THE UNIVERSITYOF NEWMEXICOHEALTHSCIENCESCENTER

COLLEGEOF PHARMACYALBUQUERQUE, NEW MEXICO

The University of New Mexico

Correspondence Continuing Education Coursesfor

Nuclear Pharmacists and Nuclear Medicine

Breast Cancer

Professionals

VOLUME VIII, NUMBER 6

Diagnosis andBy:

Treatment

WilliamE. Bumk, Jr, MDAssistant Professor of Surgery

Arthur G. JamesCancerHospitaland RichardJ. SoloveResearchInstituteThe Ohio StateUniversity

Columbus,OHand

JullianaNewman,ELSAssistantClinicalProfessorof Phnmacy ContinuingEducation

Universityof NewMexicoCollegeof PharmacyAlbuquerque.NM

GuestEditorMichaelLinver,~. FACR

Director,X-RayAssociatesof NewMexicoClinical AssociateProfessor,Radiology

Universityof NewMexico.Schoolof MedicineAlbuquerql]c.NM

M The University of New Mexico Health Sciences Center College of P-cy is approved by theAmerim 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.

Coordinating Editor and Director of Phamaey Continuing EducationWilliam B. Hladik ITI, MS, RPh

College of PharmacyUniversity of New Mexico Ilcalth Sciences Center

Managing EditorJulliana Newman, ELS

Wellman Publishing Inc.Albuquerque, New Mexico

Editorial BoardGeorge H. Hinkle, hlS, RPh, BCNP

William B. Hladik ITI, MS, RPhJeffrey P. Norenberg, MS, RPh, BCNP

Laura L. Boles Ponto, PhD, RPhTimothy M. Quinton, PharmD, MS, RPh, BCNP

Guest ReviewerMichael Linver, MD, FACR

Director, X-Ray Associates of New MexicoClinical Associate Professor, Radiology

University of New Mexico, School of MedicineAlbuquerque, 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.

Copyright 2000University of New Mexico Health Scimces Center

Pharmacy Continuing EducationAlbuquerque, New Mexico

BREAST CANCER DIAGNOSIS AND TREATMENT

STATEMENT OF OBJECTIVES

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

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

1.

2.

3,

4.

5,

● 6.

7.

8.

9.

Identify risk factors for the development of breast cancer.

Describe the current recommendations for breast cancer screening.

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

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

Compare and contrast the radiopharmaceuticals utilized for breast cancer imaging.

Describe breast cancer staging using the TNM classification.

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

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

Describe the role of adjuvant therapy in breast cancer treatment.

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COURSE OUTLINE

I. INTRODUCTION

II. PATHOPEYSIOLOGY

A. Histopatholo~

B. Etiology and Risk Factors

III* DIAGNOSTIC STUDIES

A. Mammography

B. Ultrasound

C. Magnetic Resonance Imaging (MRI)

D. Nuclear Medicine Imaging

v. STAGING

v. TREATMENT

A. Non-invasive cancer

B, Invasive cancer

VI. SUMMARY

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BREAST CANCER DIAGNOSIS

AND TREAT~NT

By:

William E. Burak, Jr, MD

Assistant Professor of Surgety,Arthur G. James Cancer Hospital and Richard J.

Solove Research Institute,The Ohio State University

Columbus, OHand

Julliana Newman, ELSAssistant Clinical Professor of Pharmacy

Department of Continuing EducationUniversity of New Mexico

College of PharmacyAlbuquerque, NM

INTRODUCTIONCancer of the breast remains a significant healthissue despite recent advances resulting in earlierdiagnosis and management. Although it isprimarily a disease of older women, it can affectany age group and is characterized as having awide variation in its clinical course. Thetreatment of breast cancer has evolved over thelast several decades due to the results of well-controlled clinical trials and the development ofpromising new drugs, and should serve as an

example for evaluating new treatments for othermalignancies.

TO understand the impact of earlY

detection on breast cancer morbidity and

mortality in the United States, it is important tolook at how breast cancer trends have changedover time. All of the statistics that follow arecompiled from estimates published by NationalCancer Institute (NCI) Surveillance,

Epidemiology and End Results (SEER)

Program, 19981 and from Vital Statistics of theUnited States, 1998.2 Breast cancer remains theleading cause of estimated new cancer cases inthe United States. In 1999 breast canceraccounted for 29°/0 of all new cancer cases as

compared to lung and bronchus cancerestimated at 13°/0. 1 Women of all ages have a

one in eight chance (12. 5°/0) of developing

breast cancer at some point in their lifetime,with a peak incidence of 6.~Oi0 (1 in 15)between the ages of 60 and 79. Once the datahave been tabulated, it is predicted that 176,300new cases of invasive cancer will be reportedfor 1999: 1,300 in men and 175,000 in women.It also is estimated that there will be 43,700

breast cancer deaths with 400 in men and43,300 in women in 1999.3 For the period of1993 to 1995, breast cancer continued to havean age-related trend. However, that trend isreversed when predicting cancer related deathsin 1999, with lung and bronchus cancerpredicted to account for 25V0 of cancer deathsin 1999 while breast cancer is predicted in 16°/0of cancer deaths.4

According to race and ethnicity, the

incidence of breast cancer per 100,000 women

during 1990-1995 was highest in white women(113 .2), followed by black women (990),Asian/Pacific island women (71 .4), Hispanicwomen (69. 3), and finally Native Americanwomen (31 .9). ] The mortality rate is highest

among black women at 31,5 (per 100,000),

followed by white women (26.0), Hispanicwomen (15.3), Native American women (1 1.7),and Asian/Pacific island women (1 1.6),2

The variation in the incidence of breast

cancer between races may be related to factorssuch as differences in diet, socioeconomicstatus, heredity patterns and other culturallylinked traits. The differences in mortality seenbetween races may be due to the stage at whichbreast cancer is diagnosed. For the period of1980 to 1994, 62°A of breast cancer cases inwhite females were detected at a localizedstage, compared with only 50°/0 in black

women. During this same period of time, breastcancer was detected at a regional phase in 29°/0of white women compared to 35°/0 in blackwomen, and distant met ast ases were present in6% of white women as compared with 9% inblack women. These data suggest that breastcancer is detected earlier and at a less advancedstage in white women than in their blackcount erparts,

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The trend toward a reduction in breastcancer mortality in some countries, and in theUnited States in particular, is encouraging. Thisdecreased mortality rate is due in part toconcerted effofis at patient and professionaleducation advocating the importance of earlydetection in conjunction with the widespreadavailability of high-quality, low-cost screeningprograms. More women are being screened thanever before, resulting in earlier detection ofbreast cancer at a more curable stage. Earlydetection remains the primary opportunity tocatch breast cancer in its most treatable phase.Improved diagnosis and better stagingtechniques will continue to have a positiveimpact on mortality rates. A major goal inbreast cancer diagnosis is the ability todistinguish between benign and malignantlesions. Emerging diagnostic modalities arebeing developed as a way to supplementmammography screening,

PATHOPHYSIOLOGYPrimary tumors of the breast are

classified as invasive or non-invasive, dependingupon whether the tumor cells have violated thebasement membrane of the mammary ducts.Non-invasive lesions include ductal carcinomain situ (DCIS), or lobular carcinoma in situ

(LCIS), depending on the cell of origin. Ductalcarcinoma is the most common type of invasivebreast malignancy, arising from the epithelialcells that line the mammary ducts.

HistopathologyThere are several subtypes of invasive

ducial carcinoma including tubular, medullary,

papillary, and colloid (mutinous). Invasive

lobular carcinoma accounts for 3-4% of

invasive breast cancers and originates from the

mammary lobules. Theses malignancies have aunique histologic appearance characterized bysmall cells in a linear arrangement (Indian-file)with a tendency to proliferate around ducts andlobules (targeted growth).

