Breast Cancer Molecular Subtype as a Predictor of the Utility of Preoperative MRI

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1 Women s Imaging Original Research Ha et al. reast Cancer Molecular Subtye and MRI Women s Imaging Original Research Richard Ha 1 rian Jin 1 Victoria Mango 1 Lauren Friedlander 1 Vesco Miloshev 1 Shar Malak 2 Ralh Wynn 1 Ha R, Jin, Mango V, et al. Keywords: breast cancer, breast MRI, ER2, immunohistochemical staining, molecular subtye DOI: /JR Received ugust 21, 2014; acceted after revision October 15, Deartment of Radiology, Columbia University Medical Center, Herbert Irving Pavilion, 161 Fort Washington ve, 10th Fl, New York, NY ddress corresondence to R. Ha (rh2616@columbia.edu). 2 Deartment of Radiology, University of rkansas for Medical Sciences, Little Rock, R. JR 2015; 204: X/15/ merican Roentgen Ray Society reast Cancer Molecular Subtye as a Predictor of the Utility of Preoerative MRI OJECTIVE. The urose of this study was to discern whether breast cancer molecular subtye, a known rognostic indicator, can be used to select atients with the highest likelihood of having clinically significant additional findings on breast MRI. MTERILS ND METHODS. database review from January 2010 through December 2013 identified 299 atients who underwent reoerative breast MRI with tumors classifiable into molecular subtyes. Subtyes were classified on the basis of immunohistochemical staining surrogates as luminal (hormone recetor [ER or PR] ositive, ER2 [formerly HER2 or HER2/neu] negative, luminal (hormone recetor ositive, ER2 ositive), ER2 (hormone recetor negative, ER2 ositive), or basal (hormone recetor and ER2 negative). Univariate and multivariate logistic regression analyses were used to determine the association between subtye and additional breast MRI findings, including multicentric or multifocal disease, contralateral disease, chest wall involvement, skin and nile involvement, and internal mammary and axillary lymhadenoathy. RESULTS. The subtye distribution was luminal, 70.6% (211/299); luminal, 14.1% (42/299); ER2, 5.4% (16/299); and basal, 10.0% (30/299). ER2 and luminal subtyes were more often associated with multicentric disease (25.0% and 26.2%), multifocal disease (37.5% and 35.7%), and axillary disease (50.0% and 45.2%) than were luminal cancers (multicentric disease, 10.9%; multifocal disease 20.4%; axillary disease, 22.7%) ( < 0.001). In multivariate analysis, after control for atient age, tumor size, and nuclear grade, atients with ER2-overexressing tumors were 2.4 times as likely as atients with luminal tumors to have multicentric disease ( = 0.016), 2.0 times as likely to have multifocal disease ( = 0.024), 1.7 times as likely to have skin and nile involvement ( = 0.013), and 1.9 times as likely to have axillary disease ( = 0.011). CONCLUSION. Preoerative MRI may most benefit atients with tumors with ER2 overexression because of the increased likelihood of the resence of additional disease. reast MRI is commonly used for screening for breast cancer in oulations at high risk and for evaluating the extent of disease when a diagnosis has been made [1]. reast cancer screening among those at high risk has become a well-acceted indication for breast MRI [2, 3], but routine use for evaluating the extent of disease in those in whom breast cancer has been diagnosed remains less clear [4, 5]. Preoerative erformance of breast MRI for atients with newly diagnosed breast cancer increases the sensitivity of characterizing the extent of disease by imroving assessment of tumor size and detection of additional tumor foci, involvement of adjacent skin and muscles, and lymh node involvement [6 9]. However, several studies [10 13] have shown that this imroved sensitivity does not necessarily translate into imrovements in overall survival or local and distant recurrence rates. s a result, it is difficult to justify the routine use of MRI in the reoerative worku of all atients with newly diagnosed breast cancer. The ossible benefit of breast MRI has to be weighed against the additional biosies recommended on the basis of the MRI findings, the cost, and the otential delay in surgical treatment. The true challenge lies in identifying atients for whom breast MRI is most likely to affect reoerative lanning and thus influence clinical outcome. reast cancer has tremendous biochemical diversity. Gene exression rofiling has identified distinct molecular subtyes of breast cancer that vary in clinical resentation and rognosis. Immunohistochemical staining 1354 JR:204, June 2015

