Advances in breast cancer detection and management

Med Clin N Am 87 (2003) 997–1028

Advances in breast cancer detection and management Lisa A. Newman, MD, MPH*, Michael Sabel, MD University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, 3308 Cancer Center, Ann Arbor, MI 48109–0932, USA

The past several decades have witnessed tremendous advances in breast cancer management. As recently as 15 years ago, a palpable breast mass was routinely approached with an open biopsy performed under general anesthesia and frozen section analysis, followed by immediate mastectomy if the intraoperative report revealed cancer. Consideration of breast reconstruction was routinely deferred until after the patient had survived a several-year disease-free interval. Fortunately, partnership between the breast cancer advocacy and oncology research communities has empowered women to take an active role in breast cancer detection and treatment planning, and survivorship issues have become prominent in clinical investigations. Several benefits have resulted from the breast health awareness movement. Earlier detection of breast cancer with routine surveillance methods, coupled with the recognition that breast conservation is equivalent to mastectomy for breast cancer survival, have largely eliminated the singlestage diagnosis and treatment sequence described previously. Today, women have options regarding nearly every stage of the breast cancer detection and treatment experience, ranging from risk-reduction strategies, such as chemoprevention and prophylactic surgery, to a full complement of surgical management approaches, including breast conservation and immediate reconstruction performed at the time of mastectomy. In contrast to the now-antiquated single-stage biopsy and mastectomy procedure, women with abnormal breast findings undergo aggressive and sophisticated diagnostic maneuvers. Every effort should be made to establish the cancer diagnosis efficiently by a minimal-morbidity outpatient procedure before the definitive cancer surgery. Frequently this can be accomplished with percutaneous needle biopsy, often performed with image

* Corresponding author. E-mail address: [email protected] (L.A. Newman). 0025-7125/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0025-7125(03)00101-9

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guidance. When percutaneous biopsy is inconclusive, or if this technology is unavailable, a diagnostic surgical biopsy can usually be obtained as an outpatient procedure. Patients can then be educated about their cancer diagnosis and fully evaluate their treatment options so that they make well-informed, rational decisions. The complexities associated with current breast cancer screening and risk assessment mandate that primary care providers maintain a familiarity with evolving trends and standards of care. Furthermore, diagnostic procedures and referrals initiated by the primary care providers can have significant downstream effects regarding the identification of women who might benefit from risk reduction strategies, and can also impact stage of breast cancer diagnosis and treatment options. This article presents an overview of advances made in several aspects of breast cancer detection and management: screening, evaluation and management of the abnormal breast evaluation, breast cancer risk assessment, breast cancer risk reduction, and breast cancer treatment.

Breast cancer screening The most commonly accepted age-appropriate breast cancer screening recommendations and those promoted by the American Cancer Society are as follows: 20 to 40 years old, monthly breast self-examination (optional) and clinical breast examination every 1 to 3 years; greater than 40 years old, monthly breast self-examination (optional) and annual or biannual clinical breast examination and annual mammography. Breast self-examination is generally perceived as a cost-efficient means of promoting breast health awareness, but data to document its efficacy in reducing breast cancer mortality are lacking [1–3]. Some clinicians have even criticized this approach because of concerns that it creates excessive cancerphobia in some women, and one meta-analysis revealed that it tended to result in an excess of unnecessary biopsies for benign fibrocystic changes [2]. It may represent the only viable alternative for women who do not meet screening eligibility requirements, however, or for whom mammography services are simply unavailable [4,5]. Furthermore, Shen and Zelen [6] analyzed data from selected mammography screening trials and found the sensitivity of breast self-examination (39% to 59%) to be appreciable. Use of annual mammographic screening in women beginning at age 40 is promoted by most medical societies and advocacy organizations, such as the American Cancer Society, the American College of Surgeons, the American Society of Clinical Oncology, and the Susan G. Komen Breast Cancer Foundation. One issue that has generated substantial controversy involves the role of screening mammography in women 40 to 49 years old. In contrast to the annual mammography recommendation espoused by most societies, the American Academy of Family Physicians and the American

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College of Preventive Medicine recommend that annual surveillance mammography should not begin until age 50. The US Preventive Services Task Force [7] has compiled a comprehensive evidence-based analysis of published screening trials and concluded that mammographic surveillance (with or without clinical breast examination) is appropriate at 1- to 2-year intervals for women beginning at age 40, and they also reported that data are inadequate to assess fully the value of breast self-examination. The history of breast imaging dates back to 1913, when Albert Solomon—a surgeon from Berlin, Germany—used conventional radiograph equipment to image mastectomy specimens. It was not until 1956, however, that dedicated film mammography was introduced by Robert Egan, a radiologist from Houston, Texas. Before the universal acceptance of standard film-screen mammography, other less sophisticated forms of breast imaging were used, such as thermomammography and xeromammography. During the 1970s studies demonstrated that mammography was associated with excellent breast cancer detection rates, and by the latter portion of the 1980s use of dedicated equipment for screen-film mammography had become widely adopted by most breast imaging facilities in the United States. Between 1963 and 1990 eight different prospective randomized studies were conducted worldwide to define the optimal standards for breast cancer surveillance with screening mammography. Breast cancer mortality was the end point for all of these studies, and participants were randomized to receive either periodic mammographic imaging or routine health care. The design of the various studies is shown in Table 1 [7–14], demonstrating notable differences between them regarding patient populations, screening intervals, and type of mammogram offered. Most of the studies were designed to be population-based, and the women in the study arm were invited to undergo mammography, but the only trials with 100% uptake on initial screen were the two national programs coordinated in Canada. Uptake in the other six trials averaged approximately 80%. Furthermore, compliance with return for the second screen in the mammography arms ranged from only 54% to 90%, and many studies had significant contamination (13% to 25%) of the control arms by patients who received mammography despite their randomization assignment. The intent-to-treat statistical design of these studies mandated that all participants were analyzed according to their randomization assignment, regardless of whether the assignment was fulfilled. Nonetheless, a 21% to 26% lower breast cancer mortality rate was seen among the women randomized to receive screening mammography in these studies (Table 2). It is likely that the survival benefit associated with mammography is underestimated by these studies as a consequence of the suboptimal compliance and contamination issues. Subset analysis based on age from these trials has revealed that most of the mammography-associated reduction in breast cancer mortality was seen

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Table 1 Eight randomized, controlled clinical trials of screening mammography No. randomized Trial HIP [7,8] Malmo [7,9] Swedish Two-County [7,9–11] Edinburgh [7,12] CNBSS–1 [7,13] CNBSS–2 [14] Stockholm [7,9] Gothenberg [7,9]

Screening Mammography No Age at Mammography No. period screening mammography accrual interval views 1963–69 1976–90 1977–85

30,239 21,088 77,080

30,256 21,195 55,985

40–64 45–70 40–74

12 18–24 24–33

2 1–2 1

1979–88 1980–87 1980–87 1981–85 1982–88

28,628 25,214 19,711 40,318 20,724

26,015 25,216 19,694 19,943 28,809

45–64 40–49 50–59 40–64 39–59

24 12 12 24–28 18

1–2 2 2 1 1–2

Abbreviations: CNBSS, Canadian National Breast Screening Study; HIP, Health Insurance Plan of Greater New York.