Etiology and Risk FactorsWhile the etiology of breast cancer

remains uncertain, genetics, hormones, anddietary factors probably play a significant role in

carcinogenesis. There continues to be extensive

ongoing research evaluating the role of riskfactors for breast cancer, however thesefindings have not yet translated into majorclinical advances in early detection, Major risk

factors include a personal history of breast

cancer, a first degree relative with breast cancer,

and biopsy proven proliferative breast disease.

Minor risk factors include precocious menarche,

primagravidas 30 years of age, and exogenoushormone (estrogen) use. These risk factors areuseful in assessing overall risk and should bediscussed with patients to help individualizetheir follow-up. While a personaI history ofbreast cancer is the strongest risk factor, a first-degree relative with breast cancer places thepatient up to 3 times greater risk than that ofthe general population. True heredita~ breastcancer is present in only 5- 10°/0 of all breast

cancer cases, while the sporadic (non-hereditary) type accounts for more than 80V0, Aprevious breast biopsy showing proliferativebreast disease places the patient at increasedrisk, especially if atypical hyperplasia is present,The relative risk for developing breast cancer is1.6 for proliferative disease without atypia and4.4 if atypia is present. Patients with atypia anda family history have a relative risk of 8.9,which approaches the risk of patients with insitu carcinoma.5

With the discovery of the hereditarybreast cancer genes BRCA-1 and BRCA-2, anindividual patient’s risk of developing breastcancer can be assessed. Unfortunately, the vastmajority of non-hereditary cases of breastcancer do not involve BRCA- 1 and 2 mutations.A major advance in the prevention of breastcancer through the use of the anti-estrogentamoxifen was recently reported.d Women witha 5-year breast cancer risk of greater than 1.7(using the Gail risk model) were enrolled into

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The double-blinded Breast Cancer Prevention

oTrial and randomized to receive tamoxifen (20mg per day) or placebo for 5 years. Tamoxifenuse reduced the development of breast cancerby 45V0 in high-risk women. This reduction inrisk was seen in both premenopausal andpostmenopausal women and was mostpronounced in those women with LCIS (lobularcarcinoma in situ) and atypical hyperplasiafound on a previous biopsy. There was a slightincrease in endometrial cancer and deep venousthrombosis in the tamoxifen group, which hasdampened enthusiasm. The number of breastcancers prevented was much greater than thefrequency of endometrial cancers attributed tothe use of tamoxifen. The STAR Trial willcompare tamoxifen to raloxifene, a selectiveestrogen receptor modulator (SERM) inreducing breast cancer onset. Newer SERMS,such as raloxifene, may provide similar benefitin preventing breast cancer without the potentialtoxicities.

o DIAGNOSTIC STUD~SThe differential diagnosis of a palpable

breast mass includes a fibroadenoma, which ismore common in the younger age group (20-30’s), and fibrocystic mastopathy, seen inprernenopausal and perimenopausal women.Other masses, such as cysts, lipomas, adenosistumors, phylloide tumors (benign andmalignant), and papillomas can present aspalpable lesions, Most nonpalpablemammographically detected masses/densitiesare cysts, however, ftbroadenomas, papillomas,radial scars, and benign lymph nodes are ofienseen. Certain microcalcifications can be a signof malignancy. Adenosis and fibrocystic changesaccount for most benign biopsies.

Most patients with breast cancer willpresent with a palpable mass or mammographicabnormality. Because mammographic screeninghas been shown to be effective in reducingbreast cancer mortality in postmenopausalwomen, it has become widely used as a

oscreening tool in addition to breast self examand examination by a physician.

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The American Cancer Society guidelinesfor screening include monthly breast self-examafier age 20, baseline mammogram at age 35 ifthere is a family history for breast cancer, and amammogram annually for women over 40.Additionally, professional physical examinationof the breasts should be performed every 3years between the ages of 20 and 40, andannually thereafter. These are only guidelinesand individual patients may require modificationbased on risk factor analysis. With the inceptionof new screening programs and the use of theseguidelines, earlier and smaller tumors are beingdiagnosed. This allows for more conservativebreast surge~ to be performed and may resultin improved survival.

MammographyMammography remains the most

effective method of detecting breast tumorsearly, when the disease is most successfullytreated. According to the U.S. Public HealthService, widespread screening of women over50, followed by prompt treatment whenrequired, can reduce breast cancer deaths by asmuch as 300/0.10 Mammography has a highsensitivity (ability to detect cancer when it isindeed present) and can visualize 85°/0 to 90°/0of breast cancers in women over 50. It also candiscover a tumor up to two years before amalignancy can be felt. 11

Despite its many successes,mammography is not unequivocal; although itssensitivity is 85°/0, it is limited in its specificity(ability to correctly identify a woman who doesnot have breast cancer) with ranges reportedfrom as low as 30V0 in some studies -- to highsof 65 °/o’2-14to 80°/0 in other studies. 15

In particular, mammography is lesssensitive and less specific in younger womenwho tend to have denser breast tissue (nearly70°A of the breast is comprised of dense tissuein young women). Mammography is also lesssensitive and less specific in older women withdenser breasts (i.e. hormone replacement

therapy), and in women who have undergonebreast surge~ or radiation therapy. Dense

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breast tissue is an important considerationbecause it can compromise mamrnographicresults by obscuring underlying tumors. Asmany as 25°A of women have radiographicallydense breasts~b, and this number is much higherin women under the age of 50.

Some studies report mammography isassociated with relatively high false-negativerates17-]g, with as many as 40°/0 of cases goingundetected with mammography alone,particularly in young premenopausal womenbecause of the confounding factor of densebreasts. Furthermore, mammography, in manycases, may be unable to accurately identi~ thetype of lesion, requiring biopsy or furtherinvestigation. In addition, mammography has arelatively low positive predictive value rangingbetween 20V0 and 30Y0. The predictive value ofmammography is calculated by dividing the totalnumber of true cancers, verified histologically,by the total number of tests thought to bepositive for breast cancer.20 In fact, only one inevery four to six biopsies will reveal breastcancer, which means that as many as 75°/0 ofbiopsies are performed for benign lesions andtherefore unnecessa~. Suspicious findings withmammography are the prima~ cause ofunnecessary biopsy. There continues to be aneed for a breast cancer imaging technique thatis highly sensitive, highly specific, relativelynoninvasive, offers a high predictive value, andis cost effective. Several potential candidates forthis “ultimate breast cancer imaging modality”are discussed in the sections that follow. Sincenone of these techniques is without itsdrawbacks the search will continue until one canbe found.

Mammographic abnormalities, which aresuggestive of malignancy, are characterized aseither masses or microcalcifications, andclassified according to the BIRADS System ascategory O-5 with 5 being highly suspicious. Ifa mass is present on mammography, it canusually be determined whether a mass is cysticor solid with an ultrasound examination of themass; often these two technologies complementone another. Biopsy is warranted if a mass does

not meet the sonographic criteria for a simplecyst, or if microcalcifications are present onmammogram. Stereotactic or ultrasound-guidedcore needle biopsy and wire localization surgicalbiopsy are both acceptable biopsy methods.Core biopsy, done under fluoroscope, has theadvantage of being less “invasive” than aneedle-localization surgical biopsy, but it shouldbe emphasized that adequate sampling of thesuspicious lesion is required, If atypiaon a stereotactic biopsy, an opennecessa~ to rule out a malignancy. 1t

As previously mentioned,ography does have its limitations.

is presentbiopsy is

mamm-With the

exception of examination of mammographica!lyclassic lesions such as calcified fibroadenomas,lipomas, fat necrosis and speculated carcinomas,mammography is not “diagnostic” and shouldnot be used alone to reliably differentiatebetween benign and malignant lesions,21 Theonly definitive means of confirmation of asuspicious lesion seen on mammography iseither excisional, fine-needle aspiration orstereotactic core biopsy for the provision oftissue to the pathologist. However, canceroustissue is only found in 25°A of the estimated700,000 biopsies completed in the United Stateseach year. This results in an estimated 525,000unnecessa~ biopsies, which leads to increasedhealth care costs and the pain and inconvenienceof an invasive medical procedure.

