Triple-Negative Breast Cancer: What the Radiologist Needs to Know

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riple-Negative Breast Cancer:hat the Radiologist Needs to Know

ary J. Whitman, MD,* Constance T. Albarracin, MD, PhD,†

nd Ana Maria Gonzalez-Angulo, MD, MSc‡

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pproximately 10% to 15% of breast carcinomas do notexpress estrogen receptor (ER) or progesterone receptor

PR) and do not exhibit overexpression or gene amplificationf human epidermal growth factor receptor 2 (HER2). Theseumors are called triple receptor-negative or triple-negativeTN) breast cancers. TN breast cancer has recently been rec-gnized as a subtype of breast cancer with aggressive clinicalehavior and a poor clinical outcome. TN breast cancers havepropensity to occur in premenopausal women and His-

anic and African-American women, and TN tumors are as-ociated with mutations in p53 and BRCA1. Therapies target-ng the estrogen receptor or the HER2/neu oncogene areikely to be ineffective against TN tumors. This article reviewshe molecular, pathologic, and imaging features of TN breastancer.

Breast cancers are a group of diseases with a wide spectrumf clinical, pathologic, and molecular characteristics. By these of gene expression profiles, 4 breast cancer subtypes withifferent prognoses have been identified: 2 ER-negative sub-ypes: basal-like (BL) and human epidermal growth factoreceptor 2 (HER2)-positive, and 2 ER-positive subtypes: lu-inal A and luminal B.1-4 Breast cancers are classified as TN

y the use of established immunohistochemical (IHC) assaysor ER, PR, and HER2, and fluorescence in situ hybridizationFISH) assays for HER2. TN breast cancers are characterizedy the absence of all 3 predictive/prognostic markers: ER, PR,nd HER2. Most TN breast cancers are high grade, and theumors are usually large with relatively well-circumscribedushing margins, lymphocytic infiltration and a high mitoticate.5,6

Departments of Diagnostic Radiology and Radiation Oncology, The Uni-versity of Texas MD Anderson Cancer Center, Houston, TX.

Department of Pathology, The University of Texas MD Anderson CancerCenter, Houston, TX.

Departments of Breast Medical Oncology and Systems Biology, The Uni-versity of Texas MD Anderson Cancer Center, Houston, TX.

ddress reprint requests to Gary J. Whitman, MD, Departments of Diag-nostic Radiology and Radiation Oncology, Division of Diagno-stic Imaging, The University of Texas MD Anderson Cancer Center,Unit 1350, PO Box 301439, Houston, TX, 77230-1439. E-mail:

[email protected]

6 0037-198X/11/$-see front matter © 2011 Elsevier Inc. All rights reserved.doi:10.1053/j.ro.2010.09.004

BL breast cancer is a molecular phenotype defined on theasis of cDNA microarray studies.7 Approximately 70% ofN breast cancers are BL tumors.1,8-12 The term BL comes

rom the resemblance between the cytokeratin expressionattern in the cancer cells and the myoepithelial cells of thereast.9,13,14 This does not mean that BL breast cancer cells areerived from myoepithelial cells. Despite the great interest inL and TN cancers, there are no universally accepted defini-ions for these tumors. In this review, we use the term BLhen cDNA or more sophisticated technology was applied

or tumor classification and TN when clinical assays for ER,R, and HER2 were used.

strogen androgesterone Receptors

R status determines which patients are most likely to benefitrom hormonal therapy.15-17 The likelihood and the degree ofreatment response correlate with the level of ER expres-ion.18 Although not well studied, PR levels have similarlyeen shown to correlate with response to hormonal thera-ies. PR is routinely measured along with ER on all breastarcinomas.19,20 ER status was previously reported by the usef a ligand binding assay. Currently, IHC is the method ofhoice for ER testing, and IHC analysis allows for tumorell-specific analysis of ER status in paraffin sections.18,21-26

Staining for ER is scored as a percentage of the invasiveumor cells that demonstrate a nuclear stain. In the Nationalnstitutes of Health Consensus Statement on Adjuvant Ther-py for Breast Cancer, any degree of ER nuclear immuno-taining was considered as a positive result and would there-ore render the patient eligible for endocrine therapy. Thellred scoring system, the Quick score, and the H score havettempted to incorporate the percentage of ER-positive tu-or cells and the intensity of staining into a single score.hese scoring methods have been shown to have similar pre-ictive values for response to hormonal therapy.27-29

At The University of Texas MD Anderson Cancer Center,e use the ER reporting system advocated by the interna-

ional Breast Cancer Study Group and supported by the Col-

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Triple-negative breast cancer 27

ege of American Pathologists and the American Society oflinical Oncology.16,30,31 The percentage of tumor cells pos-

tive for nuclear staining is quantified and reported in 1 of 3ategories: negative (0% tumor cells), low positive (1%-9%),nd positive (10%-100%; Fig. 1).

ER2he proto-oncogene ERBB2 (HER2) is located on chromo-ome 17 and encodes for a tyrosine kinase receptor that is aember of the epidermal growth factor receptor family.ER2 gene amplification has been demonstrated in approx-

mately 20% of breast cancers. The level of gene amplificationorrelates well with protein expression, and the levels of genemplification and protein expression have been shown toave prognostic and predictive values.32

The HER2 status of invasive carcinomas is evaluated byHC and/or by FISH. Positive results from any of the differentssays can be used to classify patients as having HER2-posi-ive disease, according to guidelines formulated by the Col-ege of American Pathologists and the American Society oflinical Oncology.33 Because no single assay can identify all

igure 1 IHC staining for ER in breast cancer demonstrates positiveesults with nearly all tumor nuclei showing strong staining (mag-ification, 100x). Inset: magnification, 400x.