among patients age 50 and older, where the magnitude of protection was 23%. To some extent this is an expected finding; breast cancer incidence is substantially lower for women age 40 to 49 years, and the relatively greater breast density of younger women can complicate the interpretation of mammographic images. The Canadian National Breast Screening Study represented an attempt specifically to address the question of mammography efficacy in younger women. In this study 50,000 Canadian women age 40 to 49 years were randomized to annual mammography versus routine health care and with an average follow-up of 13 years, breast cancer mortality was unaffected by screening (rate ratio 1.06, 95% confidence interval 0.80 to 1.40) [13]. A parallel study conducted in Canadian women age 50 to 59 years yielded similar 13-year results (rate ratio 1.02, 95% confidence interval 0.0.78 to 1.33) [14]. The validity of these results has been questioned, however, because of criticisms regarding trial conduct. A fourfold excess of advanced disease was seen in the screened cohort, leading to allegations of bias in the Canadian National Breast Screening Study patient selection and randomization process [15,16]. Additional screening-related controversy has been generated by investigators Gotzsche and Olsen [17,18] from the Cochrane Collaboration. Their interpretations that the methods used in the various mammography trials were substantially flawed led them to conclude that mammographic surveillance yields no longevity benefit. A counter argument, however, is that any retrospective critical review of the mammography trials is irrelevant to contemporary screening practices. Current mammography techniques and equipment are substantially more advanced in comparison with the methods of the screening trials. In fact, screening was not implemented on an annual basis in many of these trials, nor did it uniformly involve two-view imaging.

13 13 13.8 12.8

CNBSS–1 [7,13] CNBSS–2 [14] Stockholm [7,9] Gothenberg [7,9]

Adjusted for socioeconomic factors.

18 17.1 17.3 13

HIP [7,8] Malmo [7,9] Swedish Two-County [7,9–11] Edinburgh [7,12]

a

Median F/U

Trial

60,117 50,200

60,490 42,283 133,065 54,643

N

All Participants

Table 2 Mammography screening trials: outcome and results

0.91 (0.65–1.27) 0.76 (0.56–1.04)

NA

0.77 (0.61–0.98) 0.82 (0.67–1.00) 0.68 (0.59–0.80) 0.79a (0.60–1.02)

Mortality Relative Risk (95% CI)

50,430 NA 22,324 24,091

27,480 8054 35,448 22,746

N

40–49 40–49

40–49

40–49 45–49 40–49 45–49

Age range

Participants\50 y

1.52 (0.80–2.88) 0.58 (0.35–0.96)

0.97 (0.74–1.27)

0.78 (0.56–1.08) 0.73 (0.51–1.04) 0.87 (0.54–1.41) 0.75a (0.48–1.18)

Mortality relative risk (95% CI)

39,405 24,367 26,109

33,010 16,873 40,290 21,746

N

Mortality relative risk (95% CI) 0.79 (0.58–1.06) 0.80 (0.57–1.12) 0.66 (0.46–0.93) 0.99a (0.62–1.58) 0.65a (0.43–0.99) 0.80a (0.51–1.25) NA 50–59 1.02 (0.78–1.33) 50–59 0.56 (0.32–0.97) 50–59 0.94 (0.62–1.43)

50–64 55–64 50–59 50–54 55–59 60–64

Age range

Participants  50 years old

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In the United States the practices and performance of mammography centers are now regulated by the federally mandated Mammography Quality Standards Act implemented in 1992 and reauthorized by Congress in 1998. This program has established benchmarks regarding the necessary equipment used in imaging centers and for minimum mammogram volume requirements for individual radiologists to maintain adequate expertise in evaluating these studies. Furthermore, in an era of chemoprevention availability, mammography represents the primary means of identifying high-risk women harboring lesions that contain atypical hyperplasia. Although it is probably impossible to replicate a phase 3 mammography screening trial today, it seems logical to assume that widespread mammographic surveillance over the past 10 to 20 years is largely responsible for the recent declines in breast cancer mortality that have been observed in the United States and abroad in the United Kingdom [19] and Sweden [20,21]. Mammographic screening programs have also evolved into useful vehicles for medically underserved women to access the health care system. Although it may be impractical (and of questionable yield) to mobilize resources for the conduct of large-scale screening programs with clinical breast examinations, outreach with screening mammography can efficiently reach thousands of women and detect most palpable lesions and most small, nonpalpable tumors. When an abnormal breast lesion is detected on routine, surveillance mammography, comprehensive imaging maneuvers should be pursued promptly, including comparisons with prior studies whenever possible. Diagnostic mammographic views (compression, magnification, and so forth) should be obtained, and ultrasound imaging should be obtained for evaluation of densities as necessary. The abnormality should be characterized as per the American College of Radiology standardized Breast Imaging Reporting and Data Systems [22]: 0: Additional imaging required. 1: Negative; no architectural disturbances identified. 2: Benign finding; negative mammogram, but some benign-appearing lesion identified 3: Probably benign finding. Short interval follow-up suggested; some lesion identified, which has a high probability of being benign, but establishing its stability is preferred. 4: Suspicious abnormality. Biopsy should be considered; lesion detected that is not necessarily typical of cancer, but risk of malignancy is sufficiently high that a biopsy is warranted. The radiologist may comment specifically on the likelihood of cancer based on the type of lesion detected (calcifications, mass, and so forth). 5: Highly suggestive of malignancy. Appropriate action should be taken; these lesions have a high probability of being cancer, and histopathologic confirmation should be sought accordingly.

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The limitations of conventional screening mammography are wellknown. A subset of palpable breast tumors are mammographically occult, and the overall false-negative rate of mammography averages 10% to 15%. Imaging of the dense breast can be particularly challenging, leading to difficulties in evaluating the fibrocystic changes seen in young women, and in women with a history of prolonged hormone replacement therapy. These issues may result in patient call-backs for additional diagnostic views to assess overlapping densities. This in turn is the source of significant anxiety among patients, especially in those cases where a biopsy is ultimately necessary to establish definitively the benign versus malignant nature of a mammographically indeterminate lesion. Also, the burden of storing millions of screening mammograms has become an increasingly formidable task over time. The ability to compare a current mammogram with prior images is essential for optimal, accurate interpretations, but maintaining and archiving the growing volume of these studies is difficult. In response to these acknowledged limitations, several alternative imaging modalities are being explored for their potential value in breast cancer screenings. Digital mammography is an advanced form of screening that offers electronic archiving of breast studies, with improved contrast resolution over a larger dynamic range. These advantages may obviate the need for many call-backs and eliminate the film storage problem. Furthermore, electronic studies can be transmitted to radiologists at any distance from the patient, facilitating second-opinion interpretations by telemammography, and they offer the potential value of computer-aided interpretations. The major hindrances preventing widespread conversion to digital mammography programs include the considerable expenses of purchasing the advanced equipment and training staff in its use and maintenance. Another complexity is the difficulty inherent in comparing serial mammograms performed during the transition period, and accurately distinguishing true interval changes from simple differences in tissue imaging related to technique. Prospective trials evaluating these two forms of mammography are currently underway. Alternative methods for breast cancer screening, such as whole-breast ultrasound, MRI, and positron emission tomography scanning, are also being actively investigated. Ultrasound evaluation of the breast was initially used to distinguish cystic versus solid lesions detected on either mammogram or physical examination. It has evolved into a highly specialized imaging modality that is useful in targeted breast studies to characterize the nature of solid mass lesions and frequently guides the acquisition of percutaneous needle biopsies (discussed later). It is also possible that ultrasound may expand into the screening area. Unfortunately, whole-breast ultrasound is fairly labor-intensive and is always operator-dependent. Nonetheless, promising data have been emerging, indicating that screening with whole-breast ultrasound may be useful, particularly for women with