Complementary modalities such asultrasound, Doppler ultrasound, computedtomography (CT), MIU, and digitalmammography have been employed to improvethe sensitivity (detection) and specificity(distinguishing benign from malignant).Unfortunately, the sensitivity of theseprocedures is too low to replace mammographyas a screening device, and these procedureshave variable rates of specificity, Although theuse of these procedures is becoming morecommon as a complementary procedure, thereis still a need for a diagnostic procedure withgreater specificity.

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UltrasoundAlthough its usefulness as a screening

device is limited, ultrasound has proven to bevaluable as an adjunct to conventionalmammography, This is particularly true in theevaluation of radiographically dense breasts andas a supplement to mammography due tomammography’s low-positive predictive valueand its inability to reduce unnecessary biopsies.Originally, ultrasound was dismissed as a useful

detect occult malignancies in women withnormal mammographies and clinical exams. Inretrospect, many of the problems associatedwith the use of ultrasound were operatordependent. However, there have beensubstantial improvements in ultrasoundtechnology, particularly with the advent of highfrequency, hand-held devices leading to its usein a number of difficult-to-evaluate patients as

screening technique because of its inability to described below in Table 1

Table 1.

Efficacy

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Conditions for Which Ultrasound Has Demonstrated Diagnostic

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.

●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-timeenvironment .22 It is impossible to consistentlyimage microcalcifications using ultrasound only.Fuflhermore, there is significant overlap in themorphologic characteristics of benign versusmalignant lesions with ultrasound, As a result,many palpable lesions are biopsied despitenegative ultrasonographic findings. Themanagement of nonpalpable lesions is basedupon their appearance with ultrasound,

Ultrasound is extremely operatordependent. It is essential that all of the breastand surrounding tissue be imaged to adequatelyidenti@ and evaluate any lesions. The length oftime required to conduct an adequateultrasound examination of the breast is also

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skilled sonographers can perform an adequateultrasound examination of the breast in as fewas 90 seconds; other less experienced operatorsmay require as long as 9 minutes to accomplish

an examination. It is difficult to know whetherthe entire breast and surrounding tissue hasbeen imaged adequately when considering thetime involved to perform the ultrasound.=

Magnetic Resonance ImagingOver the past 15 years, there have been

numerous technologic advances in magneticresonance imaging (MRI) of the breast. Theintroduction of intravenous, gadolinium-basedcontrast agents, the development of dedicatedbreast surface coils, and introduction of

standard imaging sequences have improved

MRI imaging of the breast. Today, MRI

imaging of the breast generally is performed

with a dedicated coil that permits simultaneousimaging of both breasts. However, MRItechniques vary between institutions (eg, dosageof interventional agents and timing of imaging)leading to a lack of standardized data regardingthe potential usefulness of MRI in breastimaging.22

Magnetic resonance imaging permitsvisualization of breast lesions because theselesions are usually enhanced following theadministration of intravenous contrast agents.This phenomenon is due to the hypervascularityof growing tumors and increased uptake ofcontrast media by these lesions. However,enhancement of non-malignant lesions and evennormal breast tissue (particularly at certaintimes during the menstrual cycle), also mayoccur with MRI resulting in false-positiveresults, 24 A variety of factors has beenconsidered in an effort to distinguish benignfrom malignant tumors with MRI. For example,time-intensity curves have been developed in anattempt to understand the actual enhancementdynamics of a breast mass as it is visualizedwith MRI over time.

Patterns of enhancement that occur inbenign versus malignant lesions also have beenstudied.2572b The use of morphologic featureshas been considered as a possible means toidentify malignant tumors. Unfortunately, thereis a substantial overlap between thecharacteristics of benign and malignant lesionsdetected with MRI. Although MRIdemonstrates high sensitivity in the detection ofbreast cancer, its specificity remains rather low.

MRI can successfully identifi additionalfoci of breast cancer not evident withmammography or clinical examination. 27 In

addition, MRI is more accurate than

mammography in evaluating the actual size of a

malignancy. This may be usefil in selecting amore appropriate treatment protocol for somepatients, For example, confirmation of a smallprimary lesion may warrant a change in the

surgical approach from a mastectomy to aIumpectomy. At the other end of the spectrum,identification of additional foci of breast cancermay preclude a planned lumpectomy andrequire consideration of other treatment optionssuch as chemotherapy. MRI evaluation canprovide important information in the follow upof women who have undergone breastconservation or chemotherapy in whommammographic findings are inconclusive. It alsois possible to use MRI to identify primary breastcancer in patients with metastatic axillaryadenopathy in whom previous mammographyand clinical examination yielded normal results.

In the future, it is predicted that MRIwill become a usefil biopsy-guidance technique.However, this will require that MRI-guidedbiopsy is possible in lesions detected with ~1or its usefulness will be limited. Furthermore,small, dedicated and low-cost MRI breastimaging systems must become commerciallyavailable if MRI is to play a substantial role inthe fiture diagnosis of breast cancer, If not, thehigh cost of MRI will continue to limit itswidespread use.

Nuclear Medicine ImagingMechanisms of Action

Over the years, two approaches havebeen used to image soft tissue tumors. The firstapproach utilizes a function of normal tissue notshared by malignant tissue and thus uptake ofthe radiopharmaceuticalcancer. An example ofimaging of masses in theTc-99m sulfur colloidoccupying lesion that

is excluded from thethis technique is theliver using technetium

where the space-replaces the normal

reticuloendothelial system tissue appears as a“cold” defect in a normally “hot” background.

Imaging a “cold” defect in a “hot” organis more difficult due to interference fromradioactivity in surrounding tissue. This methodof detecting tumors (indirect imaging), dependsprimarily on displacement of normal tissue,disruption of normal physiologic mechanisms,or identification of physiologic and biochemical

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reactions to tumor growth. This mechanism oflocalization is inherently nonspecific and cannotdistinguish between benign and malignantdisorders.

Another approach utilizes acharacteristic of the neoplasm not shared bynormal tissue in order to localize theradiopharmaceutical in the cancer, Thistechnique allows the tumor to be seen as an areaof increased radioactivity, or “hot” spot, as ingallium Ga-67 citrate imaging of tumors such asIymphomas, In this case, the neoplastic lymphnodes will concentrate the radioactivity whilenormal lymph nodes will not.

Imaging a “hot” spot in a “cold”background area is more desirable than the firstapproach. This method of tumor detection(direct imaging) relies upon the biochemical,physiologic, or immunologic aspects of thetumor itself to localize the radiopharmaceutical,

Characteristics of Tumor Cells Pertinent toNuclear Medicine lma~ing

oLocalization of radiopharmaceuticals in

cancer is attributed to one or more of thefollowing properties of tumors,

1. IncreusedMetabolic ActivityThe radiopharmaceutical is introduced

into a tumor as a metabolic substrate, whichenters the metabolic pathway of the specifictumor. An example is the use of fluorine-18fluorodeoxyglucose (F-18 FDG) for thediagnostic imaging of colorectal, breast, brain,lung, and skin cancer. The F-18 FDG localizes

in areas of increased glucose metabolism, which

is common in many tumor cells. Anotherexample involves the uptake of C- 11 thymidineinto certain tumor cells that demonstrateincreased DNA synthesis, e.g., some lung,brain, and head and neck tumors. In addition,the mechanism of osteoneogenesis plays a majorrole in the localization of Tc-99m skeletal

imaging agents in primary and metastatic cancerof the bone, In this example, uptake occurs atthe site of reactive bone, which has a high

●metabolic rate as it works to replace theskeleton involved with the neoplasm.