Figure 2 IHC staining for HER2 in breast cancer demomembranous staining (magnification, 400x) and (B) pos
1000x).
atients expected to benefit from anti-HER2 therapy witherfect accuracy, no single method has been advocated as theold standard. At The University of Texas MD Anderson Can-er Center, all invasive breast cancers are tested for HER2 byHC. Cases with negative but incomplete membranous stain-ng or equivocal IHC results undergo further testing withISH for HER2 gene amplification.The U.S. Food and Drug Administration (FDA) has ap-

roved 2 IHC assays, the HercepTest (Dako, North America,nc, Carpinteria, CA) with the A095 polyclonal antibody andATHWAY (Ventana Medical Systems, Oro Valley, AZ) withhe 4B5 rabbit monoclonal antibody. In addition, multiplentibodies are available, and the FDA allows the use of “in-ouse” assays in laboratories.34 Several investigators havehown HER2 results to be incorrect when reevaluated by aentral laboratory.35,36 Therefore, interpretation of cases submit-ed for review should be approached with caution and attentionhould be given to establishing appropriate controls.

The final score reflects the percentage of invasive tumorells that demonstrate HER2 staining or HER2 gene amplifi-ation. A negative stain (0 or 1�) is defined as no or weakncomplete membranous staining. Equivocal staining (2�)epresents complete membranous staining, but the staining isonuniform or has weak intensity in at least 10% of theumor cells. A positive HER2 immunostain (3�) is charac-erized by uniform intense membranous staining of greaterhan 30% of the invasive tumor cells, as described in themerican Society of Clinical Oncology /College of Americanathologists guidelines (Fig. 2).37 Cases with 1� or equivocaltaining undergo further FISH analysis to confirm the HER2tatus.

The PathVysion HER-2 DNA probe kit (Abbott Laborato-ies, Abbott Park, IL) contains fluorescent-labeled DNArobes specific for the HER2 gene locus on chromosome7q11.2-q12 and the centromeric region of chromosome 17CEP 17; 17p11.1-q11.1). The copy numbers of HER2 andEP 17 are recorded for each cell by the ratio of HER2 to CEP7 signal counts. FISH is reproducible and very reliable.ompared with IHC, FISH is less susceptible to variations in

issue fixation and processing because DNA molecules areore resistant to damage caused by formalin fixation.38-40

s (A) positive (3�) results with complete and intenseSH results for HER2 gene amplification (magnification,

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28 G.J. Whitman, C.T. Albarracin, and A.M. Gonzalez-Angulo

Chromogenic in situ hybridization (CISH; Invitrogen,arlsbad, CA) was recently approved by the FDA as an ad-

unct in assessing patients planning trastuzumab therapy. InISH, the HER2 gene is detected by a digoxigenin-labeledER2 probe, allowing histopathological evaluation with a

tandard bright-field microscope. A number of studies havehown good concordance between CISH and FISH results.reviously, a limitation of CISH was the lack of an internalontrol probe, such as CEP 17, thereby limiting the use ofISH. False-positive results can occur in cases of polysomy,nd false-negative results can occur in cases of monosomyith 4 to 5 copies of HER2.41,42 More recently, dual-colorISH (Dako, Denmark) incorporated the labeling of both theER2 gene and centromere 17, thus providing a potentialolorimetric alternative to FISH.43 Similar findings may berovided by the INFORM HER2 DNA Probe Assay (Ventanaedical Systems, Tucson, AZ), a biotin-labeled oligonucleo-

ide probe. No internal control probe is used, and polysomyannot be detected. To address this, the INFORM HER2 DNArobe Assay uses a chromogenic silver in situ hybridizationor the HER2 gene, developed to allow for concurrent detec-ion of chromosome 17 as an internal control.

hallenges inssessing Marker Status

ariability of ER, PR, and HER2 results between laboratoriesas been reported.44 The use of different assays and the lackf validation and standardization contribute to this variabil-ty.33 Concordance for HER2 results was 88% between localnd central testing laboratories and 95% when central andeference laboratories were compared.45 These findings sup-ort the importance of using high-volume, experienced lab-ratories for determining HER2 status.Several other factors are important in the evaluation ofarker status. Smaller specimens, such as those from fine-eedle aspirations and core needle biopsies, may not haveepresentative areas of the tumor. The concordance rate forarker status when core needle biopsies were compared with

xcisions has ranged between 80% and 99%.46-49 In practice,f the marker results on a core needle biopsy are questionable,hen repeat testing of the excision specimen is warranted.

When histopathologic evaluation on a breast tumor is per-ormed, the marker status is assessed in the invasive compo-ent. Thus, accurate delineation of regions of invasive carci-oma and areas of ductal carcinoma in situ (DCIS) is critical.n addition, DCIS is often associated with marked HER2xpression or amplification. The significance of HER2-posi-ive DCIS is not known and is not a basis for patient manage-ent. Therefore, determination of the HER2 status by an

xperienced pathologist is extremely important whetheruantitation uses manual scoring or digitized image analy-is.44

Another consideration is handling of the specimens beingubmitted for histopathologic evaluation and determinationf marker status. The type and the duration of fixation can
nfluence IHC staining. Overfixation can markedly reduce ER c
ositivity, presumably through cross-linkage of the antigen.t least 6 to 8 hours’ fixation time in 10% neutral-buffered

ormalin is suggested to obtain optimal and consistent ERtaining results.50

pidemiology and Risk Factorsn the past few decades, epidemiologic studies have provideduch information on important risk factors for breast cancer,

ncluding older age, family or personal history of breast can-er, and certain reproductive history factors. The risk factorsor TN are different from the classical breast cancer risk fac-ors.

