Triple Receptor Negative Breast Cancer: Imaging and Clinical Characteristics

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1 Women s Imaging Original Research Krizmanich-Conniff et al. Triple Receptor Negative Breast Cancer Women s Imaging Original Research Kristin M. Krizmanich-Conniff 1 Chintana Paramagul 2 Stephanie K. Patterson 2 Mark A. Helvie 2 Marilyn A. Roubidoux 2 Jamie D. Myles 3 Kiting Jiang 3 Michael Sabel 4 Krizmanich-Conniff KM, Paramagul C, Patterson SK, et al. Keywords: breast cancer, breast ultrasound, estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), mammography, progesterone receptor (PR), triple receptor negative breast cancer DOI: /AJR Received November 5, 2010; accepted after revision December 26, The statistical analysis for this study was supported by the National Institutes of Health (UL1RR024986). 1 Department of Radiology, Regional Medical Imaging, 3346 Lennon Rd., Flint, MI Address correspondence to C. Paramagul (chintana@umich.edu). 2 Department of Radiology, University of Michigan Health System, Ann Arbor, MI. 3 Michigan Institute for Clinical and Health Research, University of Michigan Health System, Ann Arbor, MI. 4 Department of Surgery, University of Michigan Health System, Ann Arbor, MI. AJR 2012; 198: X/12/ American Roentgen Ray Society Triple Receptor Negative Breast Cancer: Imaging and Clinical Characteristics OBJECTIVE. The objective of our study was to retrospectively evaluate the imaging findings of patients with breast cancer negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) so-called triple receptor negative cancer and to compare the mammographic findings and clinical characteristics of triple receptor negative cancer with non triple receptor negative cancers (i.e., ER-positive, PR-positive, or HER2-positive or two of the three markers positive). CONCLUSION. Triple receptor negative cancer was most commonly an irregular noncalcified mass with ill-defined or spiculated margins on mammography and a hypoechoic or complex mass with an irregular shape and noncircumscribed margins on ultrasound. Most triple receptor negative cancers were discovered on physical examination. Compared with non triple receptor negative cancers, triple receptor negative cancers were found in younger women and were a higher pathologic grade. B reast cancer negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) so-called triple receptor negative cancer is a subtype of breast cancer that has a more aggressive clinical course than other forms of breast cancer and is associated with aggressive histology and poor clinical outcomes [1]. Triple receptor negative cancers have a higher rate of distant metastatic disease with a shorter mean time to distant metastatic disease than non triple receptor negative cancers [1]. Patients with triple receptor negative breast cancer also have a high early incidence of brain metastases [2]. Triple receptor negative tumors are unresponsive to the usual endocrine therapies, contributing to a poor survival rate [1]. Although African American women have a lower risk of developing breast cancer than white women in general, premenopausal African American women have a higher risk of developing triple receptor negative cancer, which is a contributing factor to the poor prognosis of young African American women with breast cancer [3]. In addition, women with the BRCA1 mutation are reported to develop breast cancer at an early age with a high prevalence of triple receptor negative cancers [3, 4]. Numerous prior studies address the aggressive clinical characteristics of triple receptor negative breast cancer; however, only a few studies with relatively fewer patients report the imaging findings [5 7]. In the prior studies documenting the imaging characteristics of triple receptor negative breast cancers, up to 30% of these cancers were most commonly masses without calcifications with circumscribed margins on mammography [6]. On ultrasound, triple receptor negative cancers were most commonly hypoechoic irregular masses with circumscribed margins in up to 57% of cases [7]. Materials and Methods Institutional review board approval for this study was obtained. Using our cancer center registry database, we studied a cohort of women with invasive breast cancer treated at our institution (MRS Cancer Registry, Impac Medical Systems). The study group consisted of 1322 women diagnosed with invasive breast cancer between 1997 and There were 236 women diagnosed with triple receptor negative breast cancer and 1086 patients diagnosed with non triple receptor negative breast cancer (i.e., having at least one of the three biologic markers positive). The date that the patients were last seen at our institution was retrieved from our clinical database records using the Electronic Medical Record Search Engine (EMERSE). The duration of follow-up (in months) was calculated. Patients with less than 12 months follow-up after diagnosis of triple receptor negative 458 AJR:198, August 2012