2. Tumor-Specific ReceptorsA tumor may be detected using

radiolabeled antibodies or peptides that bind tospecific tumor markers such as antigens or otherreceptor compounds found in vivo. Included inthis category are the radiolabeled antibodycompounds developed over the past few yearsfor detection of colorectal, ovarian, lung, andprostate cancer, as well as the radiolabeledpeptide compounds that bind to specificreceptors found in increased concentration onthe surface of some tumor cells. Areas ofcurrent investigation include radiolabeledestradiol compounds and the usefulness of FDAapproved imaging agents such as iridium-11 1satumomab pendetide and technetium-99rnarcitumomob for imaging breast cancer,

3. Increased Tumor Blood FlowIn order to accommodate the

tremendous growth rate of tumors comparedwith the normal surrounding tissue, cancers laydown an intricate and complex network ofblood vessels in order to bring nutrients andoxygen to the tumor cells as they grow andreplicate. Increased vascularization, a commonfeature of many tumors, may promote tumoruptake in a variety of neoplasms, such as thelocalization of Ga-67 citrate in soft tissueneoplasms.

4. Altered micro vasculatureIn the ongoing effort to supply the fast

growing tumor cells with nutrients and oxygen,increased vascular permeability tomacromolecules is seen in tumors. Thischaracteristic is thought to play a role in thelocalization of gallium Ga-67 citrate inneoplasms as transferring bound Ga-67 isremoved from the circulation and incorporatedinto the tumor mass, Non-specific leakage oflarge macromolecules may also aid in theuptake of radiolabeled antibodies and peptides,which are moved from the vascular space beforebinding to specific receptors, found on thetumor cell surface.

The notion of using nuclear imagingtechniques in the detection of breast cancer isnot 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 havesuspicious lesions detected with mammography dense breast tissue or a history of biopsy orin an attempt to avoid unnecessary biopsies or surgery involving the breast. Table 2 provides asurgery. list of indications for adjunctive nuclear

Nuclear medicine breast imaging has a medicine breast imaging (in addition to thehigh 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. Theseo

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

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Nuclear lma~in~ AventsThallium TI-201 Thallous Chloride

Historically, thallium T1-201 thallouschloride (T1-201) scintigraphy was first used inthe evaluation of myocardial perfusion.However, during the mid- 1970s, Lebowitz andcolleagues2g hypothesized that T1-201 might beuseful in the imaging of tumors because of itssimilarity to cesium, which was known toconcentrate in tumors. The idea originated fromthe knowledge that a number of cations were

shown to have tumor affinity including Ga+2,

In+3, Hg+2, Bi+2, K+l, T1+2, and NH3+1.

The exact mechanism by which most of thesecations localize in tumors is unknown. As agroup, they show poor tumor specificity withequal or greater affinity for inflammatory lesionsand abscesses. Early studies demonstrated Tl-201 uptake in malignant lesions, includingtumors of the brain, bone, breast and other softtissue sarcomas

The first documented case of carcinomadetection with T1-201 was repotied in 1976, inwhich a focal area of increased uptake was seenin a male patient with lung cancer who had beenreferred for T1-201 evaluation of his heart .30Ina subsequent study of 173 patients withmalignant tumors and 76 with benign lesions(including 2 patients with known breast cancer),it was concluded that T1-201 had a sensitivity of64% and specificity of61 V0.31 In another studyof 15 patients with breast cancer, uptake of Tl-201 was observed in all.~2

The use of T1-201 in the evaluation ofmalignant tumors has increased due to technicalditiculties with procedures such asmammography, MRI, and CT, It may be usefilin distinguishing post-operative changes relatedto surgery, radiation therapy or chemotherapyfrom tumors, recurrence of lesions, or tissuenecrosis.

Technetium Tc-99m Sestamibi (MiralumaTM)Like T1-201, technetium Tc-99m

sestamibi (MIBI) also was used initially as a

cardiac imaging agent, However, ‘Tc-MIBIhas higher energy photons and a shorter half-lifethan thallium, permitting the injection of doses 5to 10 times greater than thallium. As such,images acquired with ‘Tc-MIBI are of higher

quality and improved resolution compared withimages obtained with thallium. The results fromseveral clinical trials suggest that the uptake of*Tc- MIBI far exceeds T1-201. The mean

uptake of T 1-201 is 80°/0 higher in malignantcells than in normal cells; however, ‘Tc-MIBIuptake in cancerous lesions is 4 times higherthan T1-201. This underscores the need tofurther define the role of ‘Tc-MIBI in theimaging of tumors. ~1’33

One study34 demonstrated that ‘Tc-MIBI uptake was related to angiogenesis andpossibly to oxidative metabolism involvingincreased uptake associated with elevatedmitochondrial levels in tumor cells, In practice,in order to avoid the non-specific uptake of‘Tc-MIB1 in benign structures, SMM should

be performed:1) Before or 7 to 10 days following fine

needle aspiration;2) From 4 to 6 weeks afier a breast

biopsy; or3) At least 2-3 months after breast

surgery and radiotherapy.

Questions exist regarding the optimalphase — if any — during the menstrual cycle toperform SMM. Optimal imaging positions anddosages are under investigation. At present,although standard dosages vary, the mostcommonly reported dose of ‘%Tc-M~I is 20mCi (74o MBq). Intravenous administrationinto the antecubital vein in the arm contralateralto the suspected breast lesion is recommended.This is necessary to avoid false-positive uptakein the axilla on the same side as the suspectedlesion. Injection can also be made through adorsal pedal vein if bilateral lesions aresuspected or if the patient has undergoneprevious mastectomy .34

11

Optimal imaging position remainsundetermined. Prone imaging providesimproved visualization of breast tissue and canbetter delineate the breast contour. This ishelpfi.d in identifying the precise location of asuspected lesion. It also provides improvedseparation from the heafi and the liver; organsthat demonstrate relatively high uptake of99mTc-MIBI, which can mask breast activity.This prone position also minimizes the distancebetween the breast and the camera.Furthermore, the prone position permitsevaluation of all breast tissue proximal to thethoracic wall, ~~le the prone position doesoffer some advantages in breast imaging, thesupine position offers better localization of theprima~ tumor. The supine position also tiordsbetter visualization of the axillae and possibleinternal mammary lymph node involvement. Assuch, a combination of positions is preferred.34

In general, images are acquired over 10minutes. Studies indicate that high qualitydiagnostic imaging can be accomplished in 5 to15 minutes after the injection of *Tc-~1.Timing is important, as delayed imaging canresult in a premature or false-negative result.Despite the potential advantages that may beachieved with SMM, its routine use in breastcancer detection is still debated.35

Numerous clinical studies have beenundertaken to establish the role of ‘Tc-MIBIin the detection and evaluation of breast cancer.Results of these studies suggest that thesensitivity of SMM in the detection of primarybreast cancer is 80% to 90Y0,with an averageof 850/0.28

SMM is significantly more sensitive inthe detection of palpable versus nonpalpablelesions. In addition, its sensitivity for lesions lessthan 10 mm in diameter is low and no lesionsless than 7 mm in diameter have been detectedwith this technique, possibly due to limitationsof currently available detectors. Therefore,SMM is not recommended as a screening testfor breast cancer detection. However, unlikestandard mammography, its sensitivity is notaffected by the density of breast tissue, and

therefore may be advantageous in patients asdescribed in Table 2, It may also be useful inwomen in whom recurrent disease is suspected, 9particularly if they have undergone previoussurgery, chemotherapy, radiotherapy, or breastaugrnentation.28

The specificity of *Tc-sestamibi issomewhat higher than its sensitivity, with anaverage of 89°/0. While ‘Tc-sestamibi isconcentrated in breast cancers, increased uptakecan also take place in benign breast conditions,particularly in cases of hyperproliferative (fastgrowing) fibrocystic breast disease. In general,fibrocystic disease appears as a region orregions of slight-to-moderate increased uptakethat is often more difise than localized, It isofien bilateral without well-delineated margins,and a patchy pattern of uptake.28