Carey et al10 provided the first population-based estimatesf the prevalence of the various intrinsic breast cancer sub-ypes from data from the Carolina Breast Cancer StudyCBCS), a population-based, case-control study of environ-ental and molecular determinants of breast cancer risk. Bysing IHC surrogates to identify the intrinsic breast tumorubtypes of 496 incident cases of invasive breast cancer,arey et al reported that the BL subtype was more prevalentmong premenopausal African-American women (39%)han among postmenopausal African-American women14%) and non�African-American women of any age (16%)P � 0.001). The prevalence of the HER2�/ER-subtype didot vary by race or menopausal status (range, 6% to 9%).lopade et al51 reported that 59% of breast tumors in Nige-

ian women were TN. Stead et al52 reported that blackomen of diverse backgrounds had 3 times as many TN

umors as did nonblack women, regardless of age and bodyass index.Millikan et al53 used data from the CBCS to analyze the

elationship between reproductive factors and the risk ofreast cancer molecular subtypes identified using IHC mark-rs. For luminal A breast cancer, the most common subtype,aving given birth to at least one viable child and younger aget first full-term pregnancy were associated with decreasedreast cancer risk. For BL breast cancer, by contrast, givingirth to at least one viable child and younger age at firstull-term pregnancy were associated with increased breastancer risk. Longer duration of breastfeeding, increasedumber of children breastfed, and increased number ofonths breastfeeding per child were each associated with

educed risk of BL breast cancer but not luminal A breastancer. Conversely, multiple live births in women who didot breastfeed and use of medications to suppress lactationere associated with increased risk of BL breast cancer butot luminal A breast cancer.

linical CharacteristicsN breast tumors are associated with younger patient age,ggressive clinical behavior, greater nuclear grade, and largerumor size.54 In addition, these tumors showed specific pat-erns of distant metastases, with a high predilection for vis-eral sites, such as lung and brain, and a lower predilectionor bone and liver.55 In a recent review from Fox Chase Can-
er Center,56 98 TN patients were compared with 655 other

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reast cancer patients. All patients underwent breast-con-erving surgery and postoperative whole-breast radiation.here was a significant difference noted in rates of firstistant metastases: 3%, 12%, and 7% for ER-positive orR-positive, ER-negative/PR-negative/HER2-positive, andN tumors, respectively.56 However, the 5-year locore-ional recurrence rate did not differ significantly between thegroups.56 Conversely, in a study by Nguyen et al57 fromassachusetts General Hospital, a multivariate analysis

howed higher local and distant recurrence rates for TN tu-ors than for other types of cancer after breast-conserving

reatment. TN tumors appear to have a high risk of earlyecurrence. Further, it seems that women with TN tumorsho are disease-free for more than 5 years are unlikely to dief breast cancer. A Canadian population-based study5 with aedian follow up of 8.1 years showed that patients with TN

umors had an increased likelihood of distant recurrencehazard ratio 2.6; 95% confidence interval, 2.0-3.5; P �.0001) and death (hazard ratio 3.2; 95% confidence inter-al, 2.3-4.5; P � 0.001) within 5 years of diagnosis but nothereafter. The same group of investigators published a ret-ospective review of 111 TN patients.58 The median dis-ant disease-free interval was 18 months, and the medianurvival time with metastatic disease was 13 months.58

TN breast cancer appears to have a predilection for theevelopment of brain metastases. In a large retrospectivenalysis of patients with early breast cancer, the incidence ofentral nervous system disease as a first site of metastasis wasignificantly greater among women with ER-negative tumors5-year cumulative incidence of 1.9%) than among womenith ER-positive tumors (5-year cumulative incidence of.7%).59 Other investigators have reported similar results.60

awood et al61 analyzed data from 679 patients with TNreast cancer. At a median follow-up time of 26.9 months, 42atients (6.2%) had developed brain metastases; the cumu-

ative incidences of brain metastases at 2 and 5 years were.6% and 9.6%, respectively.61 Twenty-four patients (3.5%)eveloped brain metastases as the first site of recurrence.61 Inhis study, patients with TN cancer had a high incidence ofrain metastases, which were associated with poor survival.

