Breast Cancer Treatment

THE UNIVERSITYOF NEWMEXICO HEALTHSCIENCESCENTER COLLEGEOF PHARMACY ALBUQUERQUE, NEW MEXICO

The University of New Mexico

Correspondence Continuing Education Courses for Nuclear Pharmacists and Nuclear Medicine Professionals

VOLUME VIII, NUMBER 6 Breast Cancer Diagnosis and Treatment

By:

WilliamE. Bumk, Jr, MD Assistant Professor of Surgery Arthur G. JamesCancerHospitaland RichardJ. SoloveResearchInstitute The Ohio StateUniversity Columbus,OH and JullianaNewman,ELS AssistantClinicalProfessorof Phnmacy ContinuingEducation Universityof NewMexico Collegeof Pharmacy Albuquerque.NM

GuestEditor MichaelLinver,~. FACR Director,X-RayAssociatesof NewMexico Clinical AssociateProfessor,Radiology Universityof NewMexico.Schoolof Medicine Albuquerql]c.NM

The University of New Mexico Health Sciences Center College of P-cy is approved by the Amerim Council on Pharmaceutical Fducation as a provider of continuing pharmaceutical education. Program No. 039-000-99-002 -lIM. 2.5 Contact Hours or .25 CEUS. M@ Coordinating Editor and Director of Phamaey Continuing Education William B. Hladik ITI, MS, RPh College of Pharmacy University of New Mexico Ilcalth Sciences Center

Managing Editor Julliana Newman, ELS Wellman Publishing Inc. Albuquerque, New Mexico

Editorial Board George H. Hinkle, hlS, RPh, BCNP William B. Hladik ITI, MS, RPh Jeffrey P. Norenberg, MS, RPh, BCNP Laura L. Boles Ponto, PhD, RPh Timothy M. Quinton, PharmD, MS, RPh, BCNP

Guest Reviewer Michael Linver, MD, FACR Director, X-Ray Associates of New Mexico Clinical Associate Professor, Radiology University of New Mexico, School of Medicine Albuquerque, NM

While the advice and information in this publication are believed to k true and amurate at press time, the author(s), editors, orthepublisher cannot accept any legal responsibility for any errors or omissions that maybe made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

STATEMENT OF OBJECTIVES

The primary purpose of this lesson is to increase the reader’s knowledge and understanding of the diagnosis and treatment of breast cancer.

Upon completion of this continuing education unit, the reader should be able to:

1. Identify risk factors for the development of breast cancer.

2. Describe the current recommendations for breast cancer screening.

3, List the different types of biopsy techniques available for non-palpable breast cancer.

4. Discuss the advantages and limitations of nuclear medicine imaging of breast cancer.

5, Compare and contrast the radiopharmaceuticals utilized for breast cancer imaging.

● 6. Describe breast cancer staging using the TNM classification.

7. List the treatment for patients with non-invasive and invasive breast cancer.

8. Explain the role of sentinel lymph node biopsy in breast cancer surgery.

9. Describe the role of adjuvant therapy in breast cancer treatment.

1 COURSE OUTLINE v. STAGING

I. INTRODUCTION v. TREATMENT

II. PATHOPEYSIOLOGY A. Non-invasive cancer

A. Histopatholo~ B, Invasive cancer

B. Etiology and Risk Factors VI. SUMMARY

III* DIAGNOSTIC STUDIES

A. Mammography

B. Ultrasound

C. Magnetic Resonance Imaging (MRI)

D. Nuclear Medicine Imaging o I

2 breast cancer at some point in their lifetime, BREAST CANCER DIAGNOSIS with a peak incidence of 6.~Oi0 (1 in 15) AND TREAT~NT o between the ages of 60 and 79. Once the data have been tabulated, it is predicted that 176,300 By: new cases of invasive cancer will be reported William E. Burak, Jr, MD for 1999: 1,300 in men and 175,000 in women. Assistant Professor of Surgety, It also is estimated that there will be 43,700 Arthur G. James Cancer Hospital and Richard J. breast cancer deaths with 400 in men and Solove Research Institute, 43,300 in women in 1999.3 For the period of The Ohio State University 1993 to 1995, breast cancer continued to have Columbus, OH an age-related trend. However, that trend is and reversed when predicting cancer related deaths Julliana Newman, ELS in 1999, with lung and bronchus cancer Assistant Clinical Professor of Pharmacy predicted to account for 25V0 of cancer deaths Department of Continuing Education in 1999 while breast cancer is predicted in 16°/0 University of New Mexico of cancer deaths.4 College of Pharmacy According to race and ethnicity, the Albuquerque, NM incidence of breast cancer per 100,000 women during 1990-1995 was highest in white women INTRODUCTION (113 .2), followed by black women (990), Cancer of the breast remains a significant health Asian/Pacific island women (71 .4), Hispanic issue despite recent advances resulting in earlier women (69. 3), and finally Native American diagnosis and management. Although it is women (31 .9). ] The mortality rate is highest primarily a disease of older women, it can affect among black women at 31,5 (per 100,000), ● any age group and is characterized as having a followed by white women (26.0), Hispanic wide variation in its clinical course. The women (15.3), Native American women (1 1.7), treatment of breast cancer has evolved over the and Asian/Pacific island women (1 1.6),2 last several decades due to the results of well- The variation in the incidence of breast controlled clinical trials and the development of cancer between races may be related to factors promising new drugs, and should serve as an such as differences in diet, socioeconomic example for evaluating new treatments for other status, heredity patterns and other culturally malignancies. linked traits. The differences in mortality seen TO understand the impact of earlY between races may be due to the stage at which detection on breast cancer morbidity and breast cancer is diagnosed. For the period of mortality in the United States, it is important to 1980 to 1994, 62°A of breast cancer cases in look at how breast cancer trends have changed white females were detected at a localized over time. All of the statistics that follow are stage, compared with only 50°/0 in black compiled from estimates published by National women. During this same period of time, breast Surveillance, Cancer Institute (NCI) cancer was detected at a regional phase in 29°/0 Epidemiology and End Results (SEER) of white women compared to 35°/0 in black Program, 19981 and from Vital Statistics of the women, and distant met ast ases were present in United States, 1998.2 Breast cancer remains the 6% of white women as compared with 9% in leading cause of estimated new cancer cases in black women. These data suggest that breast the United States. In 1999 breast cancer cancer is detected earlier and at a less advanced accounted for 29°/0 of all new cancer cases as stage in white women than in their black compared to lung and bronchus cancer count erparts, o estimated at 13°/0. 1 Women of all ages have a one in eight chance (12. 5°/0) of developing

3 The trend toward a reduction in breast Etiology and Risk Factors cancer mortality in some countries, and in the While the etiology of breast cancer United States in particular, is encouraging. This remains uncertain, genetics, hormones, and 9 decreased mortality rate is due in part to dietary factors probably play a significant role in concerted effofis at patient and professional carcinogenesis. There continues to be extensive education advocating the importance of early ongoing research evaluating the role of risk detection in conjunction with the widespread factors for breast cancer, however these availability of high-quality, low-cost screening findings have not yet translated into major programs. More women are being screened than clinical advances in early detection, Major risk ever before, resulting in earlier detection of factors include a personal history of breast breast cancer at a more curable stage. Early cancer, a first degree relative with breast cancer, detection remains the primary opportunity to and biopsy proven proliferative breast disease. catch breast cancer in its most treatable phase. Minor risk factors include precocious menarche, Improved diagnosis and better staging primagravidas 30 years of age, and exogenous techniques will continue to have a positive hormone (estrogen) use. These risk factors are impact on mortality rates. A major goal in useful in assessing overall risk and should be I breast cancer diagnosis is the ability to discussed with patients to help individualize distinguish between benign and malignant their follow-up. While a personaI history of lesions. Emerging diagnostic modalities are breast cancer is the strongest risk factor, a first- being developed as a way to supplement degree relative with breast cancer places the mammography screening, patient up to 3 times greater risk than that of I the general population. True heredita~ breast PATHOPHYSIOLOGY cancer is present in only 5- 10°/0 of all breast Primary tumors of the breast are cancer cases, while the sporadic (non- classified as invasive or non-invasive, depending hereditary) type accounts for more than 80V0, A upon whether the tumor cells have violated the previous breast biopsy showing proliferative basement membrane of the mammary ducts. breast disease places the patient at increased Non-invasive lesions include ductal carcinoma risk, especially if atypical hyperplasia is present, in situ (DCIS), or lobular carcinoma in situ The relative risk for developing breast cancer is (LCIS), depending on the cell of origin. Ductal 1.6 for proliferative disease without atypia and carcinoma is the most common type of invasive 4.4 if atypia is present. Patients with atypia and breast malignancy, arising from the epithelial a family history have a relative risk of 8.9, cells that line the mammary ducts. which approaches the risk of patients with in situ carcinoma.5 Histopathology With the discovery of the hereditary There are several subtypes of invasive breast cancer genes BRCA-1 and BRCA-2, an ducial carcinoma including tubular, medullary, individual patient’s risk of developing breast papillary, and colloid (mutinous). Invasive cancer can be assessed. Unfortunately, the vast lobular carcinoma accounts for 3-4% of majority of non-hereditary cases of breast invasive breast cancers and originates from the cancer do not involve BRCA- 1 and 2 mutations. mammary lobules. Theses malignancies have a A major advance in the prevention of breast unique histologic appearance characterized by cancer through the use of the anti-estrogen small cells in a linear arrangement (Indian-file) tamoxifen was recently reported.d Women with with a tendency to proliferate around ducts and a 5-year breast cancer risk of greater than 1.7 lobules (targeted growth). (using the Gail risk model) were enrolled into