2 reast Cancer Molecular Subtye and MRI has become a widely used surrogate for breast cancer subtying [14 18]. Studies have shown that tumors overexressing ER2 (redominantly luminal and ER2 [formerly HER2 or HER2/neu] subtyes) have oorer rognoses, and increased burden of disease on resentation [14, 16, 17]. The urose of our study was to examine whether these markers can be used to select the atients who may benefit the most from reoerative breast MRI. Materials and Methods Patient Selection and Molecular Subtye Classification HIP-comliant retrosective review of our database from January 2010 through December 2013 identified 299 consecutively registered atients who underwent reoerative breast MRI and had tumors classifiable into molecular subtyes and had MRI findings that could be aroriately categorized. Our institutional review board waived the requirement for informed consent. Patients with a history of treated breast cancer and revious neoadjuvant theray were excluded. Subtyes were classified on the basis of immunohistochemical staining surrogates as luminal (hormone recetor [ER or PR] ositive, ER2 negative, luminal (hormone recetor ositive, ER2 ositive), ER2 (hormone recetor negative, ER2 ositive), or basal (hormone recetor and ER2 negative). Tumors were considered ER2 ositive only if they scored 3+ at immunohistochemical staining or if ER2 amlification yielded a ratio of 2.0 or greater on the basis of fluorescence in situ hybridization results. Histologic classification of breast cancer subtyes was also recorded, including invasive ductal cancer (IDC), invasive lobular cancer (ILC), ure ductal carcinoma in situ (DCIS), and mixed ductal and lobular carcinoma. reast MRI Technique MRI was erformed with a 1.5-T commercially available system (Signa Excite, GE Healthcare) and an eight-channel breast array coil. The imaging sequence included a trilane localizing sequence followed by a sagittal fat-suressed T2-weighted sequence (TR/TE, /85; section thickness, 3 mm; matrix, ; FOV, cm; no ga). T1-weighted fat-suressed fast soiled gradientecho sequence (17/2.4; fli angle, 35 ; bandwidth, Hz) was then erformed before and three times after a raid bolus injection of gadoentetate dimeglumine (Magnevist, erlex; 0.1 mmol/l/kg of body weight), delivered through an IV catheter. Image acquisition started after contrast injection; images were obtained consecutively, and each acquisition time was 120 seconds. Section thickness was 2 3 mm with a matrix of and an FOV of cm. Frequency was in the anteroosterior direction. fter the examination, the unenhanced images were subtracted from the first contrast-enhanced images on a ixel-by-ixel basis. Images were interreted at a PCS monitor (Centricity, GE Healthcare) by one of five breast radiologists with a minimum of 3 years of exerience in breast imaging. Fig year-old woman with newly diagnosed left breast malignancy (invasive ductal cancer, luminal ). Sagittal contrast-enhanced 3D maximum-intensityrojection MR image of left breast shows known malignant lesion (arrow) measuring 1.9 cm located at 6-o clock axis 4.5 cm from nile. No other susicious enhancement is evident in remaining breast or axilla. reast MRI Findings Findings of unifocal, multifocal, and multicentric disease were confirmed at either reoerative core needle biosy or final surgical athologic examination. Unifocal disease was defined as the resence of a continuous tumor measuring less than 5 cm (Fig. 1). Multifocal disease was defined as the resence of discontinuous tumor in the same quadrant (Fig. 2). Multicentric disease was defined as the resence of tumor in multile quadrants or a large single tumor exceeding 5 cm (Fig. 3). Internal mammary nodal disease was defined as at least one enlarged internal mammary lymh node confirmed malignant at cytologic examination after fine-needle asiration or corresonding increased FDG avidity at PET/CT (Fig. 3). xillary nodal disease was de- Fig year-old woman with newly diagnosed right breast malignancy (invasive ductal cancer, luminal )., Sagittal contrast-enhanced MR image shows irregular 2.9-cm mass (arrows) in outer osterior left breast; biosy yielded malignancy. roximately 3.8-cm anterior and inferior indeterminate enhancing focus (arrowhead) is also resent., Sagittal contrast-enhanced image from MRI-guided core biosy shows targeted focus of enhancement (arrow) in relation to known malignant lesion (arrowheads). C, Postbiosy MR image shows dark round ti (arrow) of obturator at exected targeted location with adjacent ostbiosy change. Pathologic examination yielded malignancy consistent with multifocal disease. rrowheads indicate known malignant lesion. C JR:204, June