orphologic, Cytologic, andther Molecular Characteristics

N cancers can be identified from patient records on theasis of negativity for ER, PR, and HER2. It is important toecognize that TN tumors are more heterogeneous than BLreast cancers.8 BL breast cancer is characterized by lack ofxpression of ER and related genes, lack of or low expres-ion of HER2, and strong expression of high-molecular-eight basal cytokeratins (CK), including CK5/6, CK14,

nd CK17.62 Rakha et al6 recently described the heterogene-ty of TN breast cancer. The investigators compared the clin-cal outcomes of patients with TN breast cancer who ex-ressed one or more specific BL breast cancer biomarkersCK5/6, CK14, CK17, and epidermal growth factor receptor
EGFR]) with the outcomes of TN patients who expressed f
one of these markers. There were no differences betweenhe groups with respect to morphologic features, patient age,enopausal status, primary tumor size, tumor histologic

rade, or the presence of vascular invasion.6 The tumors thatxpressed BL breast cancer biomarkers had a lower preva-ence of lymph node metastases at diagnosis (P � 0.01) andere more likely to have marked cellular pleomorphism.6

he tumors that expressed BL biomarkers were significantlyore likely to express hypoxia-associated factor (CA9), p53,

nd neuroendocrine markers.6

After identifying a set of BL breast tumors using microarraynalysis, Livasy et al7 performed a histologic and IHC reviewf their properties and described the histologic features asso-iated with the BL subtype. These features included a mark-dly elevated mitotic rate, geographic tumor necrosis, push-ng margins of invasion, atypical medullary features, and atromal lymphocytic response.7 A similar study also showedhat certain morphologic characteristics, such as nuclearrade 3 and geographic necrosis, were features of BL breastancer and ER-negative breast cancer.63 One of the morpho-ogic features of TN cancer is the presence of glomeruloid

icrovascular proliferation. In Ashkenazi Jewish breast can-er patients, glomeruloid microvascular proliferation was as-ociated with p53 expression and BRCA1 mutations, and all 3f these factors were associated with worse survival and poorutcome after adjuvant chemotherapy.64

Foulkes et al65 found that glomeruloid microvascular pro-iferation and other tumor markers, including p53, p27KIP1,nd cyclin E, were closely linked to the BL phenotype.oulkes et al65 noted that independent predictors of worseutcome in TN breast cancer patients included mutations inhe BRCA1 and the p53 genes.65 BRCA1 is a tumor suppressorene localized to chromosome 17q21. BRCA1 is a multifunc-ional protein implicated in many normal cellular functions,ncluding DNA repair, transcriptional regulation, cell-cycleheckpoint control, and ubiquitination.66 It has been sug-ested that tumors expressing more than one basal CK areore likely to have a dysfunctional BRCA1 pathway.67 Spo-

adic TN breast cancers have many of the clinical, pathologic,nd molecular features of hereditary breast tumors in womenith germ line mutations in the BRCA1 gene. On the molec-lar level, most BRCA1-associated breast tumors have a BLene expression profile,68 are TN, and share other moleculareatures of sporadic TN breast cancers, including expressionf basal CKs, EGFR, cyclin E, and p53 mutations.65,69 Muta-ions in the p53 gene are the most common genetic alterationsn human cancers, including breast cancers.70 p53 is an im-ortant prognostic marker that correlates with higher his-opathologic grade, increased mitotic activity, aggressive be-avior, and, therefore, a worse prognosis.70,71 p53 mutationsnd overexpression are commonly reported in BL breast can-ers.

maginglthough TN breast cancer has been studied rather exten-ively in the oncology and the pathology literature, there are
ew reports on the imaging features of TN breast cancer.

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ammographyang et al72 evaluated the mammographic findings in 198remenopausal women with breast cancer. Thirty-eightomen (19%) had TN breast cancer, 67 women (34%) hadER2-positive tumors, and 93 women (47%) had ER-posi-

ive tumors. The median tumor sizes were 3.0, 2.2, and 2.2m, respectively, for patients in the TN, HER2-positive, andR-positive groups (P � 0.06). Breast density of �50% wasoted in 84% of the TN cases, 90% of the HER2-positiveases, and 83% of the ER-positive cases (P � 0.52).

Figure 3 A 58-year-old woman presented with a palpablregion. (A) Right lateromedial mammogram demonstratcorresponding to the palpable abnormality (triangle). (Ba portion of the mass (arrow), corresponding to the pultrasound shows a 3.4-cm hypoechoic mass (arrow) wmammographic abnormalities. Ultrasound-guided core bLongitudinal right supraclavicular ultrasound demonstsound-guided right supraclavicular fine-needle aspiratiotreated with 12 cycles of Taxol and 4 cycles of 5-fluorounderwent right segmental mastectomy, which showeaxillary lymph node dissection showed metastatic carcdissection revealed metastatic carcinoma in 5 of 45 lymnode was noted with cauterized atypical cells, consistent
therapy (50 Gy) to the right breast and the right regional lymp
In the study by Yang et al, 33 out of 38 (87%) TN tumors,4 out of 67 (96%) HER2-positive tumors, and 87 out of 9394%) ER-positive tumors were visible on mammographyP � 0.23). TN tumors were more likely to be identified asasses, compared with HER2-positive and ER-positive tu-ors. In patients with findings identified on mammography,

3 out of 33 (100%) TN tumors were seen as masses, com-ared with 35 out of 64 (55%) HER2-positive tumors and 42ut of 87 (48%) ER-positive tumors (P � 0.0001). On mam-ography, TN tumors presented most frequently as round,

rmality in the right breast in the 8-o’clock to 9-o’clockcm high-density mass (arrow) with indistinct margins,laterally exaggerated craniocaudal mammogram showsabnormality (triangle). (C) Longitudinal right breast

egular margins, corresponding to the palpable and therevealed poorly differentiated TN breast carcinoma. (D)1.5-cm hypoechoic oval lymph node (arrow). Ultra-

aled metastatic adenocarcinoma. The patient was thenadriamycin, and cyclophosphamide. The patient thenual invasive carcinoma with treatment effects. Rightin 7 of 24 lymph nodes. Right cervical lymph nodees. Between the cords of the brachial plexus, 1 lymphetastatic carcinoma. The patient then received radiation

