluster of branched or Y-shaped pleomorphic microcalcifications. By definition, intraductal disease does not invade beyond the basement membrane. Unlike patients with lobular carcinoma in situ, 30% to 50% of patients with ductal carcinoma in situ will develop an invasive ductal cancer within the same breast if treated by excisional biopsy alone (113).

Although modified radical mastectomy was previously the standard treatment for intraductal carcinoma, more conservative surgery, with or without radiation therapy, has been shown to yield good results. In NSABP trial B17, 818 patients were randomly assigned to excision alone or excision followed by radiation therapy. The mean extent of ductal carcinoma in situ lesions was 13 mm, and 88% were larger than 20 mm. All lesions were completely resected with negative margins. After a median follow-up of 43 months, the actuarial 5-year local recurrence rate was 10.4% without radiation versus 7.5% with radiation (P = 0.055) for noninvasive cancers, and 10.5% without radiation versus 2.9% with radiation (P >0.001) for invasive cancers. Of 83 recurrences, only 9 (11%) were not in the index quadrant. A recent reanalysis with a mean follow up of 90 months confirmed these results (114). These data suggest that segmental mastectomy offers excellent local control.

Axillary metastases occur in fewer than 5% of patients diagnosed with ductal carcinoma in situ, making routine axillary dissection unnecessary. When axillary disease is identified, further evaluation of the breast or surgical specimen or both is warranted because nodal metastases indicate that an invasive ductal component was missed. Sentinel node biopsy may be offered to certain individuals with ductal carcinoma in situ, especially if the lesion is high grade, contains comedonecrosis, or was diagnosed on core biopsy and has clinical or radiographic features suggesting invasive disease. About 5% of patients whose initial biopsy results show intraductal carcinoma will be found to have infiltrating ductal carcinoma when treated with mastectomy, whereas core biopsy may underestimate the invasiveness of the disease in up to 20% of patients. The incidence of contralateral breast cancer in women with intraductal carcinoma is the same as in those with invasive ductal carcinoma (5%–8%) (115).

Breast Cancer in Pregnancy

Breast cancer complicates 1 in 3,000 pregnancies (116,117). It is the second most common malignancy seen in association with pregnancy, surpassed only by cervical cancer (118). Initial studies suggested a significantly worse prognosis for patients first diagnosed during pregnancy, but recent data indicate that the hormonal changes associated with pregnancy seem to have little, if any, influence on prognosis. When pregnant patients are matched stage for stage with nonpregnant patients, survival rates seem equivalent (119). Patients typically present with a painless mass. Up to 60% will have concurrent lymph node involvement. The evaluation includes imaging with ultrasonography and mammography, which, although controversial, expose the fetus to less than 0.02 cGy of radiation and may be obtained with proper abdominal shielding (120). If biopsy is warranted, the procedure can be performed safely and should not be delayed until after delivery. Needle biopsy is safe and easily accomplished in the office setting.

The treatment of breast cancer in pregnant women must be highly individualized. Considerations include the patient's age and desire to continue the pregnancy. The overall prognosis should be considered, especially when axillary lymph nodes are involved, because adjuvant chemotherapy can be teratogenic or lethal to the fetus during the first trimester, but may be given later in the pregnancy. It is believed that interruption of pregnancy does not alter the prognosis for patients with potentially curable breast cancer.Following are generalized recommendations for treatment of pregnant women with breast cancer:

19

Traditionally, cancers diagnosed during the first or second trimester of pregnancy have been treated with modified radical mastectomy. Sentinel node biopsy remains a controversial procedure in pregnancy; the use of blue dye is contraindicated, and the safety of radiocolloid has not been documented. In addition, most centers do not offer breast conservation therapy based on the theory that radiation therapy should not be given to the gravid patient. In a patient diagnosed before the third trimester, waiting until after delivery may result in an unacceptable delay in the initiation of therapy and should not be encouraged. Adjuvant chemotherapy can be given after the first trimester, although many oncologists prefer not to give it to pregnant women outside of clinical trials. A classic study reported the risk of fetal malformations to be 20% during the first trimester, a rate which dropped to 1.5% during the second and third trimesters (121). Tamoxifen, however, is a class D drug and should not be given to pregnant or lactating patients with breast cancer.

Localized tumors found during the third trimester of pregnancy can be managed with breast conservation therapy, with radiation delayed until after delivery, or with modified radical mastectomy. Initially, tumors should be excised early in the third trimester using local anesthesia. If delivery is imminent, standard therapy can be performed immediately postpartum. In the patient with a viable fetus, it may be preferable to induce early labor to avoid delaying definitive cancer therapy.

If the breast cancer is diagnosed during lactation, lactation should be suppressed and the cancer should be treated definitively.

Advanced, incurable cancer should be treated with palliative therapy. Decisions regarding continuation of the pregnancy should be based on the therapy necessary and the desires of the mother.

Counseling regarding future childbearing is important for women who have had carcinoma of the breast. Although it generally has been assumed that subsequent pregnancies are detrimental because of the high levels of circulating estrogens, there is no clear difference in survival for women who become pregnant after the diagnosis of breast cancer. One study evaluated the effect of subsequent pregnancy on overall survival after the diagnosis of early-stage breast cancer. Although approximately 40% of the women in the study had node-positive disease, 5- and 10-year survival rates were better in women who became pregnant than in matched pair controls who did not. This study suggests that subsequent pregnancy does not adversely affect the prognosis of early-stage breast cancer (122). A subsequent investigation demonstrated no increase in the relative risk of death for patients who gave birth more than 10 months after their initial diagnosis of cancer (123). Theoretically, it may be that only women with estrogen receptor–positive or progesterone-positive tumors would be affected deleteriously by subsequent pregnancy, but this possibility has not been studied. Because recurrences are most frequent within the first 2 to 3 years after diagnosis, patients with receptor-positive tumors and advanced-stage disease probably should wait until after that time before becoming pregnant again.

20