4 The double-blinded Breast Cancer Prevention The American Cancer Society guidelines Trial and randomized to receive tamoxifen (20 for screening include monthly breast self-exam o mg per day) or placebo for 5 years. Tamoxifen afier age 20, baseline mammogram at age 35 if use reduced the development of breast cancer there is a family history for breast cancer, and a by 45V0 in high-risk women. This reduction in mammogram annually for women over 40. risk was seen in both premenopausal and Additionally, professional physical examination postmenopausal women and was most of the breasts should be performed every 3 pronounced in those women with LCIS (lobular years between the ages of 20 and 40, and carcinoma in situ) and atypical hyperplasia annually thereafter. These are only guidelines found on a previous biopsy. There was a slight and individual patients may require modification increase in endometrial cancer and deep venous based on risk factor analysis. With the inception thrombosis in the tamoxifen group, which has of new screening programs and the use of these dampened enthusiasm. The number of breast guidelines, earlier and smaller tumors are being cancers prevented was much greater than the diagnosed. This allows for more conservative frequency of endometrial cancers attributed to breast surge~ to be performed and may result the use of tamoxifen. The STAR Trial will in improved survival. compare tamoxifen to raloxifene, a selective estrogen receptor modulator (SERM) in Mammography reducing breast cancer onset. Newer SERMS, Mammography remains the most such as raloxifene, may provide similar benefit effective method of detecting breast tumors in preventing breast cancer without the potential early, when the disease is most successfully toxicities. treated. According to the U.S. Public Health Service, widespread screening of women over DIAGNOSTIC STUD~S 50, followed by prompt treatment when o The differential diagnosis of a palpable required, can reduce breast cancer deaths by as breast mass includes a fibroadenoma, which is much as 300/0.10 Mammography has a high more common in the younger age group (20- sensitivity (ability to detect cancer when it is 30’s), and fibrocystic mastopathy, seen in indeed present) and can visualize 85°/0 to 90°/0 prernenopausal and perimenopausal women. of breast cancers in women over 50. It also can Other masses, such as cysts, lipomas, adenosis discover a tumor up to two years before a tumors, phylloide tumors (benign and malignancy can be felt. 11 malignant), and papillomas can present as Despite its many successes, palpable lesions, Most nonpalpable mammography is not unequivocal; although its mammographically detected masses/densities sensitivity is 85°/0, it is limited in its specificity are cysts, however, ftbroadenomas, papillomas, (ability to correctly identify a woman who does radial scars, and benign lymph nodes are ofien not have breast cancer) with ranges reported seen. Certain microcalcifications can be a sign from as low as 30V0 in some studies -- to highs of malignancy. Adenosis and fibrocystic changes of 65 °/o’2-14to 80°/0 in other studies. 15 account for most benign biopsies. In particular, mammography is less Most patients with breast cancer will sensitive and less specific in younger women present with a palpable mass or mammographic who tend to have denser breast tissue (nearly abnormality. Because mammographic screening 70°A of the breast is comprised of dense tissue has been shown to be effective in reducing in young women). Mammography is also less breast cancer mortality in postmenopausal sensitive and less specific in older women with women, it has become widely used as a denser breasts (i.e. hormone replacement screening tool in addition to breast self exam therapy), and in women who have undergone 7.9 o and examination by a physician. breast surge~ or radiation therapy. Dense

5 breast tissue is an important consideration not meet the sonographic criteria for a simple because it can compromise mamrnographic cyst, or if microcalcifications are present on results by obscuring underlying tumors. As mammogram. Stereotactic or ultrasound-guided many as 25°A of women have radiographically core needle biopsy and wire localization surgical dense breasts~b, and this number is much higher biopsy are both acceptable biopsy methods. in women under the age of 50. Core biopsy, done under fluoroscope, has the Some studies report mammography is advantage of being less “invasive” than a associated with relatively high false-negative needle-localization surgical biopsy, but it should rates17-]g, with as many as 40°/0 of cases going be emphasized that adequate sampling of the undetected with mammography alone, suspicious lesion is required, If atypia is present particularly in young premenopausal women on a stereotactic biopsy, an open biopsy is because of the confounding factor of dense necessa~ to rule out a malignancy. 1t breasts. Furthermore, mammography, in many As previously mentioned, mamm- cases, may be unable to accurately identi~ the ography does have its limitations. With the type of lesion, requiring biopsy or further exception of examination of mammographica!ly investigation. In addition, mammography has a classic lesions such as calcified fibroadenomas, relatively low positive predictive value ranging lipomas, fat necrosis and speculated carcinomas, between 20V0 and 30Y0. The predictive value of mammography is not “diagnostic” and should mammography is calculated by dividing the total not be used alone to reliably differentiate number of true cancers, verified histologically, between benign and malignant lesions,21 The by the total number of tests thought to be only definitive means of confirmation of a positive for breast cancer.20 In fact, only one in suspicious lesion seen on mammography is every four to six biopsies will reveal breast either excisional, fine-needle aspiration or cancer, which means that as many as 75°/0 of stereotactic core biopsy for the provision of biopsies are performed for benign lesions and tissue to the pathologist. However, cancerous therefore unnecessa~. Suspicious findings with tissue is only found in 25°A of the estimated mammography are the prima~ cause of 700,000 biopsies completed in the United States unnecessary biopsy. There continues to be a each year. This results in an estimated 525,000 need for a breast cancer imaging technique that unnecessa~ biopsies, which leads to increased is highly sensitive, highly specific, relatively health care costs and the pain and inconvenience noninvasive, offers a high predictive value, and of an invasive medical procedure. is cost effective. Several potential candidates for Complementary modalities such as this “ultimate breast cancer imaging modality” ultrasound, Doppler ultrasound, computed are discussed in the sections that follow. Since tomography (CT), MIU, and digital none of these techniques is without its mammography have been employed to improve drawbacks the search will continue until one can the sensitivity (detection) and specificity be found. (distinguishing benign from malignant). Mammographic abnormalities, which are Unfortunately, the sensitivity of these suggestive of malignancy, are characterized as procedures is too low to replace mammography either masses or microcalcifications, and as a screening device, and these procedures classified according to the BIRADS System as have variable rates of specificity, Although the category O-5 with 5 being highly suspicious. If use of these procedures is becoming more a mass is present on mammography, it can common as a complementary procedure, there usually be determined whether a mass is cystic is still a need for a diagnostic procedure with or solid with an ultrasound examination of the greater specificity. mass; often these two technologies complement one another. Biopsy is warranted if a mass does

6 Ultrasound Although its usefulness as a screening detect occult malignancies in women with ● device is limited, ultrasound has proven to be normal mammographies and clinical exams. In valuable as an adjunct to conventional retrospect, many of the problems associated mammography, This is particularly true in the with the use of ultrasound were operator evaluation of radiographically dense breasts and dependent. However, there have been as a supplement to mammography due to substantial improvements in ultrasound mammography’s low-positive predictive value technology, particularly with the advent of high and its inability to reduce unnecessary biopsies. frequency, hand-held devices leading to its use Originally, ultrasound was dismissed as a useful in a number of difficult-to-evaluate patients as screening technique because of its inability to described below in Table 1

Table 1. Conditions for Which Ultrasound Has Demonstrated Diagnostic

Efficacy in Breast Disease.