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val, or lobular masses with indistinct margins (Fig. 3). Com-ared with the HER2-positive tumors and the ER-positiveumors, the TN tumors were less frequently irregular in shapend less likely to have spiculated margins.72

On mammography, TN tumors were less frequently asso-iated with calcifications, compared with HER2-positive tu-ors and ER-positive tumors in the study by Yang et al. Five

f 33 (15%) TN cases were associated with calcifications,ompared with 43 of 64 (67%) HER2-positive cases, and 53f 87 (61%) ER-positive cases (P � 0.0001). Associated DCISas reported in 7 of 38 (18%) TN cases, 38 of 67 (57%)ER2-positive cases, and 52 of 93 (48%) ER-positive cases

P � 0.0003). The relative lack of calcifications in the TNroup was consistent with the low prevalence of DCIS in theN tumors.72

In the report by Yang et al,72 the most common features ofN tumors were circumscribed masses with no associatedicrocalcifications. Yang et al noted that characteristic fea-

ures of malignancy, such as irregular spiculated masses andleomorphic calcifications, were usually not present in TNreast cancers. The authors noted that the mammographiceatures of TN breast cancer suggested rapid carcinogenesis,eading directly to the development of invasive cancers. Yangt al suggested that the presumed rapid carcinogenesis mayequire additional imaging modalities, such as sonography,agnetic resonance imaging (MRI), and positron emission

omography (PET) for early diagnosis.Dogan et al73 retrospectively reviewed the mammographic,

onographic, and MRI findings in 44 TN breast cancer pa-ients. TN cancers were visible on mammography in 39 of the3 (90.7%) mammograms that were available for review. In 4N patients, the cancers were mammographically occult. Re-arding the 39 cases with visible mammographic findings,here were 25 (58.1%) masses, 9 (21%) focal asymmetries, 25%) architectural distortions (Fig. 4), and 3 (7%) groups ofalcifications without masses. Fifteen (60%) of the 25 massesere round or oval, and 8 (32%) masses had circumscribedargins.Ko et al74 evaluated the mammographic and sonographic

ndings in 87 TN patients; in 93 ER-positive, PR-negative,ER2-negative patients; and in 65 ER-negative, PR-negative,ER2-positive patients. On mammography, TN cancers usu-

lly presented with a mass (43/87%, 49%) or with a focalsymmetry (19/87%, 22%). TN cancers were less likely to bessociated with calcifications when compared with ER-posi-ive, PR-negative, HER2-negative cancers and ER-negative,R-negative, HER2-positive cancers.Ma et al75 noted that increased mammographic breast den-

ity was associated with TN breast cancer. This associationas noted when the analysis was restricted to white, African-merican, premenopausal, and postmenopausal women. Inddition, the associations were similar when nulliparous andarous women were considered separately. Ma et al notedhat screening mammography studies may support theirndings. Interval breast cancers are more common in womenith dense breasts, and women with screen-detected breast

ancers tend to have less dense parenchyma. t

ltrasoundn the study by Dogan et al,73 44 TN patients underwentonography, and a sonographic abnormality was noted in 4193%) cases. Thirty-eight (86%) of the 44 cancers appeareds masses. One patient demonstrated global skin thickeningnd diffuse architectural distortion with shadowing, consis-ent with inflammatory carcinoma, proven by skin punchiopsy. Eight (21.1%) of the 38 masses had circumscribedargins. Nine (23.7%) of the masses were associated withosterior acoustic enhancement. In 3 cases, no abnormalitiesere identified on ultrasound. In 2 of these cases, calcifica-

ions were identified on mammography. In the third case,here was evidence of axillary metastasis from a primary tu-or identified only on MRI.In the study by Ko et al,74 75 (86%) of 87 TN patients

resented with masses and 12 (14%) patients exhibited non-ass lesions on ultrasound. On sonography, TN tumors wereore likely to have circumscribed margins (43/75%, 57%)

nd less likely to show posterior shadowing (4/75%, 5%). TNumors were complex echoic (11%), hypoechoic (41%), andarkedly hypoechoic (48%).Sonography plays a major role in evaluating the axillary

Fig. 5), infraclavicular, supraclavicular (Fig. 6), and internalammary lymph nodes in TN breast cancer patients.76,77

urrent ultrasound technology is not capable of demonstrat-ng micrometastatic disease. Macrometastatic disease is notedn sonography as cortical thickening, hilar displacement, hi-ar compression, and loss of the normal echogenic hilum.78 Ifxpert cytologic support is available, then ultrasound-guidedne needle aspiration of suspicious lymph nodes is feasi-le.79,80 If expert cytologic support is not available, then ul-rasound-guided core biopsy of suspicious lymph nodeshould be performed. When neoadjuvant chemotherapy iseing considered, pretreatment imaging is necessary to stagehe regional (axillary, infraclavicular, supraclavicular, and in-ernal mammary) nodal basins. Also, detailed informationegarding regional nodal disease is critical for surgical andadiation therapy planning.