2 Triple Receptor Negative Breast Cancer TABLE 1: Mammographic Findings for Women With Triple Receptor Negative Cancer Versus Those With Non Triple Receptor Negative Cancer No. (%) of Women Mammographic Findings Triple Receptor Negative (n = 207) Non Triple- Negative (n = 967) p a Findings Mass without calcifications 121 (58) 435 (45) Mass with calcifications 60 (29) 311 (32) Suspicious calcifications alone 15 (7) 109 (11) Other 11 (5) 112 (12) Negative 5 90 Not available 6 22 Breast density b 0.72 Fatty 10 (5) 39 (5) Scattered densities 68 (33) 233 (30) Heterogeneously dense 106 (51) 439 (57) Dense 19 (9) 66 (8) BI-RADS descriptor (BI-RADS category) 0.25 Suspicious (4) 122 (59) 522 (54) Highly suggestive (5) 71 (34) 291 (30) Other or not available 14 (7) 154 (16) Negative (1) 5 90 Benign (2) 0 0 Probably benign (3) 1 15 Known cancer (4) 5 19 Not available 3 30 a Chi-square test. b Findings were not available for four triple receptor negative and 190 non triple receptor negative cases. breast cancer were removed from our study group (29 triple receptor negative and 119 non triple receptor negative cases). Therefore, a total of 207 women diagnosed with triple receptor negative cancer and 967 patients with non triple receptor negative cancer were the subjects of our investigation. Our study group consisted of white (triple receptor negative cancer, 84%; non triple receptor negative cancer, 87%), African American (triple receptor negative cancer, 8%; non triple receptor negative cancer, 5%), Asian (triple receptor negative cancer, 3%; non triple receptor negative cancer, 3%), and Hispanic (triple receptor negative cancer, 2%; non triple receptor negative cancer, 1%) women. Data were extracted from our institutional cancer center database that contained imaging and clinical information. Imaging information had been entered into this database from the breast imaging reports in which one of 12 Mammography Quality Standards Act (MQSA) certified radiologists (11 of 12 of whom are breast fellowship trained) at our institution had dictated the breast imaging findings for each patient. The data we extracted from this database for both triple receptor negative and non triple receptor negative cancers included age at diagnosis, date of diagnosis, method of detection (pain or discomfort, nipple discharge, mass detected on mammography, or self or clinical breast examination), tumor grade at diagnosis (using Bloom- Richardson grading system), receptor status (ER, PR, HER2), and date of prior mammogram. The mammographic findings for both triple receptor negative and non triple receptor negative cancers were also acquired from the database and were classified as mass without calcifications, mass with calcifications, calcifications alone, or occult. Breast density and BI-RADS assessment [8] were also acquired from the database entries for triple receptor negative and non triple receptor negative cancers. Regional lymph node status at the time of diagnosis for triple receptor negative cancers was obtained from this database as well as size for the triple receptor negative tumors using both mammography and ultrasound reports. The overall triple receptor negative tumor size at diagnosis TABLE 2: Mammographic Characteristics of Masses in Triple Receptor Negative Breast Cancer Cases With Masses No. (%) of Patients Mass Characteristic With Masses (n = 133) a Margin Noncircumscribed 122 (92) Ill-defined 63 (47) Spiculated 27 (21) Obscured 25 (19) Microlobulated 7 (5) Circumscribed 11 (8) Shape Irregular 65 (49) Lobulated 27 (20) Oval 23 (17) Round 18 (14) a Of the cases available for review, three were negative on mammography (2%) and eight had calcifications only (6%). was determined on the basis of the size indicated in the mammography and ultrasound reports, averaged. Pathologic size was not used because a large proportion of the patients received neoadjuvant chemotherapy before mass resection. Mammographic and ultrasound images of triple receptor negative cancers were additionally retrospectively reviewed by two MQSA-certified, dedicated breast imagers with 16 and 30 years of experience. Both mammograms and ultrasound images for triple receptor negative cases were reviewed if available; a total of 172 cases were available for review, some of which contained only mammographic, only sonographic, or both mammographic and sonographic images. If a mass was identified by both reviewers on mammography (n = 133), mass margin and shape were categorized using the BI-RADS lexicon [8]. In the other 39 cases available for review, the mammogram portion was either unavailable (28 cases), negative (three cases), or calcifications only (eight cases). If a mass was identified by both reviewers on ultrasound (n = 120), the shape, margin, echo pattern, orientation in relation to the skin surface, mass boundary, and posterior acoustic features were classified according to the BI-RADS ultrasound descriptors [8]. In the other 52 cases available for review, the ultrasound portion was either unavailable (49 cases) or negative (three cases). The images were reviewed independently by the two reviewers and individual data were recorded. The overall data for the triple receptor negative imaging section is the average of these two independent AJR:198, August