● Differentiating cysts from solid masses (palpable or non-palpable).

● Imaging of women with a palpable mass who are less than 25 years old,

devaluating a palpable mass that is occult with mammography. o ●Providing imaging guidance for core-needle biopsy and cyst aspiration.

● Evaluating ruptured silicone breast implants.

. Evaluating abscesses.

These new devices offer the advantage of extremely operator dependent. In some cases, enhanced spatial resolution in a real-time skilled sonographers can perform an adequate environment.22 It is impossible to consistently ultrasound examination of the breast in as few image microcalcifications using ultrasound only. as 90 seconds; other less experienced operators Fuflhermore, there is significant overlap in the may require as long as 9 minutes to accomplish morphologic characteristics of benign versus an examination. It is difficult to know whether malignant lesions with ultrasound, As a result, the entire breast and surrounding tissue has many palpable lesions are biopsied despite been imaged adequately when considering the negative ultrasonographic findings. The time involved to perform the ultrasound.= management of nonpalpable lesions is based upon their appearance with ultrasound, Magnetic Resonance Imaging Ultrasound is extremely operator Over the past 15 years, there have been dependent. It is essential that all of the breast numerous technologic advances in magnetic and surrounding tissue be imaged to adequately resonance imaging (MRI) of the breast. The identi@ and evaluate any lesions. The length of introduction of intravenous, gadolinium-based time required to conduct an adequate contrast agents, the development of dedicated ● ultrasound examination of the breast is also breast surface coils, and introduction of

7 standard imaging sequences have improved surgical approach from a mastectomy to a MRI imaging of the breast. Today, MRI Iumpectomy. At the other end of the spectrum, imaging of the breast generally is performed identification of additional foci of breast cancer o with a dedicated coil that permits simultaneous may preclude a planned lumpectomy and imaging of both breasts. However, MRI require consideration of other treatment options techniques vary between institutions (eg, dosage such as chemotherapy. MRI evaluation can of interventional agents and timing of imaging) provide important information in the follow up leading to a lack of standardized data regarding of women who have undergone breast the potential usefulness of MRI in breast conservation or chemotherapy in whom imaging.22 mammographic findings are inconclusive. It also Magnetic resonance imaging permits is possible to use MRI to identify primary breast visualization of breast lesions because these cancer in patients with metastatic axillary lesions are usually enhanced following the adenopathy in whom previous mammography administration of intravenous contrast agents. and clinical examination yielded normal results. This phenomenon is due to the hypervascularity In the future, it is predicted that MRI of growing tumors and increased uptake of will become a usefil biopsy-guidance technique. contrast media by these lesions. However, However, this will require that MRI-guided enhancement of non-malignant lesions and even biopsy is possible in lesions detected with ~1 normal breast tissue (particularly at certain or its usefulness will be limited. Furthermore, times during the menstrual cycle), also may small, dedicated and low-cost MRI breast occur with MRI resulting in false-positive imaging systems must become commercially results, 24 A variety of factors has been available if MRI is to play a substantial role in considered in an effort to distinguish benign the fiture diagnosis of breast cancer, If not, the from malignant tumors with MRI. For example, high cost of MRI will continue to limit its time-intensity curves have been developed in an widespread use. 0 attempt to understand the actual enhancement dynamics of a breast mass as it is visualized Nuclear Medicine Imaging with MRI over time. Mechanisms of Action Patterns of enhancement that occur in benign versus malignant lesions also have been Over the years, two approaches have studied.2572b The use of morphologic features been used to image soft tissue tumors. The first has been considered as a possible means to approach utilizes a function of normal tissue not identify malignant tumors. Unfortunately, there shared by malignant tissue and thus uptake of is a substantial overlap between the the radiopharmaceutical is excluded from the characteristics of benign and malignant lesions cancer. An example of this technique is the detected with MRI. Although MRI imaging of masses in the liver using technetium demonstrates high sensitivity in the detection of Tc-99m sulfur colloid where the space- breast cancer, its specificity remains rather low. occupying lesion that replaces the normal MRI can successfully identifi additional reticuloendothelial system tissue appears as a foci of breast cancer not evident with “cold” defect in a normally “hot” background. mammography or clinical examination. 27 In Imaging a “cold” defect in a “hot” organ addition, MRI is more accurate than is more difficult due to interference from mammography in evaluating the actual size of a radioactivity in surrounding tissue. This method malignancy. This may be usefil in selecting a of detecting tumors (indirect imaging), depends more appropriate treatment protocol for some primarily on displacement of normal tissue, patients, For example, confirmation of a small disruption of normal physiologic mechanisms, primary lesion may warrant a change in the or identification of physiologic and biochemical 9

8 reactions to tumor growth. This mechanism of 2. Tumor-Specific Receptors localization is inherently nonspecific and cannot A tumor may be detected using distinguish between benign and malignant radiolabeled antibodies or peptides that bind to disorders. specific tumor markers such as antigens or other Another approach utilizes a receptor compounds found in vivo. Included in characteristic of the neoplasm not shared by this category are the radiolabeled antibody normal tissue in order to localize the compounds developed over the past few years radiopharmaceutical in the cancer, This for detection of colorectal, ovarian, lung, and technique allows the tumor to be seen as an area prostate cancer, as well as the radiolabeled of increased radioactivity, or “hot” spot, as in peptide compounds that bind to specific gallium Ga-67 citrate imaging of tumors such as receptors found in increased concentration on Iymphomas, In this case, the neoplastic lymph the surface of some tumor cells. Areas of nodes will concentrate the radioactivity while current investigation include radiolabeled normal lymph nodes will not. estradiol compounds and the usefulness of FDA Imaging a “hot” spot in a “cold” approved imaging agents such as iridium-11 1 background area is more desirable than the first satumomab pendetide and technetium-99rn approach. This method of tumor detection arcitumomob for imaging breast cancer, (direct imaging) relies upon the biochemical, 3. Increased Tumor Blood Flow physiologic, or immunologic aspects of the In order to accommodate the tumor itself to localize the radiopharmaceutical, tremendous growth rate of tumors compared with the normal surrounding tissue, cancers lay Characteristics of Tumor Cells Pertinent to down an intricate and complex network of Nuclear Medicine lma~ing blood vessels in order to bring nutrients and Localization of radiopharmaceuticals in oxygen to the tumor cells as they grow and o cancer is attributed to one or more of the replicate. Increased vascularization, a common following properties of tumors, feature of many tumors, may promote tumor 1. IncreusedMetabolic Activity uptake in a variety of neoplasms, such as the The radiopharmaceutical is introduced localization of Ga-67 citrate in soft tissue into a tumor as a metabolic substrate, which neoplasms. enters the metabolic pathway of the specific 4. Altered micro vasculature tumor. An example is the use of fluorine-18 In the ongoing effort to supply the fast fluorodeoxyglucose (F-18 FDG) for the growing tumor cells with nutrients and oxygen, diagnostic imaging of colorectal, breast, brain, increased vascular permeability to lung, and skin cancer. The F-18 FDG localizes macromolecules is seen in tumors. This in areas of increased glucose metabolism, which characteristic is thought to play a role in the is common in many tumor cells. Another localization of gallium Ga-67 citrate in example involves the uptake of C- 11 thymidine neoplasms as transferring bound Ga-67 is into certain tumor cells that demonstrate removed from the circulation and incorporated increased DNA synthesis, e.g., some lung, into the tumor mass, Non-specific leakage of brain, and head and neck tumors. In addition, large macromolecules may also aid in the the mechanism of osteoneogenesis plays a major uptake of radiolabeled antibodies and peptides, role in the localization of Tc-99m skeletal which are moved from the vascular space before imaging agents in primary and metastatic cancer binding to specific receptors, found on the of the bone, In this example, uptake occurs at tumor cell surface. the site of reactive bone, which has a high The notion of using nuclear imaging metabolic rate as it works to replace the techniques in the detection of breast cancer is ● skeleton involved with the neoplasm. not new, with a variety of radiopharmaceuticals undergoing evaluation for breast cancer imaging biological characteristics of the breast cancer. over the years. Nuclear medicine breast imaging The nuclear medicine breast image is especially _ or scintimammography (SMM) is primarily used useful when mammogram findings are difficult = as a complementary procedure to evaluate to interpret. This may include patients who have suspicious lesions detected with mammography dense breast tissue or a history of biopsy or in an attempt to avoid unnecessary biopsies or surgery involving the breast. Table 2 provides a surgery. list of indications for adjunctive nuclear Nuclear medicine breast imaging has a medicine breast imaging (in addition to the high degree of accuracy for detecting breast mammogram). cancer depending on the location, size and