agnetic Resonance Imagingn the study by Dogan et al,73 all 44 TN breast cancers weredentified on MRI and all 44 tumors demonstrated significantbnormal contrast enhancement. Thirty-four (77.3%) of the4 TN tumors showed mass-like enhancement (Fig. 7), andhe other 10 (22.7%) demonstrated nonmass-like enhance-ent. The 34 TN cancers with mass-like enhancement most

ommonly had round or oval shapes, and the margins wererregular in 16 (47.1%) cases, spiculated in 14 (41.2%) cases,nd smooth in 4 (11.7%) cases. Twenty-six (76.5%) of the 34N cancers with mass-like enhancement demonstrated rimnhancement. In 8 of these 26 cases, enhancing internal septaere noted along with a lobulated mass shape and rim en-ancement.There were 10 TN cancers with nonmasslike enhancement

n the study by Dogan et al.73 Seven (70%) of the 10 tumorsemonstrated a heterogeneous internal enhancement pat-
ern. All 3 TN tumors presenting with calcifications without


Figure 4 A 49-year-old woman underwent screening mammography, which revealed a right breast mass at 6 o’clock andarchitectural distortion in the upper right breast. (A) Right craniocaudal mammogram shows an obscured mass (arrow)in the central breast. (B) Right lateromedial mammogram demonstrates the obscured mass in the lower breast (shortarrow) and architectural distortion (large arrow) in the upper breast, near the region where prior excision revealedbenign findings. Also, a dense round low axillary lymph node (arrowhead) is noted. (C) Longitudinal right breastextended-field-of-view ultrasound shows an irregular hypoechoic mass (arrow) at 11 o’clock. (D) Right breast 11-o’clock core needle biopsy was performed. Sonography reveals the targeted hypoechoic mass (small arrow) and the16-gauge core biopsy needle (large arrow). Pathology from the core biopsy demonstrated high grade, poorly differen-tiated invasive ductal TN carcinoma. A satellite mass was seen on sonography at 8 o’clock, and ultrasound-guidedfine-needle aspiration revealed poorly differentiated ductal breast carcinoma. Ultrasound-guided fine needle aspirationwas also performed on the obscured 6 o’clock mass seen on mammography, and cytology showed benign ductalepithelium and leaf-like fragments of cellular stroma, consistent with a cellular fibroepithelial lesion. Ultrasound-guided fine needle aspiration of a right axillary lymph node demonstrated metastatic carcinoma. (E) Postbiopsy rightcraniocaudal mammogram shows the clip marker (arrow) within the known 11-o’clock malignancy. (F) Postbiopsy
right lateromedial mammogram demonstrates the clip marker (arrow) in the known malignancy.


Figure 5 A 44-year-old woman presented with palpable masses in the left breast and the left axillary region. (A) Leftcraniocaudal mammogram shows an obscured oval mass (arrow) with a clip marker noted at the anterior aspect of themass. Multiple groups of heterogeneous calcifications were seen in the left breast. Ultrasound-guided core biopsyperformed 1 day earlier demonstrated poorly differentiated, high grade TN invasive ductal carcinoma and high gradesolid type ductal carcinoma in situ with necrosis. (B) Left lateromedial mammogram shows the known malignant mass(short arrow) and the clip marker at the anterior aspect of the mass, along with multiple groups of heterogeneouscalcifications. In the left axillary region, an enlarged lymph node (long arrow) was noted with internal calcifications. (C)Transverse left breast 6 o’clock extended-field-of-view ultrasound shows the known malignancy (arrow) with somecalcifications within the mass and adjacent to the mass. (D) Transverse left axillary ultrasound shows the enlarged hypoechoiclymph node with internal calcifications. (E) Ultrasound-guided fine-needle biopsy was performed on the enlarged left axillarylymph node (short arrow) with a 21-gauge needle (long arrow). Cytology demonstrated metastatic adenocarcinoma. Leftbreast stereotactic biopsies were then performed at 12 to 1 o’clock and 2 to 3 o’clock, revealing breast parenchyma withadenosis and cysts. The patient was then treated with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophospha-
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ssociated masses on mammography demonstrated non-asslike enhancement on MRI. In 2 of these cases, the en-ancement was regional, and in 1 case, segmental enhance-ent was noted.In the study by Dogan et al,73 MRI demonstrated intratu-oral high signal intensity on unenhanced T2-weighted im-

ges in 21 (48%) of 44 patients. In 40 (91%) of 44 TNumors, there was evidence of type 3 enhancement (a fastnitial upstroke, followed by early washout). The 4 remainingN cancers demonstrated progressive or plateau type time-

ntensity curves.MRI showed multicentric disease in 10 (22.7%) of 44 pa-

ients in the study by Dogan et al.73 In 5 of the patients

igure 6 A 43-year-old woman presented for routine follow-up afteraving been diagnosed with high nuclear grade TN invasive ductalarcinoma involving the right breast 2 years earlier. The patienteceived neoadjuvant Taxol, 5-fluorouracil, epirubicin, and cyclo-hosphamide before right mastectomy. The patient then underwentadiation therapy and right breast reconstruction. At the routineollow-up visit, left supraclavicular lymphadenopathy was palpated.A) Longitudinal left supraclavicular sonography demonstrates 2uspicious oval hypoechoic lymph nodes. In the left supraclavicularegion, 10 suspicious lymph nodes were noted. (B) Ultrasound-uided fine-needle aspiration was performed on a 1.3-cm hypo-choic lobular left supraclavicular lymph node (long arrow) with a1-gauge needle (short arrow). Cytology revealed poorly differenti-ted metastatic carcinoma. The patient was then treated with Ixem-ra.