Breast cancer, on the other hand,generally appears to be much more focal and isofien unilateral, with relatively well-definedcontours, Uptake of ‘Tc-sestamibi varies frommild to intense depending on several factors,such as size, type, location, and hormonalfactors. In general, a tumor to background oactivity ratio of greater than 1.2 to 1.4 isthought to suggest a malignant lesion.However, many benign conditions such ashighly mitotic juvenile adenomas, papillomas,abscesses, local inflammation or highlyproliferative breast disease can present withratios greater than 1.5,28

Because it is well known that theaxillary nodes are the primary drainage sites forbreast, axillary node involvement is consideredone of the most important prognosticators inbreast cancer. Once a diagnosis of breast cancerhas been made, nearly all patients with invasiveand noninvasive breast cancer will undergoaxillary dissection.28

While axillary dissection does provideimportant information about the staging ofbreast cancer, it is associated with morbiditysuch as arm edema (swelling), lymphostasis andinfections of the ipsilateral (same side)extremity. A noninvasive way of evaluating theaxillary nodes would be useful. As Taillefer2s o

12

describes it, numerous studies3b4b have

o evaluated a variety of imaging techniques for

their potential in the evaluation of possible

metastatic involvement of the axilla~ lymph

nodes. When considered together, results of

these studies suggest an average sensitivity of

77% and a specificity of 89% in the detection of

axillary metastasis in patients with primary

breast cancer. The positive predictive value was

86%; “negative” value was 84V0.28

Technetium Tc-99m $estamibi Case StudyFigure 1 shows four different views of a

patient who received 20mCi of Tc-99msestamibi to aid in the diagnosis of breastcancer. The patient is a 48-year-old womanwho had previous breast implants in both of herbreasts. The patient had noticed a lump in herleft breast, which was also palpated by herphysician. The presence of the silicone implantmade the mammogram difficult to interpret.The SMM shows increased uptake in the massin the Iefi breast slightly below the silicone

oirnplant, which appears as a circular object with

slightly decreased radioactivity. The mass canbe seen in the anterior views near the apex ofthe heart. A core biopsy proved the mass to bean infiltrating ductal carcinoma.

Technetium Tc-99m Tetrofosmin(Myovieww-Nycomed Amersham)

While technetium Tc-99m tetrofosmin isnot currently approved for use in the detectionof breast cancer, it may offer some clinicalpotential. In 1996, abnormal uptake in a breastcarcinoma was reported in a patient undergoingmyocardial pefision scintigraphy.28

Similar to *Tc-sestamibi, % Tc-tetrofosmin is a Iipophilic cation with demon-strated uptake in turnor cells. Although itsuptake in tumor cells is less than ‘Tc-sestamibi, its target-to-background activity ratiois high enough to permit detection of the breasttumor. However, unlike ‘Tc-sestamibi, theuptake of* Tc-tetrofosmin is hypothesized tobe less related to mitochondrial activity.However, similar to % Tc-sestamibi, there is no

1

#

‘,,,f,jj: ,

,’,,

;,’

T. ,,,

‘1

‘; ‘I*,,;,

‘,,,i,

Figure 1. Shown are four different views of a 48-year-old woman who received 20mCi ofTc-99m sestamibi for detection of breast cancer. See text for more detailed information

13

significant myocardial washout with m Tc-tetrofosmin. It demonstrates faster lung andliver clearance, which may prove useful in thedetection of breast tumors near these regions.However, more research is needed to establishthe possible advantages of a particularradiopharmaceutical over the other.28

The administration, image acquisition,and analysis are virtually identical with bothradioph~aceuticals. Although data arelimited, preliminary results suggest similarsensitivity as well as similar positive andnegative predictive values for *Tc-sestamibiversus * Tc-tetrofosrnin. Again, the data arelimited and most studies were performed withpalpable lesions (diameter greater than 1 cm). Itboasts similar accuracy rates when comparedwith *Tc-sestamibi in the evaluation of axillarynode metastasis.28

Sentinel Lymph Node Localization-Lymphoscintigraphy

In general, while there may be instancesof complex lymphatic drainage, there ofien isordy a single sentinel node. The notion of lymphnode staging was first proposed by Morton eta14bin the treatment of melanoma. Cabanas alsoproposed its use in the treatment of penilecancer.47 In 1994 Guiliano and colleagues4gproposed its use in breast cancer using blue dye;and Krag proposed the use of the sentinel nodeapproach using a radiation sensitive probe ayear earlier.4g

Recent approaches involve theintramammary injection of radiotracer tovisualize drainage of the tumor itself Theradiotracer is injected directly into the tumor orinto surrounding tissue to identify the node(s) tofirst receive lymphatic drainage for that tumor.The most relevant node(s), identified by theradiotracer or blue dye are then removed andexamined.

Several different techniques are usedcurrently with variations in the injection oftechnetium Tc-99m sulfur colloid (filtered orunfiltered) from 1 rnL to 10 mL, It is importantto note that other countries may use differentcolloids, for example, antimony sulfide colloid is

used in Australia. The essential factor is that thesize range of the particle be selected inaccordance with the colloid to be used. 9

Injection may be intratumoral,peritumoral, or subdermally over the tumor. Itis not known whether injection outside themargins of the tumor will yield accuratedrainage patterns. Furthermore, the intratumoralinjection may pose some risk of spreadingtumor cells with the drainage of the radiotraceror poor drainage in the case of solid tumors. Inaddition, the injection of too much or too littleradiotracer can also hamper the accuracy ofresults --not enough can result in little to nodrainage; too much can result in pooling oftracer, thereby obscuring the results. Glass andcolleagues3b recommend volumes between 3 mLand 7 mL, injected around the tumor margins tooptimize visualization of drainage patterns.They note that larger volumes of radiotracermay be required in patients with large breasts.Ultrasound can be used to help pinpoint thedesired site of injection. Imaging should beconducted within minutes after the injection ofthe radiotracer, Allowing too great an interval oof time between injection and imaging can resultin the mistaken identification of the sentinelnode or nodes.

The preferred position for the patient isin a semi-recumbent position with the ipsilateralshoulder elevated and that arm raised over thepatient’s head, Imaging done with the patient inthe supine position can mask the sentinel nodedue to scatter radiation from the injection sites.Migration of radiotracer can be hastened withthe application of heat or massage at the site ofinjection or by elevating the venous pressure.Having the patient move the arm can alsoaccelerate migration of the radiotracer. 36

Once the sentinel node(s) has beenidentified, the first node to become radioactive,the location is then marked on the patient’sskin. This method, however, is subject topatient movement and positioning, among otherthings. The ideal method of localization requiresthe use of a hand-held, radiosensitive probe thatis used while the patient is in the same position 9

that will be used during surgery. Many surgeons

14

use blue dye in addition to a radiotracer to

●provide a visual clue for excision. Once thesentinel node(s) has been identified, the node isverified using the hand-held probe to confirmthat this is indeed the sentinel node. Without theuse of blue dye, the surgeon must rely solely onthe radiosensitive probe. If blue dye is used,identification is somewhat easier, as the sentinelnode is the node that is both blue andradioactive.~~

Sentinel node localization in the stagingof breast cancer continues to gain popularity. Itis a minimally invasive technique and can sparepatients many of the complications associatedwith axillary dissection, Furthermore, it isconsidered very accurate in the identification ofthe sentinel node and is a less morbidprocedure.