Table 2. Clinical Indications for Scintimammography

1. Assessment of radiographically dense breasts, 2. Assessment of scarring or architectural distortion of the breast due to previous breast surgery, radiation therapy, chemotherapy, or biopsy. 3. Assessment of breast implants (scintimammography is not affected by attenuation of silicone implants). 4. Assessment of palpable masses and normal or equivocal mammography and ultrmonography, It is not rare for patients to present with a palpable mass that is difficult to diagnosis with mammography and ultrasound alone. This is particularly true in patients with dense breasts or fibrocystic disease. These o patients are often referred for biopsy or follow up mammography. Since the positive and negative predictive values for scintimammography are high in palpable lesions, scintimammography could be

performed immediately aficr mammography, If the results are positive, biopsy is recommended.

5. Assessment of rnultifocal disease. Scintimammography may be useful in patients with normal or

inconclusive mammography who are scheduled to undergo Iumpectomy. Scintimarnmography can be

useful in the evaluation of multifocal disease. If multifocal disease is shown to be present, a different

surgical approach will be employed. 6. Evaluation of patients at high risk for breast cancer.

7. Evaluation of tumor response to chemotherapy.

8. Evaluation of metastatic axillary lymph nodes, The diagnostic accuracy of scintimammography (80Y0 to

85Yo) is too low to replace axillary lymph node dissection in patients with proven invasive primary breast

cancer. However, it could be useful in patients reluctant to undergo axillary node dissection if there is positive uptake. Or, on the other hand, if there is focal uptake in the breast, but no uptake in the axilla, axillary dissection maybe canceled.28

10 Nuclear lma~in~ Avents cardiac imaging agent, However, ‘Tc-MIBI Thallium TI-201 Thallous Chloride has higher energy photons and a shorter half-life Historically, thallium T1-201 thallous than thallium, permitting the injection of doses 5 chloride (T1-201) scintigraphy was first used in to 10 times greater than thallium. As such, the evaluation of myocardial perfusion. images acquired with ‘Tc-MIBI are of higher However, during the mid- 1970s, Lebowitz and quality and improved resolution compared with colleagues2g hypothesized that T1-201 might be images obtained with thallium. The results from useful in the imaging of tumors because of its several clinical trials suggest that the uptake of similarity to cesium, which was known to *Tc- MIBI far exceeds T1-201. The mean concentrate in tumors. The idea originated from uptake of T 1-201 is 80°/0 higher in malignant the knowledge that a number of cations were cells than in normal cells; however, ‘Tc-MIBI shown to have tumor affinity including Ga+2, uptake in cancerous lesions is 4 times higher than T1-201. This underscores the need to In+3, Hg+2, Bi+2, K+l, T1+2, and NH3+1. further define the role of ‘Tc-MIBI in the The exact mechanism by which most of these imaging of tumors. ~1’33 cations localize in tumors is unknown. As a One study34 demonstrated that ‘Tc- group, they show poor tumor specificity with MIBI uptake was related to angiogenesis and equal or greater affinity for inflammatory lesions possibly to oxidative metabolism involving and abscesses. Early studies demonstrated Tl- increased uptake associated with elevated 201 uptake in malignant lesions, including mitochondrial levels in tumor cells, In practice, tumors of the brain, bone, breast and other soft in order to avoid the non-specific uptake of tissue sarcomas ‘Tc-MIB1 in benign structures, SMM should The first documented case of carcinoma be performed: detection with T1-201 was repotied in 1976, in 1) Before or 7 to 10 days following fine which a focal area of increased uptake was seen needle aspiration; in a male patient with lung cancer who had been 2) From 4 to 6 weeks afier a breast referred for T1-201 evaluation of his heart .30In biopsy; or a subsequent study of 173 patients with 3) At least 2-3 months after breast malignant tumors and 76 with benign lesions surgery and radiotherapy. (including 2 patients with known breast cancer), it was concluded that T1-201 had a sensitivity of Questions exist regarding the optimal 64% and specificity of61 V0.31 In another study phase — if any — during the menstrual cycle to of 15 patients with breast cancer, uptake of Tl- perform SMM. Optimal imaging positions and 201 was observed in all.~2 dosages are under investigation. At present, The use of T1-201 in the evaluation of although standard dosages vary, the most malignant tumors has increased due to technical commonly reported dose of ‘%Tc-M~I is 20 with procedures such as diticulties mCi (74o MBq). Intravenous administration mammography, MRI, and CT, It may be usefil into the antecubital vein in the arm contralateral in distinguishing post-operative changes related to the suspected breast lesion is recommended. to surgery, radiation therapy or chemotherapy This is necessary to avoid false-positive uptake from tumors, recurrence of lesions, or tissue in the axilla on the same side as the suspected necrosis. lesion. Injection can also be made through a dorsal pedal vein if bilateral lesions are Technetium Tc-99m Sestamibi (MiralumaTM) suspected or if the patient has undergone Like T1-201, technetium Tc-99m previous mastectomy .34 sestamibi (MIBI) also was used initially as a

11 Optimal imaging position remains therefore may be advantageous in patients as undetermined. Prone imaging provides described in Table 2, It may also be useful in improved visualization of breast tissue and can women in whom recurrent disease is suspected, 9 better delineate the breast contour. This is particularly if they have undergone previous helpfi.d in identifying the precise location of a surgery, chemotherapy, radiotherapy, or breast suspected lesion. It also provides improved augrnentation.28 separation from the heafi and the liver; organs The specificity of *Tc-sestamibi is that demonstrate relatively high uptake of somewhat higher than its sensitivity, with an 99mTc-MIBI, which can mask breast activity. average of 89°/0. While ‘Tc-sestamibi is This prone position also minimizes the distance concentrated in breast cancers, increased uptake between the breast and the camera. can also take place in benign breast conditions, Furthermore, the prone position permits particularly in cases of hyperproliferative (fast evaluation of all breast tissue proximal to the growing) fibrocystic breast disease. In general, thoracic wall, ~~le the prone position does fibrocystic disease appears as a region or offer some advantages in breast imaging, the regions of slight-to-moderate increased uptake supine position offers better localization of the that is often more difise than localized, It is prima~ tumor. The supine position also tiords ofien bilateral without well-delineated margins, better visualization of the axillae and possible and a patchy pattern of uptake.28 internal mammary lymph node involvement. As Breast cancer, on the other hand, such, a combination of positions is preferred.34 generally appears to be much more focal and is In general, images are acquired over 10 ofien unilateral, with relatively well-defined minutes. Studies indicate that high quality contours, Uptake of ‘Tc-sestamibi varies from diagnostic imaging can be accomplished in 5 to mild to intense depending on several factors, 15 minutes after the injection of *Tc-~1. such as size, type, location, and hormonal Timing is important, as delayed imaging can factors. In general, a tumor to background o result in a premature or false-negative result. activity ratio of greater than 1.2 to 1.4 is Despite the potential advantages that may be thought to suggest a malignant lesion. achieved with SMM, its routine use in breast However, many benign conditions such as cancer detection is still debated.35 highly mitotic juvenile adenomas, papillomas, Numerous clinical studies have been abscesses, local inflammation or highly undertaken to establish the role of ‘Tc-MIBI proliferative breast disease can present with in the detection and evaluation of breast cancer. ratios greater than 1.5,28 Results of these studies suggest that the Because it is well known that the sensitivity of SMM in the detection of primary axillary nodes are the primary drainage sites for breast cancer is 80% to 90Y0,with an average breast, axillary node involvement is considered of 850/0.28 one of the most important prognosticators in SMM is significantly more sensitive in breast cancer. Once a diagnosis of breast cancer the detection of palpable versus nonpalpable has been made, nearly all patients with invasive lesions. In addition, its sensitivity for lesions less and noninvasive breast cancer will undergo than 10 mm in diameter is low and no lesions axillary dissection.28 less than 7 mm in diameter have been detected While axillary dissection does provide with this technique, possibly due to limitations important information about the staging of of currently available detectors. Therefore, breast cancer, it is associated with morbidity SMM is not recommended as a screening test such as arm edema (swelling), lymphostasis and for breast cancer detection. However, unlike infections of the ipsilateral (same side) standard mammography, its sensitivity is not extremity. A noninvasive way of evaluating the affected by the density of breast tissue, and axillary nodes would be useful. As Taillefer2s o

