HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Supplemental Tables All Versions of this Article: 2462070169v1 246/2/367    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, Y. Articles by Jeffrey, S. S. Search for Related Content PubMed PubMed Citation Articles by Wang, Y. Articles by Jeffrey, S. S.

Estrogen Receptor–Negative Invasive Breast Cancer: Imaging Features of Tumors with and without Human Epidermal Growth Factor Receptor Type 2 Overexpression¹

¹ From the Departments of Surgery (Y.W., S.S.J.), Radiology (D.M.I., S.P., R.J.J.), Health Research and Policy (B.N.), and Pathology (T.A.L.), Stanford University School of Medicine, Medical School Lab Surge Bldg Room P214, 1201 Welch Rd, Stanford, CA 94305-5494; and Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pa (R.J.B.). Received January 25, 2007; revision requested March 16; revision received May 11; accepted June 11; final version accepted July 23. S.S.J. supported in part by the California Breast Cancer Research Program of the University of California (grant 11IB-0175). Address correspondence to S.S.J. (e-mail: ssj{at}stanford.edu).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATION FOR PATIENT CARE... References

 
Purpose: To prospectively determine if estrogen receptor (ER)-negative human epidermal growth factor receptor type 2 (HER2)-positive and ER-negative HER2-negative breast cancers have distinguishing clinical and imaging features with use of retrospectively identified patients and tissue samples.

Materials and Methods: This HIPAA-compliant study was institutional review board approved. Informed consent was obtained from living patients and waived for deceased patients. Mean patient age at diagnosis was 53 years (range, 31–84 years). Clinical history; histopathologic, mammographic, and breast sonographic findings; and HER2 status as determined with immunohistochemistry or fluorescent in situ hybridization were evaluated in 56 women with ER-negative breast cancer. Imaging appearances and clinicopathologic characteristics were correlated with tumor HER2 status. P < .05 indicated a significant difference.

Results: Lesion margins on mammograms (P = .028) and sonograms (P = .023), calcifications on mammograms (P = .003), and clinical cancer stage at diagnosis (P = .029) were significantly associated with HER2 status. In contrast to ER-negative HER2-negative tumors, ER-negative HER2-positive tumors were more likely to have spiculated margins (56% vs 15%), be associated with calcifications (65% vs 21%), and be detected at a higher cancer stage (74% vs 57%).

Conclusion: Biologic diversity of cancers may manifest in imaging characteristics, and, conversely, studying the range of imaging features of cancers may help refine current molecular phenotypes.

Supplemental material: http://radiology.rsnajnls.org/cgi/content/full/2462070169/DC1

© RSNA, 2008

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATION FOR PATIENT CARE... References

 
Estrogen receptor (ER)-negative breast cancers are tumors with a distinct natural history, treatment response, and prognostic profile (1–3). They account for 25%–30% of all breast cancers, and their clinical course tends to be more aggressive than that of other breast cancers (4). Patients with ER-negative breast cancer generally have shorter disease-free survival and overall survival times (2). Most patients with ER-negative tumors do not benefit from antihormonal therapy (5), and many of these tumors are unaffected by conventional cytotoxic chemotherapeutic regimens (6).

Approximately 20%–25% of patients with breast cancer have overexpression of a membrane receptor protein in the epidermal growth factor receptor family: the human epidermal growth factor receptor type 2 (HER2) (7–9). The proto-oncogene encoding this protein was originally termed neu and is known as HER2/neu or c-erb-b2. Amplification of the HER2 gene (also known as the ERBB2 gene) at the DNA level results in overexpression at the protein level (7). Approximately 30%–40% of ER-negative breast cancers overexpress HER2 (10). Trastuzumab is a humanized recombinant monoclonal antibody that targets the extracellular domain of the HER2 protein. About 25%–30% of patients with HER2-overexpressing metastatic breast cancer will respond to trastuzumab therapy (11,12). When trastuzumab is administered adjuvantly with other chemotherapy in patients with HER2-overexpressing breast cancer, trastuzumab therapy is associated with an absolute difference of 6%–16% in disease-free survival rates at 3 years (13–15). In contrast, to our knowledge, there are currently no targeted therapies for ER-negative HER2-negative breast cancers (16). The survival curves of patients with ER-negative HER2-negative cancer and those with ER-negative HER2-positive cancer are also different, with patients with ER-negative HER2-positive cancer having a lower cumulative survival rate (17,18). However, introduction of trastuzumab to the treatment of patients with HER2-positive cancer may alter the relative survival rates of patients with one of these types of ER-negative breast cancer.