3 Krizmanich-Conniff et al. A B Fig year-old postmenopausal woman who presented with palpable mass that was found to be breast cancer negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 so-called triple receptor negative cancer. A, Mammogram shows irregular mass with spiculated margins without calcifications (arrows). B, Ultrasound image shows irregular, hypoechoic mass with spiculated margins (arrows). Fig year-old woman with triple receptor negative breast cancer. Mammogram shows round mass with microlobulated margins (arrows). datasets. For example, for mass shape on ultrasound, reviewer 1 classified 75 masses as irregular and reviewer 2 classified 80 masses as irregular; thus, 77.5 masses (rounded to the nearest whole number for simplicity) were documented as irregular in the overall results displayed in the tables and throughout the remaining text. For triple receptor negative mass margin on both mammography and ultrasound, when one reader called the margins circumscribed and the other called noncircumscribed, the third reader, an MQSAcertified dedicated breast imager with 20 years experience, determined the consensus result on margins for these cases (21 mammogram cases and 20 ultrasound cases). Because of interobserver variability inherent in interpreting these images according to the BI-RADS lexicon [9], the other categories were kept as an average of the first two readers, and a consensus read was not sought; however, given that the results of our study concerning the imaging margins of triple receptor negative cancer is different from prior studies, we thought a consensus read in this category would provide more validation for this point. Among triple receptor-negative breast cancer group, mammographic lesions were reviewed prior to surgical biopsy, three patients had undergone core biopsy (with clip markers in place), and none had undergone surgical biopsy. All of the ultrasound examinations were performed by an MQSA-certified dedicated breast imager at our institution. Statistical Analysis The data were summarized using means and SDs for continuous data and counts and percentages for categoric data. Comparisons were made between the groups using a two-sample Student t test for the continuous data and chi-square test for the categoric data. Distribution assumptions were reviewed and found to be satisfied, and nonparametric tests gave the same results as the Student t tests. The variables associated with type of cancer were evaluated using a logistic regression model and found to be independent predictors. A significance level of p < 0.05 was used to determine significance. No corrections were made for multiple tests. All analyses were conducted using statistics software (SAS, version 9.2, SAS Institute). Fig year-old woman with triple receptor negative breast cancer. Mammogram shows irregular retroareolar mass with ill-defined margins (arrows). Results The mammographic findings of the triple receptor negative cancers are summarized in Tables 1 and 2. Triple receptor negative cancers were most commonly masses without calcifications (121/207, 58%) and less commonly masses with calcifications (60/207, 29%) or suspicious calcifications alone (15/207, 7%). On review of the mass margins on mammography for triple receptor negative cancer, most had ill-defined (63/133, 47%), spiculated (27/133, 20%), or obscured (25/133, 19%) margins, with the remaining categories much less common including circumscribed (11/133, 8%) and microlobulated (7/133, 5%) margins (Figs. 1A, 2, and 3). Mass shape on mammography for triple receptor negative cancer was most commonly irregular (65/133, 49%), with the remaining categories being less common. Mammographic findings were negative in five triple receptor negative cases (2%) and were not available in six triple receptor negative cases (3%) of the original triple receptor negative cases (Table 1); similarly, mammographic findings were negative in 2% of triple receptor negative cases available for review by both readers (3/144; 133 cases with masses, eight with calcifications alone and three negative) (Table 2). Non triple receptor negative cancers were more equally divided between masses without calcifications (435/967, 45%), masses with calcifications (311/967, 32%), and suspicious calcifications alone (109/967, 11%). Breast density and BI-RADS category assignment were not significantly different in triple receptor negative cancer in comparison with non triple receptor negative cancer (Table 1). 460 AJR:198, August 2012