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mammographically dense tissue. Kolb et al [23] reported a 97% sensitivity rate for the combination of whole-breast ultrasound and mammography in screening 4897 Breast Imaging Reporting and Data Systems category II to IV cases compared with 74% for the combination of mammography and physical examination. Kaplan [24] reported a 0.3% cancer detection rate among women previously found to have a normal mammogram and clinical breast examination. Breast imaging with MRI is of well-documented benefit in the evaluation of occult breast cancer in patients presenting with palpable axillary nodal metastases, where it reliably identifies those patients who may be treated safely with breast conservation (ie, axillary surgery and breast irradiation) [25]. It is also useful in detecting leakage from silicone implant rupture. In screening the otherwise normal and clinically negative breast, the indications for MRI are less clear. The potential advantages and limitations of breast MRI are summarized by Morris [26]. MRI can detect invasive breast cancer with a sensitivity rate approaching 100% and a negative study can confidently clear the breast. False-negative MRIs can occur in the presence of ductal carcinoma in situ, and this modality may be somewhat less reliable in evaluating microcalcifications. Invasive lobular cancer may also be missed, although MRI has been reported to be more sensitive in detecting this histopathology than other imaging modalities. Any hypervascular lesion may show enhancement on breast MRI, and even benign fibroadenomas may occasionally result in a false-positive study. These patterns contribute to the unreliable MRI specificities ranging from 37% to 97% [27]. Nonetheless, breast MRI may be a more efficacious means of screening women at risk for the early onset disease associated with mutations in the BRCA 1 and 2 breast cancer susceptibility genes [28,29]. Use of breast MRI has also been suggested as a means of screening newly diagnosed breast cancer patients for the presence of multicentric disease, thereby refining the identification of candidates for breast-conservation therapy (BCT), especially in women with mammographically dense breasts [30,31]. The sensitivity of breast MRI may actually be so high, however, that occult foci of disease are detected that might otherwise have been eradicated by breast radiotherapy. Whether a breast cancer diagnosis has been established or not, a final limitation of breast MRI is that few institutions have the capability directly to obtain biopsy of MRI-detected lesions.

Work-up of the abnormal breast finding Palpable masses Management strategies for new palpable breast masses may vary to some extent, based on the patientÕs age and overall character of the breast examination. For example, it might be appropriate to follow a 24-year-old

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woman over one or two menstrual cycles to re-evaluate an area of indeterminate nodularity within a field of diffuse fibrocystic changes; in this scenario follow-up serves to rule out whether or not a mass lesion has become more discretely palpable. In contrast, a more aggressive approach (including plans for biopsy) is indicated for a 55-year-old woman who develops a new breast mass. Although obtaining tissue for histopathologic evaluation is the only definitive means of distinguishing a benign from a cancerous lesion, a few guidelines should be followed consistently in the work-up of most new breast masses. A careful and comprehensive breast examination, including palpation of the axillary and supraclavicular nodal basins, is the first step. If the lesion seems to be a discretely palpable nodule, or if the patient is convinced that there has been a new finding on breast self-examination, then it is reasonable to proceed with imaging. When there is strong suspicion that the mass is a simple cyst, if there is concern that the patient will be noncompliant with follow-up diagnostic appointments (including breast imaging), or if available resources are limited and imaging would result in an excessive delay in further management, then it might be appropriate to proceed with an immediate percutaneous aspirate for fluid or tissue analysis. If a decision is made to proceed with aspiration before imaging, it should be cautioned that trauma to a cystic lesion can result in a complex or suspicious appearance on subsequent sonographic imaging. Aspiration of cystic lesion that reveals benign-appearing (greenish or golden) fluid and which results in complete, permanent resolution of the mass should be considered definitive management. Cytopathology or follow-up surgical biopsy is not necessary information unless the fluid appears bloody, there is a persistent mass after aspiration, or the mass recurs. An additional cautionary note is warranted for the special circumstance of aspirations performed in pregnant women. The hormonal influences of pregnancy cause proliferative changes that can yield false-positive findings on cytology, and fine-needle aspiration biopsies require special attention in this context. When time, resources, and patient compliance permit, the new palpable breast mass should be evaluated further with bilateral mammographic imaging and targeted breast ultrasound. Even if previous mammography had been normal within the routine screening interval, a change on breast examination justifies repeat imaging, including diagnostic views to assess the new lesion and bilateral studies to identify contralateral or multicentric disease. Focused breast ultrasound can clarify whether the lesion is a pure, simple cyst versus a suspicious-appearing solid tumor. In the latter cases, ultrasound may also serve to guide a percutaneous needle biopsy. Nonpalpable masses When a nonpalpable breast abnormality is detected on surveillance mammogram and a diagnostic biopsy is warranted, obtaining an

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image-directed percutaneous needle biopsy should be the primary strategy whenever possible. Until approximately 10 years ago, any attempt to obtain a biopsy of a screen-detected lesion was performed as an open surgical, excisional procedure with preoperative wire localization. For these procedures, the radiologist repeats the mammogram on the day of surgery and inserts a wire into the breast, the tip of which should be located at the site of the abnormality. The surgeon then resects a wedge of breast tissue surrounding the wire, a mammogram of the specimen is performed to document inclusion of the abnormal finding, and histopathologic evaluation follows. As screening mammography practices became more widespread, detection of increasing numbers of nonpalpable, indeterminate lesions resulted in the performance of large numbers of negative wire localization biopsies. Approximately 85% of these cases yielded benign pathology results. The volume of negative biopsy specimens motivated the development of improved diagnostic maneuvers for accurate diagnosis of nonpalpable abnormalities with minimally invasive techniques. Percutaneous needle biopsy performed under ultrasound guidance is one option. Mammographically guided needle biopsy using a computer-assisted triangulation method of targeting (stereotaxis) is another option. These maneuvers have proved to be well-tolerated and accurate. Selection of stereotactic versus ultrasonographic guidance for the percutaneous needle biopsy should be based on whichever modality best visualizes the lesion. Microcalcifications in general are poorly imaged on ultrasound and require the stereotactic technique. If ultrasound-guided or stereotactic needle biopsy options are not readily available, then the patient should be referred for an open surgical biopsy with image-guided wire localization. Situations mandating immediate referral for open excisional biopsy include suspicious patterns of calcifications that are inadequately visualized with stereotactic equipment, a patient who cannot lie prone on the stereotactic mammography table for a prolonged period of time, previous attempt at percutaneous image-guided biopsy yielding a discordant result or atypical hyperplasia, and a mammographic density consistent with possible radial scar. Fine-needle aspiration versus core needle biopsy versus open excisional biopsy For palpable solid masses undergoing direct, freehand percutaneous needle biopsy (without image-guidance) the major risk is the possibility of a false-negative result, reviewed by Shah et al [32]. Sampling error easily can occur when the needle retrieves material from a nonmalignant area within or surrounding a cancerous lesion, and a negative needle biopsy from a palpable, suspicious mass should always be followed by additional diagnostic maneuvers. A falsely negative needle biopsy can also result from retrieval of an insufficient quantity of material to establish a diagnosis, and this risk is