ApplicationsBecause of its limited sensitivity in the

detection of breast tumors less than 10 mm in

size, SMM is not recommended in breast cancer

●screening in asymptomatic patients. Its use isreserved as a complementa~ diagnosticprocedure to mammography when its results aresuspicious as described in Table 2.28 One of theprimary limitations of SMM s the spatialresolution of the gamma camera. New gammacameras dedicated for scintimammography areunder development in an effort to improvespatial resolution. Another problem involves thelocalization of a lesion that is neither palpablenor visible with mammography but issubsequently identified using SMM. There areseveral approaches used to locate such a lesionbut none is ideal. A skin marker can be used toidentify lesion from an anterior supine view anda lateral view if possible to deter~ine the depthof the lesion. This is a relatively gross methodof localization, however. A second techniqueinvolves the use of a radionuclide-guided,stereotactic pre-biopsy needle to help locate anabnormality seen with SMM. This approachrequires that a post-biopsy SMM be performed

to confirm that the targeted area was indeedbiopsied. A third technique requires the use of agamma probe immediately following theinjection of the radiotracer during surgery as ameans to locate the lesion.28’52

STAGINGThe staging of breast cancer relies on

clinical and pathologic criteria that are helpful inboth treatment and prognosis. The currentstaging method is the TNM system similar tothe TNM system used in other malignancies(Table 3). Physical examination and histologicconfirmation are essential for accurate staging;physical examination should include an estimateas to tumor size (T, tumor), relative mobility, orfixation to the underlying pectoral fascia, orskin involvement (ulceration, erythema, edema).Skin dimpling and pagetoid changes in thenipple do not indicate skin involvement unlessaccompanied by signs of ulceration, erythema,or edema.

Physical examination can be used toassess the axilla~ lymph node status (N,nodes), however it is not an accurateassessment and requires histologic evaluation ofthe lymph nodes obtained at the time oflumpectomy or mastectomy. A clinically“negative” axilla may contain histologicallypositive lymph nodes in up to 30°A of patients.

Evidence of distant metastasis, (M,metastasis), should be obtained through acarefil history, physical examination, along withthe selective use of imaging studies. Since themost common sites of metastasis are bone,lung, and liver, a chest x-ray and liver functiontests are appropriate. A bone scan can beobtained, however its yield in the asymptomaticpatient is extremely low. It can serve as a usefilbaseline study in the event that skeletal paindoes develop in the follow-up period, Patientswho initially present with symptoms suggestiveof metastatic disease benefit from the use ofselected imaging studies (i.e., CT chest,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)Data suggest that many breast cancers

have increased levels of metabolic activity thatcan be detected with fluorine F-18fluorodeoxyglucose (FDG). Several studieshave evaluated the use of FDG in the detectionand diagnosis of breast cancer, reporting anincreased uptake in cancers of the breast and inaxilla~ nodes positive for cancer. The use ofpositron emission tomography (PET) thereforemay prove useful in the staging of breast cancerand in the assessment of metastatic spread orrecurrence of cancer. 35,51,52

Early studies showed promising resultsboasting high sensitivities, visualizing 82% ofprimary breast tumors in one study53 and 100%in another study54, although all of the patients inthe second study had prima~ tumors >5 cm indiameter. Studies that are more recent reportsensitivity rates ranging between 80°/0 and 90°/0,Variations between these studies may be due tothe patient selection process, image acquisition(length of time), primary tumor size (>1.0 cm indiameter), etc. Tumor size is particularlyimportant since the larger the primary tumor,the more likely the chance of metastasis,

Due to the overall lack of data it isimpossible to accurately predict specificity andthe negative prediction value of FDG. FDGmay be usefil when other imaging modalitiesare insufficient, such as in the detection oflesions in patients with silicone breast implantsor in patients with radiographically densebreasts. However, the use of % Tc-sestamibimay yield equally accurate results. Only onestudy55 compared the use of FDG with * Tc-

sestarnibi and both modalities yielded similar

results, but the sample size (20 patients) was

relatively small and the primary lesions were

large with a mean diameter of 2,9 cm. As such,more data are required before an adequatecomparison of FDG and % Tc-sestamibi can bemade.

One concern that is consistent with bothFDG imaging and W Tc-sestamibi is the cost ofthe procedure and the appropriate follow up

17

once a lesion has been detected. Inherent inboth techniques is the problem of accuratelocalization that is required in order to performbiopsy, lumpectomy, or surgery. Bothtechniques suffer from the lack of an anatomicalreference that is available with modalities likemammography, ultrasound, and MRI. Untilanatomic resolution of a lesion detected withPET or SPECT can be accomplished,localization afier detection will remain alimitation of FDG and ‘Tc-sestamibiscintimammography.50

FDG also has potential application in theevaluation of axillary node status. It is knownthat FDG has high accumulation in the axillatynodes containing metastasis.5b-5g Although thesensitivities reported in these studies werehigher than the specificities reported, it isthought that the use of FDG in the assessmentof axillary node involvement could help tominimize false-negative findings.

Whole body FDG PET can also be usedto identify metastatic breast lesions.54’5g It mayprove useful in staging and monitoring ofpatients undergoing chemotherapy or radiationtherapy. It may also be useful in the monitoringof the effectiveness of chemotherapy inpatients. b0”b2 As treatment with chemotherapyprogresses, the metabolic changes in breastcancer lesions can occur within 8 days followinginitiation of treatment, and the amount of FDGuptake in tumors can be used to assess itseffectiveness. Changes in metabolic activity canoccur without an appreciable change in tumorsize.bo Results from another study showed asignificant decrease in FDG tumor uptake in75% of patients (8/12) who showed aconventional response to chemotherapy. Thisdecrease could be measured with PET within 6-13 days after chemotherapy had been initiated.Obviously, this could be particularly useful inmeasuring the response of breast cancer tumorsin patients undergoing chemotherapy,promoting a change in the chemotherapeutic

regimen if necessary. At present, FDG PET is

still relatively expensive compared with other

imaging modalities and more studies are need todetermine its potential cost-benefit ratio, and toverify its effectiveness in the diagnosis of breastcancer, and for perhaps its even more importantpotential role in the evaluation of the effective-ness of chemotherapy for some patients. 52

Unfortunately, at present, this is anexpensive procedure that involves theproduction of radioactive tracers with veryshort half-lives that must be produced in an on-site accelerator. At present, insufficient large-scale clinical trials have been conducted todemonstrate the role of PET in the imaging ofbreast cancer. With the advent of new imagingequipment (coincidence imaging) and theregional distribution of FDG, the COSt-effectiveness of this agent will be improved.

Case Study: 51-Year-O1d Woman ImagedWith Fluorine F-18 Fluorodeoxyglucose

A 51-year old woman noticed a lump inthe upper-outer quadrant of her right breastduring self-exam after being bumped by herhorse. A mammogram showed a speculatedlesion, which was followed by an excisionalbiopsy that revealed a 3.5cm invasive,moderately differentiated, ductal carcinoma.The patient presented for a second opinionregarding follow-up treatment.

The patient’s past medical history wasnegative except for hormonal replacementtherapy for two years since post-menopausalsymptoms. Physical examination of the breastsrevealed no left breast masses or axillaryadenopathy. She had a well-healed biopsy scarin the upper-outer quadrant of her right breastwith no other masses or axillary adenopathy onthe right side. Further discussions with thepatient reviewed options for treatment includingmastectomy, breast conservation surgery (lump-ectomy) and the need to evaluate lymph nodes.

The patient was studied with 8.2mCi ofFDG with images of the brain and total bodycompleted for staging as shown in Figures 2 and3. Images of the chest revealed several foci of

abnormally increased uptake in the right axillaand an irregular accumulation of radioactivity in

the upper-outer aspect of the right breast. Theremainder of the study demonstrated uptakewithin the brain, liver, bone marrow, kidneys, e

and G.I. tract. Findings were reported asconsistent with a right breast malignancy withmetastatic disease to the right axilla.

One week later, the patient underwentright breast lumpectomy with sentinel nodebiopsy and axillary dissection. During theprocedure, two sentinel lymph nodes wereidentified in the tight axilla which were bothpositive for metastatic carcinoma upon frozensection pathological examination. Based on thisinformation, the patient underwent an axillarydissection removing twenty lymph nodes, whichwere all negative for tumor upon pathologicalexamination. The Iumpectomy tissue, whichwas positive on the FDG images, was found tohave an invasive ductal carcinoma, Grade 11/111.