4 Triple Receptor Negative Breast Cancer TABLE 3: Ultrasound Characteristics of Masses in Triple Receptor Negative Breast Cancer Cases With Masses No. (%) of Patients With Mass Characteristic Masses (n = 120) a Echo pattern Anechoic 2 (2) Hypoechoic 92 (77) Isoechoic 4 (3) Hyperechoic 0 Complex 22 (18) Shape Irregular 78 (65) Oval 27 (20) Round 15 (13) Margin Noncircumscribed 104 (87) Ill-defined 57 (48) Microlobulated 38 (32) Spiculated 8 (7) Obscured 1 (< 1) Circumscribed 16 (13) Orientation relative to skin surface Parallel 70 (58) Nonparallel 50 (42) Boundary Abrupt surface 86 (72) Eschogenic halo 34 (28) Posterior acoustic features None 51 (43) Mixed 28 (23) Enhancement 28 (23) Shadowing 13 (11) a Of the cases available for review, ultrasound findings were negative in three cases (3/123, 2%). BI-RADS category was most commonly category 4 (suspicious) in both triple receptor negative (122/207, 59%) and non triple receptor negative (522/967, 54%) cancers and less commonly was category 5 (highly suggestive) (71/207 [34%] for triple receptor negative and 291/967 [30%] for non triple receptor negative cancers) (p = 0.25). For the triple receptor negative cancers, the Other or not available category on Table 1 is broken down as follows: BI-RADS category 1 (five cases), category 3 (one case), category 6 (five cases), and not available (three cases). The one triple receptor Fig year-old woman with triple receptor negative breast cancer. Ultrasound image shows round mass with microlobulated margins (arrows) and complex echo pattern. negative cancer that was assessed as category 3 on mammography appeared as a hypoechoic, irregular mass with noncircumscribed (microlobulated) margins on ultrasound; therefore, a biopsy was indicated. There were not any category 2 triple receptor negative lesions. As summarized in Table 3, on ultrasound, the echo pattern of most triple receptor negative cancers was hypoechoic (92/120, 77%) or complex (mixed echogenicity containing both echogenic and hypoechoic areas) (22/120, 18%). The shape of triple receptor negative cancers on ultrasound was most commonly irregular (78/120, 65%) and was less commonly oval (27/120, 23%) or round (15/120, 13%). The margins of triple receptor negative cancers on ultrasound were most commonly noncircumscribed (104/120, 87%) in comparison with circumscribed (16/120, 13%). The noncircumscribed masses were ill defined in 48% of cases (57/120) with the remainder microlobulated (38/120, 32%) and spiculated (8/120, 7%) (Figs. 1B, 4, and 5). The triple receptor negative mass orientations on ultrasound was parallel to the skin surface in 58% (70/120) and nonparallel in 42% (50/120). The triple receptor negative mass boundaries most commonly had an abrupt surface (86/120, 72%) and less commonly had an echogenic halo (34/120, 28%). The triple receptor negative mass posterior acoustic features on ultrasound were none (51/120, 43%), followed by mixed (both echogenic and shadowing components) (28/120, 23%) and enhancement (28/120, 23%). Of the cases available for review by both readers, ultrasound findings were negative for three triple receptor negative cases (3/123, 2%) (Table 3). The three ultrasound-negative Fig year-old woman with triple receptor negative breast cancer. Ultrasound image shows irregular mass (cursors) with ill-defined margins and complex echo pattern. A = medial to lateral margins of the ultrasound mass.. triple receptor negative cases were detected on mammography: All were masses with noncircumscribed margins (two ill-defined and one spiculated) on mammography. The three mammography-negative triple receptor negative cases available for review were detected by ultrasound: All were masses with noncircumscribed (all ill-defined) margins on ultrasound except one that was negative on both modalities and was diagnosed by surgical biopsy of a palpable finding. Note that this latter case was not available for review by both reviewers. There were significant clinical differences between triple receptor negative and non triple receptor negative cancers (as summarized in Table 4). Triple receptor negative cancer in our series was significantly more likely to be detected clinically, either on breast examination performed by the patient or a clinician or by clinical symptoms such as breast pain or nipple discharge, in comparison with non triple receptor negative cancers (141/207 [68%] vs 468/967 [48%], respectively; p ). The remaining cancers were found on screening mammography (66/207 [32%] for triple receptor negative vs 499/967 [52%] for non triple receptor negative). Of the patients with clinically detected triple receptor negative cancer, 35% (48 patients) had no prior mammogram. In addition, in both the clinically detected and imaging-detected triple receptor negative cancers with prior mammograms, many of the cancers were found within 12 months of a prior mammogram (70/207, 34%). Triple receptor negative breast cancer was more commonly found in younger women (mean age, 51.1 years; age range, years) than non triple receptor negative (mean age, AJR:198, August