The results of studies relating HER2 status to prognosis provide evidence that ER-negative breast cancers can be separated into two distinct subgroups of tumors with different underlying biologic characteristics. This has also been shown on the molecular level (19). It follows that ER-negative HER2-negative tumors and ER-negative HER2-positive tumors may also have distinct imaging and clinical features. We hypothesized that comparison of mammographic and sonographic appearance, other clinical features, and tumor subtype could yield additional data that could assist in pretreatment planning and discussion of prognosis, as well as add to our understanding of tumor biologic characteristics. Thus, the purpose of our study was to prospectively determine if ER-negative HER2-positive and ER-negative HER2-negative breast cancers have distinguishing clinical and imaging features with use of retrospectively identified patients and tissue samples.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATION FOR PATIENT CARE... References

 
Patient Selection
Our study was compliant with the Health Insurance Portability and Accountability Act and was approved by the Stanford University institutional review board. An author (Y.W.) searched the Stanford University Hospital pathology database to identify women who underwent surgical breast biopsy, breast cancer treatment, or both between January 1997 and June 2003. We mailed consent forms to 185 women with ER-negative breast cancer according to pathology reports. The institutional review board ruled that the relatives of 22 women who died of breast cancer before the start of this study were exempt from providing written informed consent. We obtained written informed consent from 69 living patients. Of the 91 patients, 35 were excluded when we could not obtain archival paraffin-embedded tumor specimens, clinical information, or hard-copy preoperative mammograms for analysis. All 56 patients included in this study had primary breast cancer without distant metastases at the time of diagnosis. Patient age ranged from 31 to 84 years (mean age, 53 years ± 14 [standard deviation]).

Clinicopathologic Data
An author (Y.W.) reviewed the patients' medical records and compiled data on age, tumor manifestation (palpable mass vs lesion identified with screening mammography), and cancer stage at diagnosis. Pathology reports were also reviewed to determine tumor type, size, and grade with the Nottingham grading system for breast carcinoma (20), as well as to determine the presence of angiolymphatic invasion, ductal carcinoma in situ, and axillary lymph node metastasis. ER, progesterone receptor, and HER2 status were recorded, as described later in this article.

Immunohistologic and Fluorescent in Situ Hybridization Analysis
The Stanford University Pathology Department Immunodiagnosis Service used antibodies from Dako (Carpinteria, Calif) to perform immunohistochemical analyses for ER, progesterone receptor, and HER2 (HercepTest). Specimens with HER2 staining scores of 3+, representing strong complete membrane staining in more than 10% of cells, were considered HER2 positive. Specimens with a score of 0 or 1+, representing no or barely perceptible membrane staining, were considered HER2 negative. A breast and gynecologic pathologist (T.A.L., 17 years of experience) retrieved all archived pathology blocks and further assayed tumor specimens that showed an intermediate HER2 staining score of 2+ with fluorescent in situ hybridization, as HER2 gene amplification occurs in less than 25% of such cases (21,22).

Fluorescent in situ hybridization was performed by using the PathVysion HER-2 DNA Probe Kit (Abbott-Vysis, Des Plaines, Ill). Slides were viewed with fluorescence microscopy, and we examined 25 cells per slide. The level of gene amplification is often heterogeneous among the nuclei of the same specimen; thus, an average HER2/neu gene copy number and an average centromere 17 copy number were determined for each preparation. Results were expressed as a ratio of the number of copies of the HER2/neu gene to the number of chromosome 17 centromeric markers, with a ratio of more than 2.0 considered amplified. Aneuploidy of chromosome 17 was noted if it was the source of increased HER2/neu copy number.

Image Analysis
Three experienced Mammography Quality Standards Act–certified breast imaging radiologists (S.P., D.M.I., and R.J.J.; 3, 18, and 41 years of breast imaging experience, respectively) reviewed all mammograms and breast sonograms without knowledge of the clinicopathologic findings. Each image was read by two of the three radiologists; both radiologists who read an image had to agree on an interpretation before the results were recorded.