3 Ha et al. fined as at least one enlarged axillary lymh node with athologic confirmation of metastasis by either reoerative core biosy or final surgical athologic examination. Contralateral disease was defined as susicious enhancement in the contralateral breast corresonding to malignancy at athologic examination that was occult before reoerative breast MRI (Fig. 4). Chest wall disease was defined as the resence of a tumor involving the chest wall or ectoralis musculature only if enhancement was resent within the muscle. Skin and nile-eriareolar comlex disease was defined as any susicious enhancement either directly involving or in roximity to ( 1 cm) the nile and skin with athologic confirmation by either skin unch biosy or final surgical athologic examination (Fig. 5). Statistical nalysis The chi-square test was used for binary variables, and the t test was used for continuous variables. Multivariate logistic regression analysis was used to determine whether subtye was indeendently redictive of the MRI findings after control for age (continuous), tumor size (continuous), and nuclear grade (low and intermediate vs high) comared with luminal. Two-sided 0.05 was considered significant. ll statistical analyses were erformed with statistical software. Results The average age of the atients was 54.6 years (range, years). The molecular subtye distribution was luminal, 70.6% (211/299); luminal, 14.1% (42/299); ER2, 5.4% (16/299); and basal, 10.0% (30/299). The study oulation, tumor characteristics by subtye, and breast MRI findings are summarized in Table 1. mong the four breast cancer subtyes, the ER2 and luminal subtyes were associated with more cases of multicentric disease, multifocal disease, skin-nile-eriareolar involvement, and axillary disease than were luminal cancers ( < 0.001). ER2-overexressing (luminal and ER2 subtyes) and basal subtye tumors occurred more in younger women and were higher-grade, larger tumors than were luminal tumors. No statistical difference was identified between subtyes with resect to chest wall involvement, contralateral breast carcinoma, or internal mammary adenoathy on MRI. In multivariate analysis, after control for atient age, tumor size, and nuclear grade, atients with ER2-overexressing tumors (luminal and ER2 subtyes) were 2.4 times as likely as atients with luminal tumors to have multicentric disease ( = 0.016), 2.0 times as likely to have multifocal disease ( = 0.024), 1.7 times as likely to have skin-nile-eriareolar involvement ( = 0.013), and 1.9 times as likely to have axillary disease ( = 0.011). The results of the multivariate analysis are summarized in Table 2. Fig year-old woman with newly diagnosed left breast malignancy (invasive ductal cancer, ER2)., Sagittal contrast-enhanced MR image shows irregular 4.1-cm mass in uer inner asect of breast with central biosy cli artifact (arrow), which yielded malignancy. Diffuse skin thickening (arrowheads) was likely secondary to lymhatic obstruction from bulky axillary adenoathy (not shown)., xial contrast-enhanced MR image shows two smaller (0.7 and 0.8 cm) enhancing masses (arrows) in osterior uer outer asect of breast. These masses are searated by at least 8 cm from index mass (arrowheads). Targeted ultrasound showed 0.8-cm mass (mammograhically not evident). iosy yielded malignancy (invasive ductal cancer, estrogen and rogesterone recetor negative, ER2 ositive) consistent with multicentric disease. C, MR image shows enlarged (1.6 cm) left internal mammary lymh node (arrows). D, PET/CT image shows FDG utake (standardized utake value, 4.3) (circle) likely reresenting metastatic disease. The histologic subtye distribution was IDC, 87.6% (262/299); ILC, 8.0% (24/299); DCIS, 3.7% (11/299); and mixed ductal-lobular carcinoma, 0.7% (2/299). mong ILC lesions, the molecular subtye distribution was luminal, 83.3% (20/24); luminal, 12.5% (3/24); ER2, 0%; and basal 4.2% (1/24). mong DCIS lesions, the molecular subtye distribution was luminal, 63.6% (7/11);, luminal, 18.2% (2/11); ER2, 9.1% (1/11); and basal 9.1% (1/11). Two cases of mixed ductal-lobular carcinoma were both luminal. dditional subanalysis of only the IDC histologic subtye yielded similar results. mong IDC lesions, ER2 and luminal subtyes were associated with more multicentric disease (26.7% and 26.3%), multifocal disease (40.0% and 36.8%), skin-nile-eriareolar involvement (13.3% and 21.1%), and axillary disease (46.7 and 44.7%) than were luminal cancers (multicentric disease, C D 1356 JR:204, June 2015