5 Krizmanich-Conniff et al. TABLE 4: Clinical Characteristics of Women With Triple Receptor Negative Cancer Versus Those With Non Triple Receptor Negative Cancer Characteristic Triple Receptor Negative (n = 207) Non Triple Receptor Negative (n = 967) p a Age (y) Mean (SD) 51.1 (12.7) 55.9 (12.9) Range Grade b, no. (%) of patients (3) 220 (25) 2 51 (26) 490 (55) (71) 180 (20) Mode of detection, no. (%) of patients Mammography 66 (32) 499 (52) Clinical findings c 141 (68) 468 (48) a Chi-square test. b Grade was unknown for 12 triple receptor negative and 77 non triple receptor negative cases. c Detected at patient- or clinician-performed breast examination or on imaging performed because of breast pain or nipple discharge years; age range, years) (p ). The triple receptor negative tumors were a higher grade than the non triple receptor negative tumors (grade 3 tumors: 138/195 [71%] vs 180/891 [20%], respectively) (p ). In triple receptor negative cancers, the masses were categorized by size at diagnosis and regional lymph node status was documented. The mean size of triple receptor negative tumors was 2.4 cm on mammography (range, cm), 2.1 cm on ultrasound (range, cm), and 2.3 cm when the mammography and ultrasound values were averaged (range, cm). With average tumor sizes from 0 to 0.9 cm, cm, and cm, the majority of patients had negative regional nodes at diagnosis (20/24 [83%], 44/74 [59%], and 38/54 [70%], respectively). With average tumor sizes from 3.0 to 3.9 cm and cm, the majority had positive regional lymph nodes at diagnosis (18/26 [69%] and 10/14 [71%], respectively). In 14 patients with masses larger than 5.0 cm, regional lymph nodes were positive in six patients (43%). Discussion Our study addresses the imaging characteristics and clinical features of triple receptor negative breast cancer and compares the features of triple receptor negative breast cancer with the features of breast cancers that have at least one of the three receptors positive that is, non triple receptor negative cancers. Although numerous prior studies have reported the clinical characteristics of triple receptor negative breast cancer, only some studies, with fewer cases, have reported the imaging characteristics of these cancers. Triple receptor negative breast cancer is defined as cancer with negative findings for the following biologic markers: ER, PR, and HER2. The mammographic findings among triple receptor negative cancers were most commonly a mass without calcifications (58%) with ill-defined (47%) or spiculated (20%) margins and an irregular shape (49%) (Figs. 1A, 2, and 3). Mammographic findings were negative in 2% (5/207) and not available in 3% (6/207) of the original triple receptor negative cases (Table 1); similarly, in the cases available for review by both readers, mammographic findings were negative in 2% of cases (3/144) (Table 2). This false-negative rate may be lower than that for non triple receptor negative breast cancers in part because of the nature of our patients with triple receptor negative cancer: They often presented with advanced disease for a second opinion or specialty-level care, and mammographic examinations were often diagnostic rather than screening in most cases. Breast density and BI-RADS category assignments were not significantly different in patients with triple receptor negative cancer compared with those with non triple receptor negative cancer. Yang et al. [5] reported the mammographic findings of triple receptor negative cancer in 2008 in 38 cases. They found that triple receptor negative cancer was most likely a mass without calcifications (85%) and was less likely a mass with calcifications (15%). In their study [5], the most common mass margins on mammography were indistinct (45%); less commonly, mass margins were circumscribed (24%) or spiculated (18%). In 2008, Wang et al. [6] compared the mammographic findings of ER-negative and HER2-negative cancers (96% of which were also PR-negative, and thus triple receptor negative [n = 32]) with those of ER-negative and HER2-positive cancer; they concluded that ER-negative and HER2-negative cancers were most often masses without calcifications (48%) and were less likely occult (18%) or masses with calcifications (12%). The margins on mammography were indistinct in 45%, circumscribed in 30%, and spiculated in 15%. In 2010, Ko et al. [7] found that triple receptor negative cancers (n = 87) were most commonly masses without calcifications (49%) and were less likely focal asymmetries (22%), masses with calcifications (21%), or calcifications alone (7%). In 2010, Dogan et al. [10] found that the majority of triple receptor negative cancers (n = 44) were masses without calcifications (54%) and that 32% had circumscribed margins. The results of our study confirm findings from the prior studies [5 7, 10] that triple receptor negative cancer was most commonly an irregular mass without calcifications with illdefined margins by mammography; in comparison with