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present with freehand and image-guided biopsies. In this regard, the fineneedle aspiration biopsy (performed with a 20- or 22-gauge needle) consistently faces an increased risk for a false-negative result compared with a core needle biopsy (which may be performed with a 14-, 16-, or 18-gauge needle, or with an automated core needle biopsy device). The 25% to 30% fineneedle aspiration–associated false-negative rate can be reduced to 10% with a core-needle biopsy. Furthermore, the core-needle biopsy retrieves a cylinder of tissue that may be analyzed pathologically. The fine-needle aspiration biopsy material is limited to cellular contents for cytologic review, and cannot distinguish an in situ cancer from an invasive lesion. When a percutaneous needle biopsy yields a benign result that is discordant with the clinical or radiographic impression, it is incumbent on the health care provider to pursue the situation with a different diagnostic maneuver. If the initial biopsy was obtained by a freehand procedure, then repeating the procedure with image-guidance (sonographic or stereotactic) might be appropriate. Another alternative is to resort to an open excisional procedure. An open excisional biopsy obtained with wire localization is the appropriate step to follow a nondiagnostic or unsatisfactory image-guided needle biopsy. Although the excisional biopsy is the most definitive diagnostic maneuver, it is associated with some consequences that can impact subsequent management options for a cancerous diagnosis, justifying the time and effort invested in percutaneous needle biopsies. First, the goal of obtaining an excisional biopsy for diagnostic purposes by definition is to determine the pathologic nature of a lesion, and in this circumstance the surgeon is unlikely to perform a wide resection of normal tissue surrounding the mass, so that the resulting cosmetic defect is minimized. If the biopsy turns out to be cancerous, it is likely that the microscopic margins are not clear, and if the patient desires BCT then a re-excision lumpectomy is necessary to achieve margin control. When a cancer-directed lumpectomy is performed after the diagnosis has already been established by prior percutaneous needle biopsy, it is more likely that negative microscopic margins are achieved with a single surgical procedure, resulting in an improved cosmetic result for the cancer patient. Staradub et al [33] have recently documented the larger cumulative volume resection that results when the cancer diagnosis is initially made by needle biopsy as opposed to open excisional biopsy. Second, as the advantages of induction chemotherapy (monitoring chemosensitivity in vivo, primary tumor downsizing to facilitate lumpectomy) become more widely appreciated, application of this sequence has been expanded to the setting of early stage breast cancer. Deriving the benefits of this approach, however, mandates the presence of measurable disease in the breast after histopathologic confirmation of the cancer diagnosis. Lastly, a percutaneous needle biopsy that documents cancer affords the patient an opportunity to plan her breast and axillary surgical management as a singlestage procedure while preserving her options of breast conservation versus mastectomy, and induction versus postoperative systemic therapy.

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Breast cancer risk reduction Until recently, the primary message of breast health awareness programs has been that ‘‘early detection is a womanÕs best protection’’ against breast cancer because there was no way to prevent the disease. Currently, however, tamoxifen is approved by the U.S. Food and Drug Administration for chemoprevention of breast cancer in high-risk women and numerous investigators are evaluating other medications that may decrease the risk of breast cancer. Data have also become available regarding the efficacy of surgical strategies to reduce breast cancer risk. The ability hormonally to manipulate breast tissue and thereby reduce proliferative changes that would otherwise evolve into cancer has been recognized over the past several decades. Women using tamoxifen for a unilateral breast cancer were seen to have a 40% lower risk of second primary or contralateral breast cancer compared with breast cancer patients not treated with tamoxifen. These data motivated implementation of the first large-scale chemoprevention trial conducted in the United States, the National Surgical Adjuvant Breast Project (NSABP) P-1 study [34]. This was a prospective, placebo-controlled, randomized study of tamoxifen in 13,880 high-risk women. Eligibility criteria to participate in the P-1 study included age at least 60 years, a 5-year Gail model breast cancer risk estimate of more than 1.66%, and history of lobular carcinoma in situ (LCIS). After 54 months median follow-up, the trial was unblinded early because of the magnitude of difference in breast cancer incidence between the treated and control arms of the study, revealing that tamoxifen lowered breast cancer risk by 49%. It is now considered standard of care to evaluate breast cancer risk factor information in women and to counsel high-risk women about the options of chemoprevention. Unfortunately, however, making a commitment to 5 years of tamoxifen is not easy, because several potentially severe adverse reactions can be associated with this therapy. The effects of tamoxifen on estrogen receptors in the uterus, vascular system, and central nervous system increase risks of uterine cancer, thromboembolic phenomena (deep vein thrombosis and pulmonary emboli), and vasomotor symptoms (eg, hot flashes, night sweats), respectively. Partially offsetting these risks are tamoxifenÕs estrogen agonist effects on the skeletal system and lipid profile, resulting in a reduced incidence of osteoporosis and lower serum cholesterol levels. NSABP P-1 study participants in the premenopausal age range seemed to be relatively protected from adverse tamoxifen effects [34]; however, the safety of tamoxifen during fetal development has not been established, and chemoprevention with this agent is contraindicated in women who are contemplating pregnancy. Complicating the chemoprevention decision process further is the fact that tamoxifen only reduces the incidence of estrogen receptor–positive tumors. Tamoxifen has no impact on the occurrence of estrogen

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receptor–negative disease, a potentially significant issue in counseling women who harbor mutations in one of the breast cancer susceptibility genes. Subset analysis of genetically tested NSABP P-1 participants demonstrated that tamoxifen does not reduce breast cancer risk in BRCA-1 mutation carriers; however, it does seem to offer some chemoprevention benefit in BRCA-2 mutation carriers [35]. This is consistent with prior studies revealing that BRCA-2 mutation–associated tumors are similar in histopathology to sporadic breast cancer, whereas BRCA-1 cancers are more likely to be estrogen receptor–negative and aneuploid. The ideal selective estrogen receptor modulator retains antiproliferative activity in the breast, but without subjecting the patient to the negative risks. Toward this end, the NSABP is currently accruing to the second chemoprevention trial, the Study of Tamoxifen and Raloxifen (STAR). STAR randomizes high-risk postmenopausal women to receive either tamoxifen or raloxifene, a SERM that is presently approved by the Food and Drug Administration for treatment of osteoporosis. Preliminary evidence indicates that raloxifene has similar breast cancer risk reduction activity compared with tamoxifen, but with a lower incidence of uterine neoplasia. Premenopausal women are ineligible for STAR participation because of the absence of data on raloxifene effects in young, ovulating women. One theory of breast carcinogenesis proposes that risk of malignant transformation is related to lifetime exposure of breast tissue to cyclic extremes in the levels of circulating hormones. Accordingly, it is postulated that stabilization of estrogen levels decreases the incidence of mammary neoplasia. Studies of gonadotropin-releasing hormone agonists in conjunction with low-dose hormone replacement therapy are underway as a means of testing this hypothesis, and preliminary results have shown that this approach successfully can decrease mammographic density [36]; however, longer follow-up is needed to evaluate actual chemoprevention efficacy. Recent data on the efficacy of aromatase inhibitors for adjuvant therapy in breast cancer have revealed that these agents also possess significant chemoprevention activity [37]. Table 3 [34,37–46] summarizes reported data on the risk-reducing strength of various medical therapies. Premenopausal prophylactic oophorectomy and prophylactic mastectomy are additional options as surgical strategies for breast cancer risk reduction. Surgical menopause before age 35 years is an established protective factor against breast cancer risk. Availability of BRCA testing has resulted in the identification of women from hereditary breast-ovarian cancer families, and these women are especially motivated to consider prophylactic removal of the ovaries. Published data by Rebbeck et al [47] have confirmed that prophylactic oophorectomy in this setting can decrease breast cancer incidence by approximately 50%. Premature menopause, however, is associated with an increased risk of osteoporosis and atherosclerotic cardiovascular disease. Interestingly, the breast cancer

Tamoxifen Yes, collective Chemoprevention review Overview Analysis [38] MORE [38,44] No

Yes

IBIS [38,43]

7705

28,406

7139

5408

13,388

Yes

Yes

2471

Yes

Italian Tamoxifen Study Group [38,40–42]

Royal Marsden [38,39] NSABP P-01 [34,38]