TREATMENTN[jn-Invasive CarcinomaDuctal Carcinoma In Situ (DCIS)

DCIS rarely presents as a breast mass,either palpable or discovered on a mammogram. o

More ofien, it presents as a new non-palpablemammographic finding of clusteredmicrocalcifications without an associated mass.Occasionally, it maybe present (microscopic) inbreast tissue surrounding a benign lesiondiscovered incidentally with a biopsy. Bydefinition, DCIS is non-invasive so metastasisoutside of the breast is not found unless thereare areas of microinvasion that gounrecognized. Patients with DCIS are usuallytreated with lumpectomy followed by radiationtherapy to the breast, as their lifetime risk ofdeveloping invasive cancer, in that breast,approaches 30°/0.b3 Although radiation has beenshown to decrease the recurrence rate wheninstituted following complete excision withnegative margins, some recent studies haveshown lumpectomy alone to be sufficienttreatmentparticularlygrade. b4-h5

unless an

for certain types of DCIS,those lesions that are small and low-Mlllary dissection is not indicated

accompanying invasive cancer is e

18

o

0

0

present. Difise, extensive DCIS ofien requirestotal mastectomy. Tamoxifen has been shown toreduce the rate of contralateral breast cancer byapproximately 50°/0 in patients treated withIumpectomy and radiation for DCIS.K6

Lobular Carcinoma in Situ (LCIS)LCIS is a diagnosis usually made

coincidentally when examining breast tissue foranother reason. It does not present as a massand is not evident on mammogram. Patientswith LCIS are at a lifetime risk for developinginvasive carcinoma, in either breast, of 17-37%.67

Because of these factors, LCIS is notconsidered an early stage of breast cancer, butrather a marker for subsequent cancerdevelopment. Therefore, patients with thediagnosis of LCIS should be followed in a “highrisk” clinic with frequent (6 months) exams,annual mammography, and should beconsidered for enrollment into breast cancerprevention trials. Tamoxifen should be stronglyconsidered as it has been proven to reducebreast cancer risk by 45°A.K An alternative butextreme treatment involves bilateral simplemastectomy with breast reconstruction, whichcan be offered to selected patients.

Invasive CarcinomaSurgical Options

Following the diagnosis of invasivecancer, the options for treatment should becompletely discussed with the patient. Asurgeon, radiation therapist, and plastic surgeonshould be included in the discussions; the moreinformation provided to the patient, the betteropportunity she will have to make an educateddecision. The final decision should not beinfluenced by the specific bias of the surgeon orother physician. Surgery remains the initialtreatment for AJCC Stage I, II, and some StageIII breast cancer patients. In Stage I and mostStage II cancers, the surgical options include amodified radical mastectomy or a lumpectomywith axillary dissection or sentinel node biopsyfollowed by breast irradiation. For large Stage

11 and Stage II tumors, modified radicalmastectomy is the procedure of choice. Patientswith advanced loco-regional disease (includinginflammatory cancer) may benefit frompreoperative (neoadjuvant) chemotherapy andpost-operative radiation therapy.

Illlmpectomy vs. MastectomyFor early stage cancers (Stage I and 11),

modified radical mastectomy orlumpectomy/axillary dissection with breastirradiation should both be considered viableoptions. Several prospective studies have shownthat these procedures both result in the samelong-term survival rate, despite an increasedlocal recurrence rate in patients treated withlumpectomy/axillary dissection. K8’Ag There areseveral contraindications to breast conservationincluding multicentric cancer, previous breast orchest wall radiation, and large tumor size inrelation to the breast size. Since the goal ofbreast-sparing surgery is to achieve an optimalcosmetic result, a lumpectomy that results in aless than desirable appearance should beavoided. Patients with small breasts are oftenpoor candidates for lumpectomy/axillatydissection as the Iumpectomy followed byradiation produces a suboptimal cosmetic result.Therefore, while no particular tumor size is anabsolute contraindication, the relative breast sizeshould be considered. Additionally, patients withlarge breasts are not ideal candidates because thecosmetic appearance afier radiation is ofienpoor.

If a modified radical mastectomy ischosen, immediate reconstruction can be offeredto selected patients. Those with advanced loco-regional disease are not good candidates as localrecurrence rates are high and post-operativeradiation therapy may be necessa~. Otherwise,the options for immediate reconstruction includesaline tissue expanders/implants or autologoustissue transfer with a latissmus dorsi or rectusabdominus myocutaneous (TRAM) flap. Plasticsurgical consultation should be obtained prior tosurgery in order for the patient to make aneducated decision.

21

Sentinel Lymph Node Biop~Sentinel node biopsy has recently been

described as an alternative to axillary nodedissection in selected women.70 The drivingforce behind this new technology is therealization that most wornen with early stagebreast cancer do not have axill~ nodalmetastasis. However, axillary dissection isperformed routinely because there is noaccurate predictor of nodal metastasis. Axillarydissection can result in significant long-termmorbidity such as Iymphedema. As describedearlier, the sentinel node is the first lymphnode(s) to drain the prim~ tumor. If this nodeis histologically negative, the chance of otherlymph nodes being involved is generally lessthan 5Y0. Technetium Tc-99m sulfir colloid isinjected around the primary tumor and a hand-held gamma detector probe is used to identi@radioactive lymph nodes during surgery. Bluedye is also used to aid in the visualization of thelymphatic pathway. For palpable breast lesionsor biopsy cavities, the lymphatic mapping agentcan be injected directly around the tumor site,while nonpalpable lesions should be injectedusing ultrasound or mammographic guidance.Although used widely, the role of routinepreoperative lymphoscintigraphy has yet to bedefined. Contraindications to sentinel nodebiopsy include palpable nodes, a tumor ~ 5 cmin size, multifocal invasive carcinoma, previousextensive breast or axillary surgery, andpreoperative chemotherapy. It is also essentialthat each surgeon perform 20-30 sentinel nodebiopsies followed by an axillary node dissectionto validate hifier technique, as this procedureis associated with a significant learning curve.Results indicate this technique may replaceroutine lymph node dissection in women withclinically negative nodes. There are currentlytwo multi-institutional trials underway that willassess sentinel node biopsy as an alternative tocomplete axillary lymphadenectomy.

Adjuvant TherapyThe rationale for

therapy is based upon theadjuvant systemicpremise that many

patients with early breast cancer haveundetectable rnetastases that, if Iefi unaddressed,would result in recurrence. Even though thesemicrometastases may not be clinically detectable,their presence is suggested by the natural historyof many patients treated with surgery alone.There are two forms of systemic therapy used inadjuvant therapy--chemotherapy and hormonaltherapy.71”74

While chemotherapy can improvesurvival in node-positive patients, its use alsomay improve disease-free survival inpremenopausal, node-negative breast cancerpatients. However, it is important to note thatthis advantage, while statistically significant, ismodest and may not be associated with animprovement in overall survival. Since not allnode-negative patients benefit from this therapy,a tremendous amount of effort has gone intoidenti~lng “high risk” node-negative patientswho might benefit. Tumor size, estrogenreceptor content, DNA analysis, grade, andblood vessel invasion are several examples ofprognostic indicators that are taken intoconsideration in assessing one’s risk ofrecurrence. Adjuvant chemotherapy is notwithout toxicity, so the clinician ideally wouldwant to treat the group that would receive themost benefit. As more of the current clinicaltrials are completed, treatment strategies willbecome more standardized. Tamoxifen isusually added to chemotherapy in receptor-positive patients.

Postmenopausal patients generally areless likely to enjoy the same benefits ofchemotherapy as the premenopausal group.Thus, the adjuvant use of hormonal therapyalone in patients with estrogen or progesterone(ER/PR) positive tumors is associated with amodest but significant improvement in disease-free survival. Chemotherapy, in addition totamoxifen, is often used in node-positive patientsas determined by their performance status. Theuse of chemotherapy in the node-negativepostmenopausal patient is more controversial.Tamoxifen has also been shown to reduce the

22

risk of contralateral breast cancer, which isanother potential advantage.