the prior studies, masses in our study group less commonly had circumscribed margins. We think that the higher percentage of circumscribed margins in prior studies may in part be because of the strictness of a reviewer s definition of circumscribed masses as well as the smaller sample sizes of prior studies. In our study, ultrasound features among triple receptor negative cancers were most commonly hypoechoic or complex masses with an irregular shape and noncircumscribed margins (Figs. 1B, 4, and 5). Other documented features include a parallel mass orientation with an abrupt surface boundary and no posterior acoustic features. In 2008, Wang et al. [6] found that triple receptor negative cancers (n = 20) on ultrasound were likely to be hypoechoic (80%) masses with an irregular (54%) or lobulated (20%) shape and with indistinct (40%), microlobulated (33%), or circumscribed or smooth (27%) margins. Ultrasound findings were negative in 21% of their cases. In 2010, Ko et al. [7] found that triple receptor negative cancers (n = 87) on ultrasound were likely to be hypoechoic or markedly hypoechoic (89%) masses with an irregular (83%) or oval (16%) shape and circumscribed (57%), angular (16%), indistinct (12%), microlobulated (9%), or spiculated (5%) margins. Ultrasound showed a non mass lesion in 14% of their cases. Dogan et al. [10] 462 AJR:198, August 2012

6 Triple Receptor Negative Breast Cancer found that 21% of triple receptor negative cancers (n = 44) had circumscribed margins on ultrasound. In general, our study results agree with the findings of Yang et al. and Ko et al. except the mass margins. We found that 89% of the masses had noncircumscribed margins and, again, believe that this difference in findings is in part because of smaller sample sizes previously and possibly secondary to a dedicated breast imager performing all of our ultrasound examinations. We found differences in the mode of detection between triple receptor negative cancer and non triple receptor negative cancer. The majority of triple receptor negative cancers were detected clinically either by breast examination performed by the patient or physician or by clinical symptoms such as breast pain or nipple discharge. In addition, of the patients with triple receptor negative cancers detected clinically, more than one third had no prior mammogram; of the clinically detected and imaging-detected triple receptor negative cancers in patients with prior mammograms, one third of the cancers were found within 12 months of a prior mammogram. We believe that this high incidence of interval cancer may be because of the rapid growth rate and aggressive nature of triple receptor negative cancers. These results support those of prior studies; for example, Dent et al. [1] found that triple receptor negative breast cancer was less frequently detected by mammography or ultrasound than non triple receptor negative cancer, however, more likely to be detected clinically. In their study, 71% of triple receptor negative cancers (n = 92) were detected clinically (vs 53% of non triple receptor negative cancers) and only 19% were detected first by mammography (vs 36% of non triple receptor negative cancers). Collett et al. [11] evaluated cancers diagnosed in a screening program and found that triple receptor negative cancer was more likely to present in the interval between regular screening mammograms than non triple receptor negative cancer. They postulated that this difference may be because of differences in breast density. However, our study showed no difference in breast density between triple receptor negative cancers and non triple receptor negative cancers. Triple receptor negative cancer has other clinical features that were significantly different from non triple receptor negative cancer in our study. Triple receptor negative cancer was more commonly found in younger patients and was associated with a higher pathologic grade. These findings suggest that triple receptor negative cancer is a biologically more aggressive disease with a poorer prognosis. Similarly, Dent et al. [1] also found that women with triple receptor negative cancer (n = 180) were younger (mean age, 53 years) than women with non triple receptor negative cancer (mean age, 57.7 years) and that triple receptor negative cancer was a higher pathologic grade at diagnosis (grade 3 at diagnosis: 66% triple receptor negative cancer vs 28% non triple receptor negative cancer) Carey et al. [3] also found that triple receptor negative cancers are associated with a higher pathologic grade in comparison with non triple receptor negative cancers (grade 3: 84% triple receptor negative vs 46% non triple receptor negative cancers). In a large California Cancer Registry study in 2007, Bauer et al. [12] found that triple receptor negative cancers (n = 6370) were significantly more likely to be found in women younger than 40 years old (12% vs 6% for non triple receptor negative) and to have a significantly