12 describes it, numerous studies3b4b have slightly decreased radioactivity. The mass can evaluated a variety of imaging techniques for be seen in the anterior views near the apex of o their potential in the evaluation of possible the heart. A core biopsy proved the mass to be metastatic involvement of the axilla~ lymph an infiltrating ductal carcinoma. nodes. When considered together, results of these studies suggest an average sensitivity of Technetium Tc-99m Tetrofosmin 77% and a specificity of 89% in the detection of (Myovieww-Nycomed Amersham) axillary metastasis in patients with primary While technetium Tc-99m tetrofosmin is breast cancer. The positive predictive value was not currently approved for use in the detection 86%; “negative” value was 84V0.28 of breast cancer, it may offer some clinical potential. In 1996, abnormal uptake in a breast Technetium Tc-99m $estamibi Case Study carcinoma was reported in a patient undergoing Figure 1 shows four different views of a myocardial pefision scintigraphy.28 patient who received 20mCi of Tc-99m Similar to *Tc-sestamibi, % Tc- sestamibi to aid in the diagnosis of breast tetrofosmin is a Iipophilic cation with demon- cancer. The patient is a 48-year-old woman strated uptake in turnor cells. Although its who had previous breast implants in both of her uptake in tumor cells is less than ‘Tc- breasts. The patient had noticed a lump in her sestamibi, its target-to-background activity ratio left breast, which was also palpated by her is high enough to permit detection of the breast physician. The presence of the silicone implant tumor. However, unlike ‘Tc-sestamibi, the made the mammogram difficult to interpret. uptake of* Tc-tetrofosmin is hypothesized to The SMM shows increased uptake in the mass be less related to mitochondrial activity. in the Iefi breast slightly below the silicone However, similar to % Tc-sestamibi, there is no irnplant, which appears as a circular object with o 1

‘,, ,f,jj: , ,’,,

;,’ # .

,,,‘1 ‘; ‘I*,,;, T,,i,‘,

Figure 1. Shown are four different views of a 48-year-old woman who received 20mCi of Tc-99m sestamibi for detection of breast cancer. See text for more detailed information 13 significant myocardial washout with m Tc- used in Australia. The essential factor is that the tetrofosmin. It demonstrates faster lung and size range of the particle be selected in liver clearance, which may prove useful in the accordance with the colloid to be used. 9 detection of breast tumors near these regions. Injection may be intratumoral, However, more research is needed to establish peritumoral, or subdermally over the tumor. It the possible advantages of a particular is not known whether injection outside the radiopharmaceutical over the other.28 margins of the tumor will yield accurate The administration, image acquisition, drainage patterns. Furthermore, the intratumoral and analysis are virtually identical with both injection may pose some risk of spreading radioph~aceuticals. Although data are tumor cells with the drainage of the radiotracer limited, preliminary results suggest similar or poor drainage in the case of solid tumors. In sensitivity as well as similar positive and addition, the injection of too much or too little negative predictive values for *Tc-sestamibi radiotracer can also hamper the accuracy of versus * Tc-tetrofosrnin. Again, the data are results --not enough can result in little to no limited and most studies were performed with drainage; too much can result in pooling of palpable lesions (diameter greater than 1 cm). It tracer, thereby obscuring the results. Glass and boasts similar accuracy rates when compared colleagues3b recommend volumes between 3 mL with *Tc-sestamibi in the evaluation of axillary and 7 mL, injected around the tumor margins to node metastasis.28 optimize visualization of drainage patterns. They note that larger volumes of radiotracer Sentinel Lymph Node Localization- may be required in patients with large breasts. Lymphoscintigraphy Ultrasound can be used to help pinpoint the In general, while there may be instances desired site of injection. Imaging should be of complex lymphatic drainage, there ofien is conducted within minutes after the injection of ordy a single sentinel node. The notion of lymph the radiotracer, Allowing too great an interval o node staging was first proposed by Morton et of time between injection and imaging can result a14bin the treatment of melanoma. Cabanas also in the mistaken identification of the sentinel proposed its use in the treatment of penile node or nodes. cancer.47 In 1994 Guiliano and colleagues4g The preferred position for the patient is proposed its use in breast cancer using blue dye; in a semi-recumbent position with the ipsilateral and Krag proposed the use of the sentinel node shoulder elevated and that arm raised over the approach using a radiation sensitive probe a patient’s head, Imaging done with the patient in year earlier.4g the supine position can mask the sentinel node Recent approaches involve the due to scatter radiation from the injection sites. intramammary injection of radiotracer to Migration of radiotracer can be hastened with visualize drainage of the tumor itself The the application of heat or massage at the site of radiotracer is injected directly into the tumor or injection or by elevating the venous pressure. into surrounding tissue to identify the node(s) to Having the patient move the arm can also first receive lymphatic drainage for that tumor. accelerate migration of the radiotracer. 36 The most relevant node(s), identified by the Once the sentinel node(s) has been radiotracer or blue dye are then removed and identified, the first node to become radioactive, examined. the location is then marked on the patient’s Several different techniques are used skin. This method, however, is subject to currently with variations in the injection of patient movement and positioning, among other technetium Tc-99m sulfur colloid (filtered or things. The ideal method of localization requires unfiltered) from 1 rnL to 10 mL, It is important the use of a hand-held, radiosensitive probe that to note that other countries may use different is used while the patient is in the same position 9 colloids, for example, antimony sulfide colloid is that will be used during surgery. Many surgeons

14 use blue dye in addition to a radiotracer to to confirm that the targeted area was indeed provide a visual clue for excision. Once the biopsied. A third technique requires the use of a ● sentinel node(s) has been identified, the node is gamma probe immediately following the verified using the hand-held probe to confirm injection of the radiotracer during surgery as a that this is indeed the sentinel node. Without the means to locate the lesion.28’52 use of blue dye, the surgeon must rely solely on the radiosensitive probe. If blue dye is used, STAGING identification is somewhat easier, as the sentinel The staging of breast cancer relies on node is the node that is both blue and clinical and pathologic criteria that are helpful in radioactive.~~ both treatment and prognosis. The current Sentinel node localization in the staging staging method is the TNM system similar to of breast cancer continues to gain popularity. It the TNM system used in other malignancies is a minimally invasive technique and can spare (Table 3). Physical examination and histologic patients many of the complications associated confirmation are essential for accurate staging; with axillary dissection, Furthermore, it is physical examination should include an estimate considered very accurate in the identification of as to tumor size (T, tumor), relative mobility, or the sentinel node and is a less morbid fixation to the underlying pectoral fascia, or procedure. skin involvement (ulceration, erythema, edema). Skin dimpling and pagetoid changes in the Applications nipple do not indicate skin involvement unless Because of its limited sensitivity in the accompanied by signs of ulceration, erythema, detection of breast tumors less than 10 mm in or edema. size, SMM is not recommended in breast cancer Physical examination can be used to screening in asymptomatic patients. Its use is assess the axilla~ lymph node status (N, ● reserved as a complementa~ diagnostic nodes), however it is not an accurate procedure to mammography when its results are assessment and requires histologic evaluation of suspicious as described in Table 2.28 One of the the lymph nodes obtained at the time of primary limitations of SMM s the spatial lumpectomy or mastectomy. A clinically resolution of the gamma camera. New gamma “negative” axilla may contain histologically cameras dedicated for scintimammography are positive lymph nodes in up to 30°A of patients. under development in an effort to improve Evidence of distant metastasis, (M, spatial resolution. Another problem involves the metastasis), should be obtained through a localization of a lesion that is neither palpable carefil history, physical examination, along with nor visible with mammography but is the selective use of imaging studies. Since the subsequently identified using SMM. There are most common sites of metastasis are bone, several approaches used to locate such a lesion lung, and liver, a chest x-ray and liver function but none is ideal. A skin marker can be used to tests are appropriate. A bone scan can be identify lesion from an anterior supine view and obtained, however its yield in the asymptomatic a lateral view if possible to deter~ine the depth patient is extremely low. It can serve as a usefil of the lesion. This is a relatively gross method baseline study in the event that skeletal pain of localization, however. A second technique does develop in the follow-up period, Patients involves the use of a radionuclide-guided, who initially present with symptoms suggestive stereotactic pre-biopsy needle to help locate an of metastatic disease benefit from the use of abnormality seen with SMM. This approach selected imaging studies (i.e., CT chest, requires that a post-biopsy SMM be performed abdomen, brain).