Follow-upPatients with early stage breast cancer

should be followed for the remainder of theirlife, as recurrences are seen as far as 15-20years following diagnosis. Additionally, they areat increased risk of developing a second breastcancer. Therefore, follow-up is aimed to detectrecurrence, as well as screening the remainingbreast tissue for malignancy. Patients should befollowed at 3-month intervals for the first 2-3years, then at 6-month intervals, Any newsymptoms of bone pain, headaches, orneurological changes should prompt animmediate work-up. Otherwise, chest x-raysand liver function tests are performed at thetime of follow-up. Additionally, all patientsshould have annual mammograms to evaluatefor local recurrence or a new cancer.

Treatment of Metastatic DiseaseSystemic therapy for metastatic breast

cancer is aimed at improving the quality of lifeand, if possible, prolonging survival+Conventional therapy for metastatic disease hasbeen shown to provide palliation to selectedpatients; however, a survival benefit has beendifficult to document. The conventionaltreatment can be hormonal therapy orchemotherapy, depending upon the patient’sage, severity of symptoms, and hormone statusof the primary tumor. Postmenopausal patientswith E~R positive tumors who have non-lifethreatening recurrences are good candidates forhormonal therapy, usually tamoxifen. In patientsin whom a response to hormonal therapy isseen, but who subsequently progress, a second-line hormone therapy should be instituted,usually a progestin or aromatase inhibitor.Response rates of up to 60-70V0 can beexpected with hormonal therapy.

Chemotherapy is generally used inyounger, hormone-unresponsive women or in apatient with life-threatening metastasis, where aquicker response is needed. Conventional

chemotherapy consists of the same agents usedin adjuvant treatment, cyclophosphamide, 5-FU,and adriamycin or methotrexate. Taxol has alsoshown effectiveness in this setting. Responserates range from 20-50°/0 with an averageduration of 6 months.

SUMMARYWith the increasing utilization of

screening mammography and the morewidespread use of breast self-examination, breastcancer patients are presenting at an earlier stage.This allows for more effective treatment andsubsequently improved survival. It is hoped thatwith the use of genetic markers, high riskpatients will be identified at an early age,allowing for more intensive screening andchemopreventive strategies.

The treatment of breast cancer hasevolved from a philosophy of radical surgery toan approach that involves more aggressive localtherapy combined with systemic therapy. Thischange has occurred secondary to the realizationthat breast cancer in its early stages is a localdisease, but in its later stages, it is a “systemicdisease” and should be treated as such.Therefore, chemotherapy and hormonal therapyplay an extremely important role in the treatmentof more advanced disease. The goal of surgery atany stage of the disease is to loco-regionalcontrol while achieving an acceptable cosmeticresult.

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QUESTIONS

1. Which of the following can metastasize?a. DCISb. LCISc. Atypical hyperplasiad. Invasive ductal carcinoma

2. Which of the following is used to enhancemagnetic resonance imaging (MR1) studiesof the breast?

a. Iodineb. Calciumc. Gadoliniumd. Gold

3, Which of the following is not considered arisk factor for breast cancer?

a. Asbestos exposureb. Family history of breast cancerc. Personal histo~ of breast cancerd. History of atypical hyperplasia on a

previous biopsy

4. Clinical investigations have shown thattamoxifen can reduce the incidence of breastcancer in high-risk women by which of thefollowing percentages?

a. 1OOAb. 20%C, 25°10d. 45%

5. Which of the following is the currentscreening recommendation for breast cancer?

a.

b.

c.

d.

Breast self-examination beginning at

age 20

Annual clinical breast exams

beginning at age 40

Annual mammography beginning at

age 40

All of the above

27

6.

7.

8.

9.

Of the following, which typically is notimaged with mammography?

a. Clustered microcalcificationsb. Massesc. Lymph nodesd. Microcalcifications associated with

masses

Ultrasound can be used to:

:

c.

d.

Determine if a mass is cancerDetermine if a solid mass is benignDifferentiate between a solid massand cystScreen women for breast cancer

Which of the following is true concerningthe use of technetium Tc-99m sestamibi forbreast cancer imaging?

a. It can be used in women with densebreasts to detect cancer.

b. It takes advantage of highmitochondrial activity in breasttumors.

c. The most commonly reporteddosage is 20mCi.

d. All of the above

Which of the following tumor cellcharacteristics is not associated with thelocalization of technetium Tc-99m sestamibiin breast cancer?

a.

b.

c.d.

Monoclinal antibody binding to aspecific tumor-associated antigenIncreased metabolic activity oftumorsIncreased tumor blood flowAltered microvasculature within thetumor

10. Staging breast cancer:a. Utilizes the TNM classificationb. Requires surgery for complete

stagingc. Requires CT and bone scan in

symptomatic patientsd, All of the above

11. Treatment of DCIS includes all of thefollowing, except:

a. Lumpectomy ob. Radiation therapyc. Chemotherapyd. Mastectomy

12. Which of the following statements is most

true about lobular carcinoma in situ (LCIS)?

a.

b.

c.

d.

It is found frequently onmammographyIt is a risk factor for the subsequentdevelopment of breast cancerIt is treated effectively with radiation

therapy only.

It is treated effectively with

chemotherapy only.

13. Surgical options for invasive breast cancerinclude all of the following except:

a. Lurnpectomy with axilla~ dissectionb. Modified radical mastectomyc. Lumpectomy with sentinel node

biopsyd. Radical mastectomy

14.

15,

28

The diagnostic agent found in the

radiopharmaceutical, Mlralumam, wasoriginally developed for diagnostic studiesinvolving which of the following?

a. Hepatobiliary system imagingb. Lung aerosol ventilation studiesc. Myocardial perfusion imagingd. Detection of Helicobacter pylori in

the stomach

Contraindications to breast conservation(lumpectomy) surgery include:

a. Palpable axillary lymph nodesb. Tumor size >2 centimetersc. Previous chest wall radiationd. Age >60 years

o

16,

0

17.

18,

Breast reconstruction after mastectomy canbe performed using all of the followingexcept:

a. TRAM flapb. Latissmus dorsi flapc. Tissue expanderd. Allogenic breast transplant

The sentinel lymph node:a. Is always in the same locationb. Is the first node(s) to drain the

tumorc. Can only be 1 noded. Can always be found

Contraindications to sentinel node biopsyinclude:

a. Palpable axilla~ lymph node(s)b. Tumor size >5 centimetersc. Multifoical invasive carcinomad. All of the above

19. Which of the following radiopharma-

20

●

ceuticals is commonly used for sentinellymph node biopsy?

a. Technetium Tc-99m sestarnibib. Thallium T1-201 thallous chloridec. Technetium Tc-99m sulfur colloidd, Fluorine F-18 Fluorodeoxyglucose

(FDG)

Which of the following is thought to playthe major role in the localization of fluorineF-1 8 FDG in breast cancer?

a.

b,

c.d.

Altered microvasculature within thetumorIncreased metabolic activity withinthe breast massIncreased tumor blood flowTumor specific receptor uptake

21

22

23.

Which of the following is true concerning thedrug tamoxifen?

a. It is a type of anti-hormonal therapyb. It is an adjunct medication used to

enhance nuclear medicine imagingc. It can be used as a substitute for

surgeryd. It is a substitute for radiation therapy

In addition to breast cancer, which of thefollowing malignant lesions hasdemonstrated localization with thallium Tl-201 thallous chloride?

;:

c.d,

SkeletalBrainSofi Tissue SarcomasAll the above

Which of the following sensitivities werereported in clinical investigations for the useof thallium T1-201 thallous chloride forbreast cancer imaging?

a. 220/0b. 41%C. 640/od. 80%

24. Which of the following is the most commoncause of a breast mass in a 20-year-oldpatient?

a. Cancerb. Fibroadenomac. Lipomad. Cyst

25, Which of the following radiopharmaeuticalshas an FDA-approved indication for breastcancer imaging?

a. Thallium T1-201 thallous chlorideb. Technetium Tc-99m tetrofosminc. Technetium Tc-99m sestamibid. a and b only.

29