Study

Primary chemoprevention study? N 30–70

Age range

Postmenopausal osteoporosis

NA

RR > 2

Median, 66.5

NA

35–70

 1.67% 35–70+ 5-y risk LCIS Age > 60 y S/p hysterectomy 35–70

High-risk, family history

Eligibility criteria

Table 3 Efficacy of chemoprevention based on phase 3 studies

Raloxifene vs placebo

Tam vs placebo Tam vs placebo

Tam vs placebo

Tam vs placebo

Tam vs placebo

4

NA

5

5

5

5–8

Intended treatment Randomization duration

3y

70.6  103 women years

50 mo

81.2 mo

54.6 mo

70 mo

0.28 (0.17–0.46)

0.62 (0.54–0.72)

No HRT: 0.99 (0.59–1.68) HRT: 0.36 (0.14–0.91) 0.68 (0.50–0.92)

All: 0.75 (0.48–1.18)

0.51 (0.39–0.66)

1.06 (0.7–1.7) Tam vs placebo

Median F/U Breast cancer hazard

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Yes

Fenritimide/ 4-HPR [45]

9366

14,170

NA

28–67

7

5

Tam vs. no 5 adjuvant (average, therapy 5 y) Arimidex vs 5 Tam vs Tam + Arimidex

4HPR vs placebo

Accrual not Tam vs yet completed Raloxifene

Postmenopausal, Mean, 64 y early stage breast cancer

Operable breast cancer

Accrual Postmenopausal goal,  1.67% 5-y 19,000 risk LCIS 1574 Early stage unilateral breast cancer

33.3 mo

0.42 (0.22–0.79)

Accrual NA not yet completed 97 mo Premenopausal: 0.66 (0.41–1.07) Postmenopausal: 1.32 (0.82–2.15) 5y 0.54 (0.43–0.69)

Abbreviations: HRT, harmone replacement therapy; LCIs, lobular carcinoma insitu; NA, not applicable; RR, relative risk; Tam, tamoxifen.

Tamoxifen Adjuvant No Therapy Overview Analysis [38,46] ATAC [37] No

Yes

STAR [93]

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protection afforded by prophylactic oophorectomy was not diminished by hormone replacement therapy in the study by Rebbeck et al [47]. Prophylactic mastectomy is a dramatic and extreme maneuver to decrease breast cancer risk, yet only recently has its efficacy in high-risk women been documented. Animal studies of prophylactic mastectomy in carcinogen-exposed rodents or rodents with high rates of spontaneous mammary tumorigenesis have documented the inability of this approach to completely prevent breast cancer. Most disturbing, however, are the numerous case reports of failed prophylactic mastectomies in humans, where breast cancers have developed on the chest wall despite these aggressive surgical procedures. Women at risk for hereditary breast cancer are potentially most susceptible to a failed prophylactic mastectomy, because in these cases any microscopic amount of residual breast tissue harbors the germline predisposition for malignant transformation. Early reports of prophylactic mastectomy in humans [48,49] demonstrated a 1% to 2% failure rate, but these studies were flawed by limited follow-up, and by the inclusion of many women who were probably at low-risk for developing breast cancer. Hartmann et al [50], however, have made valuable contributions to the understanding of the efficacy of prophylactic mastectomy through their meticulous scrutiny of the Mayo clinic database. This analysis yielded 639 prophylactic mastectomy patients with documented increased risk on the basis of family history of breast or ovarian cancer. These high-risk patients were further stratified into very– (214 patients) and moderately– (425 patients) high-risk subsets based on extent of family history. Outcome regarding number of subsequent breast cancers occurring among the very-high-risk subset was compared with the number of breast cancers developing among the female siblings of these patients. For the moderate-risk patients, efficacy of the prophylactic surgery was evaluated by calculating the number of expected cancers based on summing of the individual Gail model risk estimates for the entire group. Survival analyses were performed by projecting anticipated longevity based on population-based data. With a median follow-up of approximately 14 years, seven breast cancers were detected in the prophylactic mastectomy patients (three in the very-high-risk subset and four in the moderate-risk subset) consistent with a 90% reduction in breast cancer risk and mortality in both categories of high-risk patients. Subsequent study of the Hartmann database [51] reported results of prophylactic mastectomy in women who were also found to be BRCA mutation carriers, and confirmed an equivalent magnitude of breast cancer risk reduction. Similarly, Meijers-Heijboer et al [52] reported outcome for 76 BRCA mutation carriers followed prospectively after having undergone prophylactic mastectomy, and found no tumors developing with an average follow-up of nearly 3 years. Reliable evidence does indicate that prophylactic mastectomy effectively and substantially reduces the incidence of breast cancer in high-risk women, although the protection conferred is not complete.

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Evaluation and identification of the high-risk woman None of the available breast cancer risk reduction interventions are free of potential for adverse sequelae. It is essential accurately to assess baseline breast cancer risk for the individual woman, so that patients can make informed decisions about embarking on one of these strategies after carefully balancing the risks and benefits. Various maneuvers based on statistical modeling, clinical features, and breast histopathology have been applied in the endeavor reliably to identify high-risk women. Within the spectrum of benign fibrocystic breast changes, particular patterns can be identified that are consistently associated with an increased risk of future breast cancer development. Women found to have LCIS have a breast cancer relative risk of approximately 10 to 12, or 1% per year [53]. LCIS is always an incidental finding, and lacks any inherent physical findings or mammographic features. Median age at detection of LCIS is generally 5 to 10 years younger than that of invasive breast cancer, and its incidence seems to be increasing, possibly as a consequence of both breast cancer screening and the effects of hormone replacement therapy. The cancers that develop are more often invasive ductal rather than lobular carcinomas, and they occur with equal frequency in the ipsilateral or contralateral side as where the LCIS was found. These patterns suggest that LCIS is a marker of diffuse and bilateral increased risk, rather than a discrete precursor lesion. Atypical ductal hyperplasia [54,55] is associated with a fourfold to fivefold relative risk for breast cancer. In contrast to the sequence of tumorigenesis seen with LCIS detection, atypical ductal hyperplasia is frequently identified because of a mammographic or clinical abnormality, such as microcalcifications or breast mass. Subsequent cancers tend to occur at the site where the atypical ductal hyperplasia was detected, and they are almost uniformly invasive ductal in histopathology. Atypical ductal hyperplasia seems to be a true precursor lesion leading to breast cancer in at least a subset of affected patients. Atypical lobular hyperplasia is distinguished from LCIS on the basis of the degree of terminal duct lobular unit distention by cancerous cells. The associated risk and sequence for breast cancer development seem to be intermediate between that of atypical ductal hyperplasia and LCIS. The relative risk is approximately fivefold. Most subsequent cancers occur at the site where the atypical lobular hyperplasia was detected, but there is also an increased risk for contralateral disease. The Gail breast cancer risk assessment tool [56] is a logistic regression equation that permits calculation of individualized breast cancer risk estimates over a lifetime, or over a predetermined interval. The conventionally established threshold for high-risk is a five-risk risk estimate of at least 1.67% [57]; this represents the risk of an average 60-year-old white American woman. The Gail model was developed by risk factor analysis