15 Table 3. Staging for Breast Carcinoma/TNM System

DEFINITIONS:

PRIMARY TUMOR (T)

Tx: Primary tumor cannot be assessed

TO: No evidence of primary tumor

Tis: Carcinoma in situ Tl: Tumor 2cm or less in greatest dimension T2: Tumor more than 2cm, but not more than 5cm in greatest dimension T3 : Tumor more than 5cm in greatest dimension T4: Tumor of any size with direct extension to chest wall or skin

REGIONAL LYMPH NODES (N) Nx: Regional lymph nodes cannot be assessed

NO: No regional lymph node metastasis Nl: Metastasis to movable ipsilateral axillaty lymph node(s) N2: Metastasis to ipsilateral axilla~ lymph nodes that are fixed to one

another or to other structures

N3 : Metastasis to ipsilateral internal mammary lymph node(s)

DISTANT METASTASIS (M) MX: Presence of distant metastasis cannot be assessed

MO: No distant metastasis

Ml: Distant metastasis [includes metastasis to ipsilateral supraclavicular 1

lymph node(s)]

16 Fluorine F-18 Fluorodeoxyglucose (FDG) once a lesion has been detected. Inherent in Data suggest that many breast cancers both techniques is the problem of accurate have increased levels of metabolic activity that localization that is required in order to perform can be detected with fluorine F-18 biopsy, lumpectomy, or surgery. Both fluorodeoxyglucose (FDG). Several studies techniques suffer from the lack of an anatomical have evaluated the use of FDG in the detection reference that is available with modalities like and diagnosis of breast cancer, reporting an mammography, ultrasound, and MRI. Until increased uptake in cancers of the breast and in anatomic resolution of a lesion detected with axilla~ nodes positive for cancer. The use of PET or SPECT can be accomplished, positron emission tomography (PET) therefore localization afier detection will remain a may prove useful in the staging of breast cancer limitation of FDG and ‘Tc-sestamibi and in the assessment of metastatic spread or scintimammography.50 35,51,52 recurrence of cancer. FDG also has potential application in the Early studies showed promising results evaluation of axillary node status. It is known boasting high sensitivities, visualizing 82% of that FDG has high accumulation in the axillaty primary breast tumors in one study53 and 100% nodes containing metastasis.5b-5g Although the in another study54, although all of the patients in sensitivities reported in these studies were the second study had prima~ tumors >5 cm in higher than the specificities reported, it is diameter. Studies that are more recent report thought that the use of FDG in the assessment sensitivity rates ranging between 80°/0 and 90°/0, of axillary node involvement could help to Variations between these studies may be due to minimize false-negative findings. the patient selection process, image acquisition Whole body FDG PET can also be used (length of time), primary tumor size (>1.0 cm in to identify metastatic breast lesions.54’5g It may diameter), etc. Tumor size is particularly prove useful in staging and monitoring of important since the larger the primary tumor, patients undergoing chemotherapy or radiation the more likely the chance of metastasis, therapy. It may also be useful in the monitoring Due to the overall lack of data it is of the effectiveness of chemotherapy in impossible to accurately predict specificity and patients. b0”b2 As treatment with chemotherapy the negative prediction value of FDG. FDG progresses, the metabolic changes in breast may be usefil when other imaging modalities cancer lesions can occur within 8 days following are insufficient, such as in the detection of initiation of treatment, and the amount of FDG lesions in patients with silicone breast implants uptake in tumors can be used to assess its or in patients with radiographically dense effectiveness. Changes in metabolic activity can breasts. However, the use of % Tc-sestamibi occur without an appreciable change in tumor may yield equally accurate results. Only one size.bo Results from another study showed a study55 compared the use of FDG with * Tc- significant decrease in FDG tumor uptake in sestarnibi and both modalities yielded similar 75% of patients (8/12) who showed a results, but the sample size (20 patients) was conventional response to chemotherapy. This relatively small and the primary lesions were decrease could be measured with PET within 6- large with a mean diameter of 2,9 cm. As such, 13 days after chemotherapy had been initiated. more data are required before an adequate Obviously, this could be particularly useful in comparison of FDG and % Tc-sestamibi can be measuring the response of breast cancer tumors made. in patients undergoing chemotherapy, One concern that is consistent with both promoting a change in the chemotherapeutic FDG imaging and W Tc-sestamibi is the cost of regimen if necessary. At present, FDG PET is the procedure and the appropriate follow up still relatively expensive compared with other

17 imaging modalities and more studies are need to the upper-outer aspect of the right breast. The determine its potential cost-benefit ratio, and to remainder of the study demonstrated uptake verify its effectiveness in the diagnosis of breast within the brain, liver, bone marrow, kidneys, e cancer, and for perhaps its even more important and G.I. tract. Findings were reported as potential role in the evaluation of the effective- consistent with a right breast malignancy with ness of chemotherapy for some patients. 52 metastatic disease to the right axilla. Unfortunately, at present, this is an One week later, the patient underwent expensive procedure that involves the right breast lumpectomy with sentinel node production of radioactive tracers with very biopsy and axillary dissection. During the short half-lives that must be produced in an on- procedure, two sentinel lymph nodes were site accelerator. At present, insufficient large- identified in the tight axilla which were both scale clinical trials have been conducted to positive for metastatic carcinoma upon frozen demonstrate the role of PET in the imaging of section pathological examination. Based on this breast cancer. With the advent of new imaging information, the patient underwent an axillary equipment (coincidence imaging) and the dissection removing twenty lymph nodes, which regional distribution of FDG, the COSt- were all negative for tumor upon pathological effectiveness of this agent will be improved. examination. The Iumpectomy tissue, which was positive on the FDG images, was found to Case Study: 51-Year-O1d Woman Imaged have an invasive ductal carcinoma, Grade 11/111. With Fluorine F-18 Fluorodeoxyglucose A 51-year old woman noticed a lump in TREATMENT the upper-outer quadrant of her right breast N[jn-Invasive Carcinoma during self-exam after being bumped by her Ductal Carcinoma In Situ (DCIS) horse. A mammogram showed a speculated DCIS rarely presents as a breast mass, lesion, which was followed by an excisional either palpable or discovered on a mammogram. o biopsy that revealed a 3.5cm invasive, More ofien, it presents as a new non-palpable moderately differentiated, ductal carcinoma. mammographic finding of clustered The patient presented for a second opinion microcalcifications without an associated mass. regarding follow-up treatment. Occasionally, it maybe present (microscopic) in The patient’s past medical history was breast tissue surrounding a benign lesion negative except for hormonal replacement discovered incidentally with a biopsy. By therapy for two years since post-menopausal definition, DCIS is non-invasive so metastasis symptoms. Physical examination of the breasts outside of the breast is not found unless there revealed no left breast masses or axillary are areas of microinvasion that go adenopathy. She had a well-healed biopsy scar unrecognized. Patients with DCIS are usually in the upper-outer quadrant of her right breast treated with lumpectomy followed by radiation with no other masses or axillary adenopathy on therapy to the breast, as their lifetime risk of the right side. Further discussions with the developing invasive cancer, in that breast, patient reviewed options for treatment including approaches 30°/0.b3 Although radiation has been mastectomy, breast conservation surgery (lump- shown to decrease the recurrence rate when ectomy) and the need to evaluate lymph nodes. instituted following complete excision with The patient was studied with 8.2mCi of negative margins, some recent studies have FDG with images of the brain and total body shown lumpectomy alone to be sufficient completed for staging as shown in Figures 2 and treatment for certain types of DCIS, 3. Images of the chest revealed several foci of particularly those lesions that are small and low- abnormally increased uptake in the right axilla grade. b4-h5 Mlllary dissection is not indicated and an irregular accumulation of radioactivity in unless an accompanying invasive cancer is e