11.4%), multicentricity was identified only on MRI. One (

atient had pectoral muscle invasion that was depicted onlyn MRI.In the series by Dogan et al,73 TN tumors were mammo-

raphically occult in 9% of the patients and sonographicallyccult in 7% of the patients. The TN tumors tended to bearge with benign or indeterminate mammographic andonographic findings, such as focal asymmetry (21%) andircumscribed round or oval masses (15.8%). Three of theancers were identified as calcifications alone on mammog-aphy. On MRI, all 44 TN cancers were visualized, and all 44umors demonstrated characteristics associated with malig-ancy according to American College of Radiology Breastmaging Reporting and Data System criteria.81 The most fre-uent MRI finding was a round or oval contrast-enhancedass with irregular or spiculated margins and rim enhance-ent.Chen et al82 analyzed the MRI features in 29 TN patients.ne patient had nonmasslike regional enhancement, and thether 28 patients (97%) had mass-type lesions. Twenty-six ofhe 28 mass-type lesions were greater than 1.5 cm in size andemonstrated strong and/or heterogeneous enhancement.im enhancement was noted in 12 (41%) patients. In 22

esions, there were documented enhancement curves and allhowed typical malignant features of a rapid up-slope fol-owed by washout.

Uematsu et al83 compared the MRI features of 59 TN can-ers to 117 ER-positive, PR-positive, HER2-negative cancers.ematsu et al83 found that high histologic grade (P � 0.001),nifocality (P � 0.012), mass lesion (P � 0.001), smoothass margins (P � 0.001), rim enhancement (P � 0.005)

nd very high intratumoral signal intensity on T2-weightedmages (P � 0.002) were significantly associated with TNreast cancer. In addition, very high signal intensity on T2-eighted images was significantly associated with intratu-oral necrosis (P � 0.001). In the study by Uematsu, et al,

1 (86%) of 59 TN tumors were high grade.MRI can be helpful in identifying multifocal and multicen-

ric disease not appreciated on mammography and in moni-oring response to neoadjuvant chemotherapy in patientsith TN breast cancer. Chen et al84 used MRI to monitor 15N patients undergoing neoadjuvant chemotherapy. MRI di-gnosed 9 complete responses, 5 partial responses, and 1onresponse. Final pathology revealed complete response inpatients, partial response in 5 patients, and nonresponse inpatient. MRI accurately predicted 8 pathologic complete

esponses (8 out of 9 patients, 89%) with 1 false-negativeRI diagnosis.

ositron Emission Tomographyasu et al85 investigated the use of fluorine-18 fluorodeoxyglu-ose (FDG)-PET to evaluate 18 patients with newly diagnosedN breast cancer and 59 patients with recently diagnosed ER-ositive, PR-positive, HER2-negative breast cancer. In thistudy, the breasts were imaged at 63 minutes and 101 min-tes after the administration of FDG. Maximum standardizedptake values (SUVmax) were measured at both time points
SUVmax1 and SUVmax2).

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In the study by Basu et al, the breast cancer lesions werebserved as areas with focally enhanced FDG uptake in allN patients. The mean SUVmax1 of the primary lesions in

he TN group was 7.27, the mean SUVmax2 was 8.29, and theercentage change in SUVmax was 14.3%. In the 59 patientsith ER-positive, PR-positive, HER2-negative breast cancer, theean values for SUVmax1 and SUVmax2 were 2.68 and 2.84,

espectively, and the percentage change in SUVmax was 3.7%.he mean values for SUVmax1 and SUVmax2 and the percent-ge change in SUVmax were significantly greater in the TNroup compared with the non-TN control group (P �.0032, P � 0.002, and P � 0.017, respectively). The au-

Figure 7 A 46-year-old woman noted fullness in the right(A) Sagittal contrast-enhanced MRI shows an enhancingright breast. (B) Axial postcontrast MRI shows the ill-deright breast. (C) Sagittal subtraction image shows theregion. Ultrasound-guided core biopsy showed TN invahigh proliferative rate. The patient was then treatedcyclophosphamide. Segmental mastectomy was performsolid type ductal carcinoma in situ. The patient underwbed.

hors noted that in the TN group, tumor grades correlated d

ignificantly with the magnitude of SUVmax1 and SUVmax2P � 0.012 and P � 0.01, respectively). Stage for stage, theN cancers appeared to have a greater mean SUVmax1hen compared with tumors from the non-TN controlroup. In patients with stage II disease, this trend reachedtatistical significance. The authors concluded that TNreast tumors were detected with very high sensitivity bysing FDG-PET imaging and the tumors demonstratednhanced FDG uptake, corresponding to their aggressiveiology.85

Tchou et al86 performed a retrospective analysis to deter-ine whether FDG uptake correlated with proliferation in-

breast. Mammography showed no suspicious findings.lar mass (arrow) with a central low signal region in theass (arrow) with an associated low signal region in theing lobular mass (arrow) with the internal low-signalammary carcinoma with a high histologic grade and aeoadjuvant Taxol and 5-fluorouracil, epirubicin, andong with 2 re-excisions, revealing intermediate grade,iation therapy (50 Gy) with a 10 Gy boost to the tumor

upper, lobu

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ex in women with TN breast cancer. In this study, 22 TN