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and statistical modeling derived from a case-control subset of the American Cancer SocietyÕs mammography screening program, the Breast Cancer Detection and Demonstration Project (BCDDP). The model uses relative risks for age at menarche, first-degree family history of breast cancer, prior breast biopsy history (including history of atypia), parity (age at first live birth versus nulliparity), and age at time of risk counseling to calculate a womanÕs absolute likelihood of developing breast cancer [56]. The profile of the BCDDP cohort provides an explanation of the modelÕs applicability and its limitations. Very few BCDDP participants were nonwhite Americans [58], and by virtue of the study design, all were receiving mammographic surveillance. The model was defined as a prediction tool to estimate likelihood of detecting breast cancer in white American women who are compliant with annual screening mammograms. It was suspected a priori that insufficient data were available regarding breast cancer risk factors in non-white women, and that the model would be more accurate if limited to a relatively homogeneous patient population. The lead-time bias of mammographically detected breast cancer results in a model that tends to overestimate risk in unscreened women. Lastly, the risk factors entered into the model were necessarily influenced by their prevalence among the BCDDP patient population. Although hormone replacement therapy was predictive of breast cancer risk and this cohort, its use was not sufficiently common for this factor to achieve the significance required for entry into the model. Hormone replacement therapy use became increasingly popular during the 1980s and 1990s, until results from the WomenÕs Health Initiative [59] documented the 26% increase in breast cancer risk associated with prolonged use. The Gail model is also limited by accounting for only firstdegree family history (resulting in paternal and extended family history being missed), and by not accounting for the increased risk conferred by LCIS. Nonetheless, the Gail model is very useful for accurately identifying high-risk women, and it has been validated in three different populations of white American women. Data on its function in African American women and women of other ethnic backgrounds remain limited [60]. Other statistical models are also available for estimating breast cancer risk in selected categories of women and are reviewed by Euhus [61]. The Claus model accounts for extended family history and age at diagnosis among affected relatives, and is appropriate in evaluating women at risk for hereditary breast cancer. The BRCAPRO model calculates breast cancer risk based on age and the estimated likelihood (determined by family history) that the individual harbors a BRCA mutation. Truly individualized breast cancer risk assessment requires the identification of a histopathologic or serologic marker indicating that the womanÕs breast tissue has initiated the preneoplastic process. In this regard, the presence of atypical hyperplasia (ductal or lobular) is probably the most consistent feature available, because it seems to confer the same magnitude of increased risk regardless of whether the atypia is detected

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histopathologically within an open surgical or core needle biopsy specimen, or cytologically within a fine-needle or nipple aspirate. Furthermore, patients with atypia are particularly sensitive to the chemoprevention benefits of tamoxifen. The NSABP P-1 [34] study included 600 patients with atypia in each of the placebo and tamoxifen-treated arms of the study. Tamoxifen resulted in an 86% lower incidence of breast cancer among these patients with a history of atypia. It is clearly impractical to perform serial invasive biopsy procedures as a means of assessing for the development of atypia, and routine nipple aspirates are usually acellular, yielding an inadequate volume of cytologically evaluable fluid. The technology of ductal lavage has been developed as a minimally invasive means of obtaining breast ductal fluid for cytologic analysis. In the first prospective study of ductal lavage, Dooley et al [62] reported on 507 high-risk women who underwent nipple aspirates followed by ductal lavage at 19 different health care facilities. The nipple aspirate yielded fluid in 82% of these women, and the ductal lavage was successfully performed in 92% of the aspirate-positive cases (76% of the total sample). The ductal lavage procedure yielded cytologically evaluable fluid in 78% of cases, with a median of 13,500 epithelial cells seen per duct (average one to two ducts cannulated per breast) compared with satisfactory cellular yield in only 27% of the nipple aspirates, where a median of 120 cells per breast were seen (McNemarÕs test, P \ .001). The ductal lavage procedure involves application of a suction device over the nipple-areolar complex as an initial screening examination. A specially designed, dual-port catheter is then used to cannulate any nipple orifices from which ductal fluid has been elicited. The cannulated ductal system is then irrigated with 10 to 20 mL of saline solution and the lavaged fluid is aspirated back and analyzed microscopically for the presence of atypical cellular material. The entire procedure is performed with a topical anesthetic, and on a 100-point scale (with 100 being maximum pain) the median level of discomfort reported by patients from the multicenter study was 24. Ductal lavage is a reasonable option for further evaluation of patients who already have clinical evidence of increased breast cancer risk, but for whom additional evidence is sought to facilitate decisions regarding chemoprevention or prophylactic surgery [63]. In a study from the Memorial Sloan Kettering Cancer Center, Port et al [64] found that fewer than 5% of high-risk women counseled about tamoxifen therapy accepted the chemoprevention option, whereas 61% remained undecided, and 35% declined definitively. Detection of atypia seems to be a more convincing element in motivating high-risk women to pursue chemoprevention, as documented by Vogel et al [65]. Recent assessment of women screened for participation in the STAR trial revealed that overall, 21% of risk-eligible women agreed to randomization. For the subset of risk-eligible women who also had atypia, however, 36% agreed to randomization [65].

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Breast cancer treatment Although breast conservation was proposed more than 50 years ago, the concept that lumpectomy and breast irradiation could adequately control local extent of disease did not receive widespread acceptance until phase 3 clinical trials conducted in the United States and abroad confirmed its safety [66–71]. As shown in Table 4, long-term results from these investigations have been reported, with the consistent demonstration that breast cancer survival is equal in early stage breast cancer patients regardless of whether they are treated with breast-sparing procedures or mastectomy. Mastectomy remains the most commonly used surgical treatment for breast cancer in the United States, and many women undergoing mastectomy also have the option of undergoing immediate breast reconstruction. Breast conservation therapy Established criteria for BCT eligibility are predicated on three issues: (1) capability to deliver breast irradiation, (2) likelihood of achieving a cosmetically acceptable result, and (3) ability to obtain a margin-negative lumpectomy. The first two issues are clearly related to the third, and all three are motivated by the goal to balance breast preservation with optimal locoregional control of disease. Radiation therapy may be influenced by access to a radiation facility or by medical conditions affecting toxicity and tolerance of treatment. Aesthetic results can be altered by the patientÕs body habitus or primary tumor location; however, the surgeon must remain Table 4 Phase 3 studies of breast conservation therapy versus mastectomy OS Trial

Accrual years

NSABP B-06 [66] 1976–84 1851

4

20

47

Milan Cancer Institute [67] NCI [94,95] EORTC [68,69] Institut Gustav Roussy [70] DBCCG [71]

IBTR

Maximum Median Mast BCT No. Pts tumor size F/U % %

Mast BCT % %

1973–80

701

2

20

58.8

Lump 46 10.2 Lump + XRT 47 58.3 2.3

1979–87

237

5

1980–86 1970–82

868 179

5 2

8 18.4 13.4 10

79 NR* 66 79

78 NR* 65 78

8 13 NR* 22 12 20 NR 4

1983–89

905

82

79

NR

6

39.2 14.3 8.8

NR

None * Survival and outcome data not fully reported in abstract, however, no significant difference noted. Abbreviations: BCT, breast conservation therapy; IBTR, ipsilateral breast tumor recurrence; Lump, lumpectomy; Mast, mastectomy; NR, not reported; OS, overall survival; Pts, patients; XRT, radiation therapy.