18 o

0 present. Difise, extensive DCIS ofien requires 11 and Stage II tumors, modified radical total mastectomy. Tamoxifen has been shown to mastectomy is the procedure of choice. Patients reduce the rate of contralateral breast cancer by with advanced loco-regional disease (including approximately 50°/0 in patients treated with inflammatory cancer) may benefit from Iumpectomy and radiation for DCIS.K6 preoperative (neoadjuvant) chemotherapy and post-operative radiation therapy. Lobular Carcinoma in Situ (LCIS) LCIS is a diagnosis usually made Illlmpectomy vs. Mastectomy coincidentally when examining breast tissue for For early stage cancers (Stage I and 11), another reason. It does not present as a mass modified radical mastectomy or and is not evident on mammogram. Patients lumpectomy/axillary dissection with breast with LCIS are at a lifetime risk for developing irradiation should both be considered viable invasive carcinoma, in either breast, of 17- options. Several prospective studies have shown 37%.67 that these procedures both result in the same Because of these factors, LCIS is not long-term survival rate, despite an increased considered an early stage of breast cancer, but local recurrence rate in patients treated with rather a marker for subsequent cancer lumpectomy/axillary dissection. K8’Ag There are development. Therefore, patients with the several contraindications to breast conservation diagnosis of LCIS should be followed in a “high including multicentric cancer, previous breast or risk” clinic with frequent (6 months) exams, chest wall radiation, and large tumor size in annual mammography, and should be relation to the breast size. Since the goal of considered for enrollment into breast cancer breast-sparing surgery is to achieve an optimal prevention trials. Tamoxifen should be strongly cosmetic result, a lumpectomy that results in a considered as it has been proven to reduce less than desirable appearance should be breast cancer risk by 45°A.K An alternative but avoided. Patients with small breasts are often extreme treatment involves bilateral simple poor candidates for lumpectomy/axillaty mastectomy with breast reconstruction, which dissection as the Iumpectomy followed by can be offered to selected patients. radiation produces a suboptimal cosmetic result. Therefore, while no particular tumor size is an Invasive Carcinoma absolute contraindication, the relative breast size Surgical Options should be considered. Additionally, patients with Following the diagnosis of invasive large breasts are not ideal candidates because the cancer, the options for treatment should be cosmetic appearance afier radiation is ofien completely discussed with the patient. A poor. surgeon, radiation therapist, and plastic surgeon If a modified radical mastectomy is should be included in the discussions; the more chosen, immediate reconstruction can be offered information provided to the patient, the better to selected patients. Those with advanced loco- opportunity she will have to make an educated regional disease are not good candidates as local decision. The final decision should not be recurrence rates are high and post-operative influenced by the specific bias of the surgeon or radiation therapy may be necessa~. Otherwise, other physician. Surgery remains the initial the options for immediate reconstruction include treatment for AJCC Stage I, II, and some Stage saline tissue expanders/implants or autologous III breast cancer patients. In Stage I and most tissue transfer with a latissmus dorsi or rectus Stage II cancers, the surgical options include a abdominus myocutaneous (TRAM) flap. Plastic modified radical mastectomy or a lumpectomy surgical consultation should be obtained prior to with axillary dissection or sentinel node biopsy surgery in order for the patient to make an followed by breast irradiation. For large Stage educated decision.

21 Sentinel Lymph Node Biop~ patients with early breast cancer have Sentinel node biopsy has recently been undetectable rnetastases that, if Iefi unaddressed, described as an alternative to axillary node would result in recurrence. Even though these dissection in selected women.70 The driving micrometastases may not be clinically detectable, force behind this new technology is the their presence is suggested by the natural history realization that most wornen with early stage of many patients treated with surgery alone. breast cancer do not have axill~ nodal There are two forms of systemic therapy used in metastasis. However, axillary dissection is adjuvant therapy--chemotherapy and hormonal performed routinely because there is no therapy.71”74 accurate predictor of nodal metastasis. Axillary While chemotherapy can improve dissection can result in significant long-term survival in node-positive patients, its use also morbidity such as Iymphedema. As described may improve disease-free survival in earlier, the sentinel node is the first lymph premenopausal, node-negative breast cancer node(s) to drain the prim~ tumor. If this node patients. However, it is important to note that is histologically negative, the chance of other this advantage, while statistically significant, is lymph nodes being involved is generally less modest and may not be associated with an than 5Y0. Technetium Tc-99m sulfir colloid is improvement in overall survival. Since not all injected around the primary tumor and a hand- node-negative patients benefit from this therapy, held gamma detector probe is used to identi@ a tremendous amount of effort has gone into radioactive lymph nodes during surgery. Blue identi~lng “high risk” node-negative patients dye is also used to aid in the visualization of the who might benefit. Tumor size, estrogen lymphatic pathway. For palpable breast lesions receptor content, DNA analysis, grade, and or biopsy cavities, the lymphatic mapping agent blood vessel invasion are several examples of can be injected directly around the tumor site, prognostic indicators that are taken into while nonpalpable lesions should be injected consideration in assessing one’s risk of using ultrasound or mammographic guidance. recurrence. Adjuvant chemotherapy is not Although used widely, the role of routine without toxicity, so the clinician ideally would preoperative lymphoscintigraphy has yet to be want to treat the group that would receive the defined. Contraindications to sentinel node most benefit. As more of the current clinical biopsy include palpable nodes, a tumor ~ 5 cm trials are completed, treatment strategies will in size, multifocal invasive carcinoma, previous become more standardized. Tamoxifen is extensive breast or axillary surgery, and usually added to chemotherapy in receptor- preoperative chemotherapy. It is also essential positive patients. that each surgeon perform 20-30 sentinel node Postmenopausal patients generally are biopsies followed by an axillary node dissection less likely to enjoy the same benefits of to validate hifier technique, as this procedure chemotherapy as the premenopausal group. is associated with a significant learning curve. Thus, the adjuvant use of hormonal therapy Results indicate this technique may replace alone in patients with estrogen or progesterone routine lymph node dissection in women with (ER/PR) positive tumors is associated with a clinically negative nodes. There are currently modest but significant improvement in disease- two multi-institutional trials underway that will free survival. Chemotherapy, in addition to assess sentinel node biopsy as an alternative to tamoxifen, is often used in node-positive patients complete axillary lymphadenectomy. as determined by their performance status. The use of chemotherapy in the node-negative Adjuvant Therapy postmenopausal patient is more controversial. The rationale for adjuvant systemic Tamoxifen has also been shown to reduce the therapy is based upon the premise that many

22 risk of contralateral breast cancer, which is chemotherapy consists of the same agents used another potential advantage. in adjuvant treatment, cyclophosphamide, 5-FU, and adriamycin or methotrexate. Taxol has also Follow-up shown effectiveness in this setting. Response Patients with early stage breast cancer rates range from 20-50°/0 with an average should be followed for the remainder of their duration of 6 months. life, as recurrences are seen as far as 15-20 years following diagnosis. Additionally, they are SUMMARY at increased risk of developing a second breast With the increasing utilization of cancer. Therefore, follow-up is aimed to detect screening mammography and the more recurrence, as well as screening the remaining widespread use of breast self-examination, breast breast tissue for malignancy. Patients should be cancer patients are presenting at an earlier stage. followed at 3-month intervals for the first 2-3 This allows for more effective treatment and years, then at 6-month intervals, Any new subsequently improved survival. It is hoped that symptoms of bone pain, headaches, or with the use of genetic markers, high risk neurological changes should prompt an patients will be identified at an early age, immediate work-up. Otherwise, chest x-rays allowing for more intensive screening and and liver function tests are performed at the chemopreventive strategies. time of follow-up. Additionally, all patients The treatment of breast cancer has should have annual mammograms to evaluate evolved from a philosophy of radical surgery to for local recurrence or a new cancer. an approach that involves more aggressive local therapy combined with systemic therapy. This Treatment of Metastatic Disease change has occurred secondary to the realization Systemic therapy for metastatic breast that breast cancer in its early stages is a local cancer is aimed at improving the quality of life disease, but in its later stages, it is a “systemic and, if possible, prolonging survival+ disease” and should be treated as such. Conventional therapy for metastatic disease has Therefore, chemotherapy and hormonal therapy been shown to provide palliation to selected play an extremely important role in the treatment patients; however, a survival benefit has been of more advanced disease. The goal of surgery at difficult to document. The conventional any stage of the disease is to loco-regional treatment can be hormonal therapy or control while achieving an acceptable cosmetic chemotherapy, depending upon the patient’s result. age, severity of symptoms, and hormone status of the primary tumor. Postmenopausal patients with E~R positive tumors who have non-life REFERENCES threatening recurrences are good candidates for hormonal therapy, usually tamoxifen. In patients 1. National Cancer Institute, SEER 1998. in whom a response to hormonal therapy is 2. Vital Statistics of the United States, 1998. seen, but who subsequently progress, a second- line hormone therapy should be instituted, 3. Wingo PA, Ries LA, Rosenberg HM, et al. usually a progestin or aromatase inhibitor. Cancer incidence and mortality, 1973-1995: a report Response rates of up to 60-70V0 can be card for the U.S. Cuncer. 1998; 82: 1197-1207. expected with hormonal therapy. Chemotherapy is generally used in 4. Mettlin C. Global breast cancer mortality younger, hormone-unresponsive women or in a statistics. CA Cancer J Clin. 1999; 49:138-144. patient with life-threatening metastasis, where a quicker response is needed. Conventional