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atients and 19 patients with non-TN breast cancer under-ent FDG-PET imaging, and the SUVmax values were com-ared with the values of Ki-67, a proliferation index marker.DG-PET was significantly more sensitive in detecting TNreast cancer than non-TN breast cancer (95.5% vs 68.4%;� 0.036). In general, the SUVmax and the percentage of Ki-67uclear stain values increased as the histologic grade wors-ned. In this study, TN cancer was more often poorly differ-ntiated, compared with non-TN breast cancer (P � 0.001).or the entire study cohort, the SUVmax correlated withercentage of Ki-67 nuclear staining (spearman correlation �.485, P � 0.002). This significant correlation appeared to beriven by the subset of patients with TN breast cancer (spear-an correlation � 0.497, P � 0.019). The authors noted that

he degree of FDG uptake correlated significantly with theroliferation index in women with TN breast cancer. Theseesults suggest a potential role for FDG-PET in monitoringesponse to neoadjuvant chemotherapy in TN breast canceratients.FDG-PET is also being evaluated as a method for identify-

ng distant metastatic disease in patients with TN breast can-er (Fig. 8). Although FDG-PET has not been recommendedor routine staging in patients with presumed early stagereast cancer, FDG-PET may play a greater role in stagingomen with TN breast cancer. FDG-PET may be helpful in

taging women with TN breast cancer because most TN tu-

Figure 8 A 34-year-old woman presented for staging fometastatic poorly differentiated carcinoma. Eighteen mwhich showed poorly differentiated TN invasive ductal clymph nodes. Axillary dissection removed 8 additional lypatient was treated with adjuvant dose-dense adriamdemonstrates bilateral supraclavicular, subpectoral, axilladenopathy, along with left prevascular lymphadenopatL3 (long arrow), and L4 vertebral bodies, the sacrum, andisease. (B) Chest CT obtained 2 days before the PET-CT
lower lobe, suspicious for metastatic disease. The patient was
ors are high grade on histology. In addition, TN tumorsay demonstrate aggressive biological behavior, even in the

bsence of involved regional lymph nodes. It is thought thatDG-PET may be able to detect nodal and distant metastases

n breast cancer patients with higher sensitivity than com-uted tomography (CT) or MRI. Hama and Nakagawa87 re-orted the use of FDG-PET in identifying distant metastaticisease following adjuvant chemotherapy and before breastadiation therapy in a 46-year-old woman with presumedarly stage TN breast cancer. In this case, fused FDG-PET/CThowed increased uptake in the right sacrum and the leftbturator externus muscle, consistent with metastatic dis-ase.

anagementN breast cancer is one of the most challenging types ofreast cancer to treat. TN breast cancer is characterized by the

ack of a dominant oncogenic factor driving proliferation ac-ivity. Hormone therapy is ineffective in treating TN breastancer. TN breast cancer is treated with chemotherapy inddition to surgery and radiation therapy. Rouzier et al88

eported that different molecular subtypes of breast cancerave different sensitivities to standard taxane and anthracy-line-based preoperative chemotherapy. In an analysis of 82atients, the BL subgroup had a pathologic complete re-

g recent right supraclavicular biopsy, which revealedearlier, the patient had undergone right mastectomy,ma. Sentinel lymph node biopsy showed 2 of 2 positiveodes, and no additional metastases were identified. Thed cytoxan, followed by Taxol. (A) 18-FDG PET-CT

ort arrow), internal mammary, and paratracheal lymph-ddition, suspicious uptake was noted involving the L2,right and the left iliac bones, consistent with metastaticnstrates a 5-mm lung nodule (arrow) in the anterior left

llowinonthsarcinomph n

ycin anary (shhy. In ad thedemo

then treated with Ixempra, capecitabine, and Zometa.

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ponse rate of 45%, showing the greatest sensitivity afterrimary systemic chemotherapy.88 A second retrospectivetudy from the same institution showed a pCR rate of 22% (tonthracycline and/or taxane based-therapy) for 255 patientsith TN breast cancer and 11% for the 863 patients withon-TN breast cancer.89 Patients who experienced a pCR hadxcellent survival regardless of breast cancer subtype. Amongatients with residual disease after chemotherapy, those withN breast cancer had significantly shorter overall and recur-ence free-survival periods than those with non-TN breastancer.89 The risk of relapse and death was significantlyigher for patients with TN breast cancer during the first 3ears of follow-up.89 A series of studies are open to treat TNreast cancers with alternative chemotherapeutic agents, in-luding platinum salts; epothilones; targeted agents, includ-ng PARP inhibitors; and anti-angiogenesis agents. Other tar-ets being studied are EGFR, c-Kit, Src, Hsp-90, andomponents of the PI3K and the mitogen-activated proteininase kinase pathways.

onclusionsN breast cancer encompasses a large, heterogeneous groupf tumors with different pathologic and clinical features com-ared with most breast cancers. Epidemiologic data suggesthat TN breast cancer may have a different etiology than otherreast cancer subtypes. Imaging is efficacious in demonstrat-

ng TN breast cancers. On mammography and sonography,N tumors may simulate benign masses. On MRI and PET,N tumors nearly always demonstrate aggressive malignant

eatures. TN breast cancer is sensitive to standard chemother-peutic agents; however, when TN breast cancer is resistanto chemotherapy, the prognosis is poor. Ultimately, the bestherapeutic approach for TN breast cancer will probably in-olve combinations of targeted agents directed to the molec-lar characteristics of the specific tumor. In the future, it is

ikely that imaging, particularly MRI and PET, will play aarger role in staging TN tumors and monitoring response toeoadjuvant chemotherapy.

cknowledgmentse thank Barbara Almarez Mahinda for help in manuscript

reparation and Sarah Burke for proofreading.

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