4 reast Cancer Molecular Subtye and MRI 11.0%; multifocal disease, 21.4%; skin, 3.8%; axillary disease, 20.3%) ( < 0.001). Discussion We investigated the relation between breast cancer molecular subtyes and reoerative TLE 1: Patient and Tumor Characteristics by Subtye (n = 299) Variable Luminal Luminal ER2 breast MRI findings. Tumors overexressing ER2 (luminal and ER2 subtyes) had significantly higher rates of multicentric and multifocal disease based on MRI findings and subsequent athologic findings. Wiechmann et al. [16] showed similar results on 6072 tumors that were classifiable into molecular subtyes. They found that the tumors overexressing ER2 were significantly more likely to manifest multifocal or multicentric disease (defined at surgical athologic examination). In addition, in the same study, multi- Fig year-old woman with newly diagnosed left breast malignancy (invasive ductal cancer, luminal )., xial contrast-enhanced MR image shows known malignant lesion (arrow) measuring 1.8 cm in central left breast., xial contrast-enhanced MR image of right breast shows 1.5-cm mass (arrow) in midmedial asect of breast. Targeted ultrasound showed corresonding mass; subsequent biosy confirmed contralateral malignancy (invasive ductal cancer, estrogen and rogesterone recetor ositive, ER2 negative). Mass was not mammograhically evident. Fig year-old woman with newly diagnosed left breast malignancy (invasive ductal cancer and ductal carcinoma in situ, luminal )., xial contrast-enhanced MR image shows segmentally distributed nonmass enhancement (arrows) corresonding to known malignancy occuying outer left breast sanning at least 7 cm in anteroosterior dimension from osterior breast toward nile., Magnified view of nile shows enhancement extending to retroareolar region (arrowheads), which was clinically occult at examination. Patient underwent mastectomy, and athologic result was nile-eriareolar skin involvement. Either Luminal or ER2 asal Subtye 211 (70.6) 42 (14.1) 16 (5.4) 58 (19.4) 30 (10.0) < a Mean age (y) Mean tumor size (cm) a High nuclear grade 60 (28.4) 24 (57.1) 14 (87.5) 38 (65.5) 26 (86.7) < a MRI findings Multicentric disease 23 (10.9) 11 (26.2) 4 (25.0) 15 (25.9) 6 (20.0) a Multifocal disease 43 (20.4) 15 (35.7) 6 (37.5) 21 (36.2) 5 (16.7) a Either multicentric or multifocal disease 66 (31.3) 26 (61.9) 10 (62.5) 36 (62.1) 11 (36.7) < a Skin-nile involvement 8 (3.8) 8 (19.0) 2 (12.5) 10 (17.2) 3 (10.0) < a xilla lymh node involvement 48 (22.7) 19 (45.2) 8 (50.0) 27 (46.6) 11 (36.7) < a Chest wall involvement 5 (2.4) 2 (4.8) 1 (6.3) 3 (5.2) 1 (3.3) Contralateral disease 12 (5.6) 2 (4.8) 2 (12.5) 4 (6.9) 2 (6.7) Internal mammary lymh node involvement b 3 (1.4) 1 (2.4) 1 (6.3) 2 (3.4) 0 (0) Note Excet for age and size, data are numbers of tumors with ercentages in arentheses. a Statistically significant at < 0.05, NOV for continuous and chi-square test for binary variables. b ll seven cases had ositive PET/CT findings. JR:204, June

5 Ha et al. TLE 2: Results of Multivariate Logistic Regression nalysis (n = 299) Outcome Variable Multicentric variate analysis after control for atient age, tumor size, lymhovascular invasion, and nuclear grade showed that atients with ER2 subtye tumors were 1.6 times as likely as those with luminal tumors to have multifocal or multicentric disease ( < ). Several studies have indicated that atients with tumors overexressing ER2 have relatively worse rognosis and increased rates of recurrence than atients with luminal cancers [18 22]. Poor outcomes in this atient oulation are likely multifactorial, including ossibly inadequate local treatment or manifestation of biologically aggressive disease. lthough the latter cannot be revented, the former may be addressed with more aggressive local treatment. There is likely an association between