higher grade (poorly differentiated or undifferentiated: 76% triple receptor negative vs 28% non triple receptor negative). Dent et al. [1] found that in non triple receptor negative cancers, the rate of regional lymph node positivity increases as tumor size increases; however, this traditional relationship was less consistently evident among the triple receptor negative group in their study (positive lymph nodes: tumors < 2 cm, 58%; tumors 2 5 cm, 49%). Foulkes et al. [13] noted that the phenomenon of no proportional relationship of tumor size to lymph node positivity was also observed in BRCA1 and BRCA2 gene mutations associated cancers. In our study, when triple receptor negative masses were categorized by average imaging size at diagnosis, a relationship between increasing mass size and regional lymph node positivity was also not evident; this finding may be caused in part by the lower number of triple receptor negative cases in the larger tumor subgroups. Even with very small tumors less than 2 cm, there was a relatively high percentage of regional lymph node positivity receptor among triple receptor negative cases in our cohort. This disproportionate relationship may be in part because of the aggressive nature and higher pathologic grade of the triple receptor negative tumors. The limitations of our study include a referral bias because our data were obtained from a large cancer center. Patients with more complex cases or with more advanced disease than the average breast cancer patient may have presented to us for a second opinion or specialty-level care. Another potential weakness was unavoidable selection bias in this retrospective study. For our study, only patients that had available ER, PR, and HER2 biologic marker data were included. In addition, there were data pieces that were missing or unavailable for review such as images and histopathologic specimens from outside institutions. Like other database studies, our study depended on the accuracy of the data entries. In conclusion, using standard BI-RADS assessment, triple receptor negative cancer was most commonly an irregular mass without calcifications with ill-defined or spiculated margins on mammography and a hypoechoic or complex mass with an irregular shape and noncircumscribed margins on ultrasound. The majority of triple receptor negative cancer cases were detected clinically, were detected in younger women, and often were detected in women without a prior mammogram. In addition, triple receptor negative cancer was more frequently associated with a higher pathologic grade and higher rate of regional lymph node positivity at diagnosis even with very small tumor sizes, reflecting its aggressive nature. References 1. Dent R, Trudeau M, Pritchard KI, et al. Triple receptor negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007; 13: Dawood S, Broglio K, Esteva FJ, et al. Survival among women with triple receptor negative breast cancer and brain metastases. Ann Oncol 2009; 20: Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006; 295: Kandel MJ, Stadler Z, Masciari S, et al. Prevalence of BRCA1 mutations in triple negative breast cancer (BC) (abstr). J Clin Oncol 2006; 24: Yang W-T, Dryden M, Broglio K, et al. Mammographic features of triple receptor negative primary breast cancers in young premenopausal women. 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7 Krizmanich-Conniff et al. BI-RADS breast imaging atlas. Reston, VA: American College of Radiology, Lazarus E, Mainiero M, Schepps B, et al. BI- RADS lexicon for US and mammography: interobserver variability and positive predictive value. Radiology 2006; 239: Dogan BE, Gonzalez-Angulo AM, Gilcrease M, Dryden MJ, Yang WT. Multimodality imaging of triple receptor negative tumors with mammography, ultrasound, and MRI. AJR 2010; 194: Collett K, Stefansson IM, Eide J, et al. A basal epithelial phenotype is more frequent in interval breast cancers compared with screen detected tumors. Cancer Epidemiol Biomarkers Prev 2005; 14: Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple receptor negative phenotype: a population-based study from the California Cancer Registry. Cancer 2007; 109: Foulkes W, Metcalfe K, Hanna W, et al. Disruption of the expected positive correlation between breast tumor size and lymph node status in BRCA1-related breast carcinoma. Cancer 2003; 98: FOR YOUR INFORMATION ARRS Breast Imaging Symposium Washington Marriott Wardman Park, Washington, DC September 19-22, 2012 Join ARRS again at this year s Breast Imaging Symposium with the additional option of attending a one-day program and earning 8 hours of tomosynthesis credit to meet FDA requirements. Earn up to 30 AMA PRA Category 1 Credits TM and 2 SAM credits one in Mammography and one in Breast MRI. Register before August 17 for the best symposium price! *The Tomosynthesis Program is limited to the first 40 registrants, so register now to ensure your spot in this exclusive program! AJR:198, August 2012