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cognizant of the fact that the patient should be the one to define the cosmetically acceptable result. Particular breast and tumor features may suggest that adequate margin control is unlikely with a lumpectomy, but occasionally even a seemingly unifocal tumor is associated with an extensive field effect of microscopic disease that results in margin involvement on multiple re-excision lumpectomy specimens. With these issues in mind, the American College of Radiology and the American College of Surgeons [72] have defined several features that are established as contraindications to breast preservation: 1. Multicentric disease (tumors in separate quadrants of the breast) generally portends an excessive tumor burden in the breast that is not well-controlled by radiation therapy; multiple tumors confined to a single quadrant of the breast (multifocal disease) may be considered for BCT if the lesions can be encompassed completely within a marginnegative lumpectomy specimen, and still leave a cosmetically satisfactory breast appearance. 2. Diffuse, malignant-appearing microcalcifications on the preoperative mammogram is a contraindication to BCT because this pattern probably suggests extensive ductal carcinoma in situ, and predicts low likelihood of obtaining negative margins. Lumpectomies in patients with indeterminate calcifications should be considered with caution and whenever possible the calcifications should be included en bloc with the lumpectomy. 3. Prior therapeutic chest irradiation, with fields that overlap the proposed breast fields. The most common example of this scenario is the case of women treated with irradiation during adolescence or early adulthood for HodgkinÕs disease; these patients face a radiation-related increase in breast cancer risk that manifests itself two to three decades after treatment, and they are generally not candidates for BCT. 4. First and second trimester pregnancy, because of the radiation contraindication. In selected cases of third trimester pregnancy the patient may proceed with surgical management, with radiation deferred until after delivery. 5. Inability to obtain negative margins on the lumpectomy specimen. There is no absolute limit on the number of attempts that should be offered in the quest for margin control, but multiple unsuccessful re-excisions may indicate the presence of an excessive breast tumor burden and they are likely to affect adversely the ultimate cosmetic result. 6. History of collagen vascular disease, such as scleroderma or lupus erythematosis, is considered a relative contraindication to BCT because these patients (particularly if steroid-dependent) may experience excessive radiation toxicity. 7. Primary tumor size greater than 5 cm. Most bulky tumors in this category are considered locally advanced disease, warranting treatment with induction chemotherapy. Otherwise, the upper size limit for breast

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conservation depends on the ratio of primary tumor to breast size, and acceptability (as assessed by the patient) of the cosmetic result following lumpectomy. Neoadjuvant chemotherapy Preoperative chemotherapy has become established as standard management for patients with locally advanced breast cancer, resulting in primary tumor response rates of approximately 80%, and progression of disease only occurs in 2% to 3%. This sequence allows for improved operability and provides for an in vivo assessment of chemosensitivity. The benefits of induction chemotherapy have led to expanded applications of this treatment approach to patients with early stage disease. Several randomized, prospective studies [73–80] have now been completed that prove its safety, and that have demonstrated that tumor downstaging does indeed improve eligibility for BCT, without compromising local control. These studies are summarized in Table 5. The NSABP B-18 trial [79] randomized more than 1500 women with stages I to IIIA breast cancer to receive preoperative versus postoperative chemotherapy. This study demonstrated a statistically significant increase in BCT use for the preoperative chemotherapy arm (68% versus 60%). With a median follow-up of 72 months, the local recurrence rates were 7.9% and 5.8% (not a statistically significant difference) following BCT in the preoperative and postoperative chemotherapy arms, respectively. The conversion rate to BCT eligibility was greatest in the patients with T3 tumors at diagnosis. Newman et al [81] analyzed a series of 100 patients treated at the M.D. Anderson Cancer Center on a prospective protocol of preoperative sequential docetaxel and doxorubicin-based chemotherapy in patients with stages I to III breast cancer. These investigators reported that 34% of patients initially ineligible for BCT were converted to lumpectomy candidates with this preoperative chemotherapy regimen. Furthermore, pathology review of all surgical specimens revealed clinical assessment of BCT eligibility following induction chemotherapy was inaccurate in patients with invasive lobular cancers, multicentric disease, and diffuse microcalcifications. Studies that have randomized women to preoperative versus postoperative chemotherapy have demonstrated equivalent survival. It is oncologically safe to defer surgery while the patient receives systemic therapy, and the benefit of improved lumpectomy eligibility make this an attractive option for any case where there is reasonable certainty that systemic adjuvant therapy is warranted and some focus of measurable disease is present. These include primary invasive tumors larger than 2 cm, and biopsy-proved node-positive cancers. Multiple core needle biopsies should be retrieved from the primary breast cancer to ensure that the lesion is predominantly invasive, as opposed to ductal carcinoma in situ with

1985–1989

1986–1990 1990–1995 1988–1993

Institut Bergonie [73,74]

Institut Curie [75,76] Royal Marsden [77,78] NSABP [79,80]

414 309 1523

272

N

IIA–IIIA I–IIIB I–IIIA

II–IIIA (T > 3 cm)

Stages

66 mo 48 mo 72 mo

124 mo

Median F/U

82 89 68

63.1

PreOp CTX %

77 78 60

0

PostOp CTX % XRT: 34 L/ALND/ XRT: 23 24 3b 7.9

Preop CTX %

Local recurrence after BCT

86 80a 80c

78 80a 80c

55a

55a 9

18 4b 5.8

PostOp CTX %

PreOp CTX %

PostOp CTX %

Overall survival at median F/U

b

Rate estimated from graph. Local recurrence rates reported for lumpectomy and mastectomy patients combined. c Overall survival rate at 5 years. Abbreviations: ALND, axillary lymph node dissection; FAC, 5-fluorouracil, doxorubicin, cyclophosphamide; L, lumpectomy; MM  M, mitoxantrone, methotrexate, with or without mitomycin-C; NA, not applicable; S, surgery; Tam, Tamoxifen; XRT, radiation.

a

Accrual years

Study

BCT rate

Table 5 Randomized studies of neoadjuvant versus adjuvant chemotherapy for breast cancer

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microinvasion, where chemotherapy in any sequence is overtreatment. It is also useful to insert a radiopaque marker into the tumor bed for patients where induction chemotherapy is planned (if there are no calcifications within the tumor), to facilitate subsequent localization of the tumor bed for lumpectomy in the event that the primary tumor shows a complete clinical response during treatment. A couple of additional issues regarding the neoadjuvant approach are worthy of note. First, concerns that preoperative treatment might obscure the prognostic significance of the axillary lymph node status are unfounded. As shown by McCready et al [82], the presence and extent of residual axillary metastases following induction chemotherapy remain very strongly predictive of outcome. Also, the value of the clinicopathologic response to preoperative chemotherapy as a surrogate marker of chemosensitivity in micrometastases is well-established by subset analyses that correlate outcome with degree of primary tumor response. Kuerer et al [83] evaluated survival among patients presenting with locally advanced breast cancer, all of whom received induction chemotherapy, and the patients found to have a complete pathologic response (no residual breast or axillary disease) at time of definitive surgery had a statistically significant 5-year survival benefit of 89% compared with patients experiencing anything less than a complete response. Fisher et al [80] reported a nearly identical 5-year survival for complete pathologic responders among participants of the NSABP B-28 trial of preoperative versus postoperative chemotherapy. Unfortunately, only approximately 12% of patients achieve a complete response with standard doxorubicin-based chemotherapy, and this proportion is not large enough to result in a survival advantage for the entire pool of preoperatively treated patients. Whether or not novel combinations of induction chemotherapies that yield a substantially higher complete pathologic response rate will be associated with a proportionately increased survival will be determined when ongoing studies are completed. Axillary surgery in early stage breast cancer The axillary nodal status is the most powerful prognostic feature available in stratifying risk of breast cancer relapse among newly diagnosed patients. The traditional (and gold standard) procedure for documenting the presence versus absence of axillary nodal metastases is a level 1 and 2 axillary lymph node dissection. This procedure involves resection of the axillary fat pad located inferolateral and deep to the pectoralis minor muscle, typically containing 10 to 20 nodes for histopathologic evaluation. Following this procedure, however, there is a lifetime risk of ipsilateral upper extremity lymphedema, which is clinically significant in approximately 25% of patients [84]. The risk of lymphedema provided the rationale for lymphatic mapping and sentinel lymph node biopsy, a minimally invasive means of evaluating