oor outcome in atients with ER2-overexressing tumors and increased rates of multicentric and multifocal disease. Women with multifocal or multicentric breast tumors have been reorted to have greater robability of relase and worse survival than women with unifocal tumors [23]. metaanalysis and systematic review of 22 studies comrising 67,557 women showed that atients with multifocal or multicentric disease had significantly worse overall survival, disease-free survival, disease-secific survival, and locoregional relase rates at 5 years with similar estimates observed at 10 years. Preoerative breast MRI may hel those treating atients with ER2-overexressing tumors better delineate the extent of the Multifocal disease for surgical lanning and otimal local treatment. The higher sensitivity of breast MRI comared with mammograhy for detecting malignancy has been well established [6 9]. In a study in which Sardanelli et al. [24] secifically evaluated the resence of multifocal and multicentric disease, breast MRI had higher sensitivity than mammograhy in the evaluation of atients with varying amounts of fibroglandular tissue. The greatest difference was observed in atents with fibroglandular and dense breasts. Larger and more invasive cancer foci were missed with mammograhy than with MRI. Desite the well-established higher sensitivity of breast MRI for detecting additional tumors, results of some studies suggest that additional foci of disease identified at breast MRI may not be clinically relevant because they are thought to be controlled with breast irradiation [25 27]. However, results of a more recent study by Nguyen et al. [19] suggest that the additional foci of disease may be clinically significant and not necessarily treated with adjuvant radiation theray. In that study of 793 consecutively registered atients, in which all atients received external beam radiation theray to the whole breast, the rate of local recurrence of ER2 subtyes was significantly higher (8.4%) than that of the luminal subtye (0.8%). The study results indicated that radiation adjuvant theray may not be sufficient to control locoregional disease in atients with ER2 xillary Lymh Node Involvement Skin-Nile Involvement Subgrou Luminal a a a a Luminal 1.7 ( ) 2.6 ( ) 1.7 ( ) 1.4 ( ) ER2 2.9 ( ) 1.4 ( ) 1.9 ( ) 2.0 ( ) Luminal or ER2 2.4 ( ) 2.0 ( ) 1.9 ( ) 1.7 ( ) asal 1.14 ( ) 0.89 ( ) 1.1 ( ) 1.2 ( ) Nuclear grade Low or intermediate a High 1.0 ( ) 1.1 ( ) 1.3 ( ) 1.1 ( ) Tumor size 2.7 ( ) a 1.2 ( ) ( ) a 1.0 ( ) 0.33 ge 0.99 ( ) ( ) ( ) ( ) 0.73 Note Values in arentheses are 95% CI. a Luminal is reference grou. tumors and suggest a otential role of more aggressive surgical management. lso in the study by Nguyen et al. [19], no statistical differences were observed among molecular subtyes regarding rates of margin ositivity at surgery. The ositive margin rates for luminal, luminal, and ER2 tumors were 3%, 3%, and 4%. This result indicates that margin status may not be a good indicator of adequate surgical treatment in these atients. s found in our cases of multicentric and multifocal disease (Figs. 2 and 3), in which additional tumors were found away from the index mass, surgical management that targeted only the index mass might have yielded a lumectomy secimen with negative margins but left behind additional disease that was clinically and mammograhically occult. Preoerative breast MRI may have an imortant role in better delineating the extent of disease for surgical lanning in these atients. reast conservation has become a standard surgical aroach in the care of many atients with breast carcinoma [25]. However, when mastectomy is necessary because of the extent of disease or ersonal reference, skin-saring mastectomy and nile-saring mastectomy are being erformed at an increasing rate because of the suerior cosmetic result and low rate of local recurrence after nile-saring surgery [28 33]. Results of more recent studies evaluating mastectomy secimens indicate that a nile-saring aroach may not be aroriate for some 1358 JR:204, June 2015