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26 66. Fisher B, Dignam J, Wolmark N, et al. intergroup study (INT 0011). N Eng JMed 320:485- Tamoxifen in treatment of intraductal breast cancer: 490, 1989. National Surgical Adjuvmt Breast and Bowel Project B-24 randomized controlled trial. Lancet. QUESTIONS 1999;353 (9169): 1993-2000. 1. Which of the following can metastasize? 67. Wheeler JE, Enterline HT, Roseman JM, a. DCIS Tomasulo JP, McIlvaine CH, Fitts, Jr. WT, b. LCIS Kirshenbaum J. Lobular carcinoma in situ of the c. Atypical hyperplasia breast: Long-term follow-up. Cancer 34:554-563, d. Invasive ductal carcinoma 1974.

68. Veronisi U, Zucali ~ Luini A: kal 2. Which of the following is used to enhance control and survival in early brmt cancer: The magnetic resonance imaging (MR1) studies Milan Trial. Int J Radial Oncol Biol Phys 12:717- of the breast? 720, 1986. a. Iodine b. Calcium 69. Fisher B, Bauer M, Margolese R. Five-year c. Gadolinium results of a randomized clinical trial comparing total d. Gold mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer, N 3, Which of the following is not considered a Eng JMed 312:665-673, 1985. risk factor for breast cancer? a. Asbestos exposure 70. Krag D, Weaver D, Ashikaga T, Moffat F, b. Family history of breast cancer Klimberg VS, Shriver C, Feldman S, Kusminsky ~ Gadd M, Kuhn J, Harlow S, Beitsch P. The sentinel c. Personal histo~ of breast cancer node in breast cancer: A multicenter validation d. History of atypical hyperplasia on a study. New Eng JMed 339:941-946, 1998. previous biopsy

71. Bonadonna G, Rossi A, Valagussor P. 4. Clinical investigations have shown that Adjuvant CMF chemotherapy in operable breast tamoxifen can reduce the incidence of breast cancer: Ten years later. World JSurg 9:707, 1985. cancer in high-risk women by which of the following percentages? 72. Henderson IC. Adjuvant systemic therapy a. 1OOA for early brast cancer. Curr Probl Cancer 11:125- b. 20% 207, 1987. C, 25°10 d. 45% 73. Fisher B, Redmond C, Dimitrov NV, Bowman D, Legault-Poisson S, Wickermm DL, 5. Which of the following is the current Wolmark N, Fisher ER, Margolese ~ Sutherland C, screening recommendation for breast cancer? Glass A, Foster R, CapIan R. A randomized clinical trial evaluating sequential methotrexate and a. Breast self-examination beginning at flourouracil in the treatment of patients with node- age 20 negative breast cancer who have estrogen-receptor b. Annual clinical breast exams negative tumors. NEng JMed 320:473-478, 1989, beginning at age 40 c. Annual mammography beginning at 74. Mmsour EG, Gray ~ Shatila AH, age 40 Osbourne CK, Tormey DC, Gilchrist KW, Cooper d. All of the above M~ Falkson G. Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer: An

27 6. Of the following, which typically is not 11. Treatment of DCIS includes all of the imaged with mammography? following, except: a. Clustered microcalcifications a. Lumpectomy o b. Masses b. Radiation therapy c. Lymph nodes c. Chemotherapy d. Microcalcifications associated with d. Mastectomy masses 12. Which of the following statements is most 7. Ultrasound can be used to: true about lobular carcinoma in situ (LCIS)? Determine if a mass is cancer a. It is found frequently on : Determine if a solid mass is benign mammography c. Differentiate between a solid mass b. It is a risk factor for the subsequent and cyst development of breast cancer d. Screen women for breast cancer c. It is treated effectively with radiation therapy only. 8. Which of the following is true concerning d. It is treated effectively with the use of technetium Tc-99m sestamibi for chemotherapy only. breast cancer imaging? a. It can be used in women with dense 13. Surgical options for invasive breast cancer breasts to detect cancer. include all of the following except: b. It takes advantage of high a. Lurnpectomy with axilla~ dissection mitochondrial activity in breast b. Modified radical mastectomy tumors. c. Lumpectomy with sentinel node c. The most commonly reported biopsy dosage is 20mCi. d. Radical mastectomy d. All of the above 14. The diagnostic agent found in the 9. Which of the following tumor cell radiopharmaceutical, Mlralumam, was characteristics is not associated with the originally developed for diagnostic studies localization of technetium Tc-99m sestamibi involving which of the following? in breast cancer? a. Hepatobiliary system imaging a. Monoclinal antibody binding to a b. Lung aerosol ventilation studies specific tumor-associated antigen c. Myocardial perfusion imaging b. Increased metabolic activity of d. Detection of Helicobacter pylori in tumors the stomach c. Increased tumor blood flow d. Altered microvasculature within the 15, Contraindications to breast conservation tumor (lumpectomy) surgery include: a. Palpable axillary lymph nodes 10. Staging breast cancer: b. Tumor size >2 centimeters a. Utilizes the TNM classification c. Previous chest wall radiation b. Requires surgery for complete d. Age >60 years staging c. Requires CT and bone scan in symptomatic patients d, All of the above o

28 16, Breast reconstruction after mastectomy can 21 Which of the following is true concerning the be performed using all of the following drug tamoxifen? 0 except: a. It is a type of anti-hormonal therapy a. TRAM flap b. It is an adjunct medication used to b. Latissmus dorsi flap enhance nuclear medicine imaging c. Tissue expander c. It can be used as a substitute for d. Allogenic breast transplant surgery d. It is a substitute for radiation therapy 17. The sentinel lymph node: a. Is always in the same location 22 In addition to breast cancer, which of the b. Is the first node(s) to drain the following malignant lesions has tumor demonstrated localization with thallium Tl- c. Can only be 1 node 201 thallous chloride? d. Can always be found Skeletal ;: Brain 18, Contraindications to sentinel node biopsy c. Sofi Tissue Sarcomas include: d, All the above a. Palpable axilla~ lymph node(s) b. Tumor size >5 centimeters 23. Which of the following sensitivities were c. Multifoical invasive carcinoma reported in clinical investigations for the use d. All of the above of thallium T1-201 thallous chloride for breast cancer imaging? 19. Which of the following radiopharma- a. 220/0 ceuticals is commonly used for sentinel b. 41% lymph node biopsy? C. 640/o a. Technetium Tc-99m sestarnibi d. 80% b. Thallium T1-201 thallous chloride c. Technetium Tc-99m sulfur colloid 24. Which of the following is the most common d, Fluorine F-18 Fluorodeoxyglucose cause of a breast mass in a 20-year-old (FDG) patient? a. Cancer 20 Which of the following is thought to play b. Fibroadenoma the major role in the localization of fluorine c. Lipoma F-1 8 FDG in breast cancer? d. Cyst a. Altered microvasculature within the tumor 25, Which of the following radiopharmaeuticals b, Increased metabolic activity within has an FDA-approved indication for breast the breast mass cancer imaging? c. Increased tumor blood flow a. Thallium T1-201 thallous chloride d. Tumor specific receptor uptake b. Technetium Tc-99m tetrofosmin c. Technetium Tc-99m sestamibi d. a and b only.

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