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the nodal basin. This technology involves injection of a vital blue dye or the radioactive label technetium sulfur colloid into the breast before the axillary surgery. These agents then travel through the intramammary lymphatics and ultimately settle into the sentinel nodes, which are the nodes most likely to harbor metastatic disease. Visual inspection permits identification of the blue node, and a hand-held gamma detector probe is used to identify the radioactive sentinel lymph nodes. The accuracy of this procedure has been validated in numerous studies where the mapping has been performed with a concomitant standard axillary lymph node dissection; false-negative sentinel lymph nodes occur in 0% to 12% of cases (average, 5%) and in approximately 30% of cases the sentinel node is the only site of metastatic axillary disease [85–88]. This procedure may be offered to lumpectomy patients and mastectomy cases. There is a learning curve associated with the likelihood of obtaining reliable results, however, and individual surgeons should not abandon the completion of axillary lymph node dissection until they have accumulated adequate expertise with the procedure. Studies indicate that the sentinel lymph node can be identified successfully regardless of whether the label is injected peritumorally, intradermally, or in the subareolar location. Furthermore, the radioactive label can be injected on the day before surgery; however, the blue dye has a more rapid transit time, and is routinely injected intraoperatively within a few minutes before making the skin incision. Ongoing research addresses questions regarding the accuracy of this procedure in patients receiving neoadjuvant chemotherapy. Although the prognostic value of the axillary lymph nodes cannot be disputed, there is persistent controversy regarding whether or not there is any survival benefit associated with performing a conventional axillary lymph node dissection in a patient with known node-positive disease (either by fine-needle aspiration biopsy of an axillary lymph node or by sentinel lymph node biopsy), as long as there is no clinically palpable, overt nodal disease. In the NSABP B-04 study, 25-year survival was equivalent in women randomized to undergo radical mastectomy (including en bloc axillary lymph node dissection) versus total mastectomy (without axillary lymph node dissection) [89]; for the latter arm, axillary lymph node dissection was reserved as a therapeutic procedure for those cases of regional recurrence. There was contamination of the non–axillary lymph node dissection arm of this study by cases where some nodal tissue was included in the total mastectomy specimen, however, and the trial was underpowered to answer fully the question of whether the axillary surgery might have contributed to outcome. The American College of Surgeons Oncology Group is addressing this question by randomizing sentinel lymph node– positive patients to undergo completion axillary lymph node dissection versus axillary observation only, with axillary lymph node dissection only performed for axillary regional relapse.

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Breast irradiation A standard course of radiation therapy following a margin-negative lumpectomy involves daily external beam radiation treatments to the whole breast for 5 weeks followed by a supplemental boost dose to the tumor bed over 1 to 2 weeks. The value of whole-breast radiation in reducing incidence of local recurrence is well-documented by the long-term results of the NSABP B-06 study [66]. This trial compared outcome in early stage breast cancer patients treated with lumpectomy and breast irradiation versus mastectomy, but there was also a third arm of this study that included women randomized to receive lumpectomy with no breast irradiation. Although the survival was equivalent for all three arms of this study, local recurrences occurred in 39.2% of the lumpectomy-only patients, compared with 14.3% of the patients treated by lumpectomy with breast irradiation. As a consequence of these data, whole-breast radiation therapy has been established as the standard of care for patients receiving BCT. Unfortunately, the duration and frequency of this treatment can be inconvenient or prohibitive for patients who are elderly, working, or lack access to a radiation therapy facility. For these reasons, coupled with the fact that most local recurrences occur in the vicinity of the lumpectomy bed, alternative strategies for the delivery of breast radiation that involve shortened courses of treatment are under investigation. Brachytherapy involves the placement of radioactive sources within or in direct proximity to the organ or tissue harboring malignant cells. This specialized technique allows restriction of the radiation dose to the tumor bed compared with conventional external radiation therapy, which encompasses the entire breast. Brachytherapy has been used in the treatment of breast cancer for over 60 years either as a method of delivering supplemental doses of radiation to the primary tumor site in patients receiving whole-breast irradiation, or as the sole modality of radiation therapy. It has been the most widely studied method of partial-breast irradiation, and can reduce the total treatment time to as little as 1 week. Older brachytherapy catheters were bulky and cumbersome. Newer devices, such as the recently Food and Drug Administration approved MammoSite (MammoSite RTS, Proxima Therapeutics, Alpharetta, GA), involve a reasonably user-friendly inflatable balloon that is inserted into the lumpectomy cavity either in the operating room or postoperatively, under ultrasound guidance [90]. Prospective trials randomizing patients to standard whole-breast radiation versus brachytherapy techniques are necessary before these modified strategies can be widely adopted. Adjuvant systemic therapy A comprehensive discussion of the various chemotherapy regimens and their indications is beyond the scope of this article; however, a few guidelines are reviewed. The goal of adjuvant systemic therapy is to

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eradicate micrometastases, while the total body tumor burden is low and amenable to treatment with curative intent. The worldwide overview analyses [46,91,92] of tamoxifen and chemotherapy delivered in the adjuvant, postoperative setting, demonstrate that these therapies can decrease the odds of breast cancer relapse by 20% to 40%. This benefit is seen in both node-negative and node-positive patients, but the absolute benefit is clearly related to the baseline risk of treatment failure. Patients presenting with very small, node-negative breast cancer derive a proportionate reduction in disease failure rate with systemic therapy, but because they face a low risk of relapse following primary locoregional management alone, the risk of adverse sequelae from adjuvant therapy must be balanced carefully against the small absolute outcome benefit that results. The conventionally accepted thresholds for recommending adjuvant systemic therapy include primary tumor size more than 1 cm and axillary node-positive disease, regardless of primary tumor size. Use of hormonally active therapy (eg, tamoxifen or an aromatase inhibitor for selected postmenopausal women) depends on the estrogen receptor status. Nodepositive patients frequently receive both hormonal therapy and chemotherapy, and estrogen receptor negative disease is limited to chemotherapy as the only adjuvant therapy option. Summary Breast cancer detection and management have undergone dramatic changes over the past three decades. Women are increasingly diagnosed with early stage disease, and leaving them with breast conserving options versus mastectomy. Furthermore, advances in the chemoprevention arena offer the promise of reduced overall breast cancer burden in the future. References [1] Baxter N. Preventive health care, 2001 update: should women be routinely taught breast self-examination to screen for breast cancer? CMAJ 2001;164:1837–46. [2] Hackshaw AK, Paul EA. Breast self-examination and death from breast cancer: a metaanalysis. Br J Cancer 2003;88:1047–53. [3] Thomas DB, Gao DL, Ray RM, et al. Randomized trial of breast self-examination in Shanghai: final results. J Natl Cancer Inst 2002;94:1445–57. [4] Liberman L. The breast imaging reporting and data system: positive predictive value of mammographic features and final assessment categories. AJR Am J Roentgenol 1998;171:35–40. [5] Warner E. Breast self-examination. CMAJ 2002;166:163–8. [6] Shen Y, Zelen M. Screening sensitivity and sojourn time from breast cancer early detection clinical trials: mammograms and physical examinations. J Clin Oncol 2001;19:3490–9. [7] Humphrey L, Helfand M, Chan B, et al. Breast cancer screening: a summary of the evidence. In: US Preventive Services Task Force, vol. 2003. Available at: http:// www.ahrg.gov/clinic/uspstf/uspstforce.htm. Accessed April 4, 2003. [8] Shapiro S. Periodic screening for breast cancer: the HIP randomized controlled trial. J Natl Cancer Inst Monogr 1997;22:27–30.

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