6 reast Cancer Molecular Subtye and MRI atients because of the resence of clinically occult disease [34, 35]. In our study, the rate of skin and nile involvement was significantly higher among atients with ER2-overexressing tumors, as illustrated in our case of nile-eriareolar involvement of a tumor that was not clinically evident (Fig. 5). Our result is consistent with those of a study by Li et al. [34]. They evaluated 2323 consecutively acquired mastectomy secimens with grossly unremarkable niles by using sagittal sections through the entire nile-subareolar tissue. Occult nileareolar comlex (NC) involvement correlated ositively with several factors, including ER2 amlification. y multivariate logistic regression analysis in the entire selection rocess, tumors with ER2 overexression remained significantly associated with nile involvement by carcinoma. Similar results were also reorted by rachtel et al. [35]. They evaluated 316 mastectomy secimens with grossly unremarkable NC by coronal sections through the entire nile. Multivariate analysis showed that ER2 amlification ( = ), tumor size ( = ), and tumor-to-nile distance ( = ) were associated with nile involvement. Results of several studies [36 39] indicate that reoerative MRI is helful in identifying and redicting clinically occult tumor involvement of the NC. MRI-measured distance from the NC, tumor size, subareolar or central location, and unilateral enhancement of the nile with continuous enhancement from the index lesion correlate with increased risk of NC involvement. In atients with ER2 tumors, with the increased likelihood of skin and nile involvement, reoerative breast MRI may be essential in surgical lanning if nile-saring mastectomy is being considered. Preoerative evaluation of the axilla is routinely erformed with ultrasound, which is a ortable and simle test for evaluating lymh node involvement [40 42]. The sensitivity (36 78%) and secificity (93 100%) of breast MRI are similar to those of ultrasound for detecting axillary metastasis [43 45]. The real advantage of breast MRI comared with ultrasound is that breast MRI is the best imaging modality for deicting anatomic features in relation to athologic changes. In addition to level 1 and level 2 axillary lymh nodes, level 3 lymh nodes and internal mammary lymh nodes that can affect staging can be evaluated. Our study showed that atients with ER2 tumors had a significantly higher likelihood of lymh node involvement. lthough our study did not secifically evaluate the volume of nodal involvement, Wiechmann et al. [16] found that atients with ER2 tumors were twice as likely as those with luminal tumors to have high-volume nodal disease ( 4 ositive lymh nodes). reast MRI is likely to be helful in delineating high-volume axillary disease for accurate clinical staging. In addition, with the adotion by the surgical community of the olicy, based on findings of the Z11 trial, of not erforming axillary lymh node dissection on a subgrou of atients with a low axillary disease burden, breast MRI with its suerior delineation of axillary anatomy is likely to be beneficial in reoerative lanning [46]. There were several ossible limitations to this study. First, classifications based on estrogen recetor, rogesterone recetor, and ER2 status are only aroximations of the underlying genotye-based breast cancer subtye, and conclusions based on recetor-based aroximations may not always correlate with the genotye-based subtyes. However, the high cost of full gene exression rofiling recludes its use in routine clinical care. Therefore, immunohistochemical staining has become a widely used and generally acceted method of aroximating true molecular subtyes [15, 18, 19]. Second, this was a retrosective single-institution study without control for which atients had undergone breast MRI, otentially leading to selection bias. The use of I-RDS might have been helful, but we did not secifically use I-RDS for our analysis. We investigated atients with known cancer (I-RDS category 6), and if additional lesions were found on MRI, followu biosy results were recorded for analysis. t our institution, we interret MRI studies on a high-resolution PCS monitor (Centricity, GE Healthcare) and rioritize the assessment of lesion morhologic features. We currently do not have a software rogram for kinetic analysis, and this not routinely included in our analysis. Last, relatively few cases of certain MRI findings were resent, including internal mammary lymh nodes, chest wall involvement, and contralateral disease. Use of a larger samle size might have revealed additional significant variables associated with molecular subtyes. 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