Mammograms were evaluated according to the American College of Radiology Breast Imaging Reporting and Data System (23). Breast density was rated as fatty, scattered fibroglandular, heterogeneously dense, or dense. Overall breast density and density of the breast parenchyma immediately surrounding the tumor were assessed. The latter was determined by evaluating tissue 1 cm around the margin of any suspicious finding on mammograms, irrespective of size. Craniocaudal and mediolateral oblique views were examined, and the lower density on the two views was recorded. Lesions were described as masses, focal asymmetries, densities seen in only one view, architectural distortions, or calcifications. The term densities refers to tissue that has the appearance of a mass but does not meet American College of Radiology criteria to be considered a mass because it is seen in only one view. Masses were evaluated for size, shape, and margins. Calcifications were described in morphologic terms.

The same three Mammography Quality Standards Act–certified radiologists performed breast sonography in a subset of 36 patients to further characterize the suspicious lesions detected at mammography or to evaluate mammographically occult palpable lesions. These sonographic images were evaluated for masses that were described according to the Breast Imaging Reporting and Data System for echogenicity, orientation, presence of calcifications, vascularity, size, shape, and margin. All mammograms and breast sonographic images reviewed in this study were stored on film.

Statistical Analysis
Three authors (S.S.J., Y.W., and B.N.) analyzed the data. One author (B.N.) preformed all statistical analyses by using R Software (version 2.4.1; The R Foundation for Statistical Computing, Vienna, Austria) (24). The association of HER2 status with tumor size, as measured on mammograms, sonographic images, or excised pathologic samples, was analyzed with the Mann-Whitney (Wilcoxon rank sum) test to determine if there was a location shift between the HER2-positive and HER2-negative samples. The association of HER2 status with all other clinicopathologic and imaging features was assessed with the Fisher exact test. All statistical tests were two sided, and significance was set at P < .05.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATION FOR PATIENT CARE... References

 
Clinicopathologic Data
Twenty-three of the 56 patients had ER-negative HER2-positive breast cancer, as determined with immunohistochemistry in 20 patients and with fluorescent in situ hybridization in three patients after immunohistochemistry yielded indeterminate results (Table 1) (Table E1, http://radiology.rsnajnls.org/cgi/content/full/2462070169/DC1). The remaining 33 patients, including four who required further fluorescent in situ hybridization analysis, had ER-negative HER2-negative breast cancer. We did not observe any association between the method of tumor detection (palpation vs screening mammography) and HER2 status (P = .116).

Mean tumor size was 2.8 cm in patients with HER2-positive cancer and 2.2 cm in those with HER2-negative cancer (range, 0.2–8.0 cm). Thirteen (23%) of the 56 tumors had a diameter of 1 cm or less. Angiolymphatic invasion was identified in eight (35%) patients with HER2-positive cancer and six (18%) patients with HER2-negative cancer. Fourteen (61%) patients with HER2-positive cancer and 16 (48%) patients with HER2-negative cancer had lymph node metastases (Table 1).

Mammographic Findings
All patients had pretreatment screening or diagnostic mammograms available for review (Table E2, http://radiology.rsnajnls.org/cgi/content/full/2462070169/DC1). Mammograms of 23 patients with HER2-positive cancer showed five (22%) masses without any associated calcifications, 11 (48%) masses with associated calcifications, one (4%) density seen on only one view, three (13%) clusters of suspicious calcifications, and one (4%) architectural distortion. Two (9%) mammograms were normal (Table 2). Mammograms of 33 patients with HER2-negative cancer showed 16 (48%) masses without associated calcifications, four (12%) masses with associated calcifications, three (9%) focal asymmetries, three (9%) clusters of suspicious calcifications, and one (3%) density seen on only one view. Six (18%) mammograms were normal. A negative mammogram or mammographic findings of a mass (with or without associated calcifications), suspicious calcification clusters, density seen on only one view, or architectural distortion were not associated with HER2 status (P = .477). The mean size of lesions detected on mammograms was 2.4 cm for HER2-positive tumors and 2.2 cm for HER2-negative tumors.

There was a significant association between presence of calcifications and HER2 status (P = .003). Overall, 15 (65%) mammograms of patients with HER2-positive breast cancer and seven (21%) mammograms of patients with HER2-negative breast cancer showed calcifications. Thirteen (87%) of 15 patients who had HER2-positive cancer with calcifications and four (57%) of seven patients who had HER2-negative cancer with calcifications had pleomorphic calcifications (Table 2). Overall, 56% of ER-negative HER2-positive tumors and 12% of ER-negative HER2-positive tumors had pleomorphic calcifications. The excised samples of 20 (87%) patients with HER2-positive cancer and 23 (70%) patients with HER2-negative cancer showed associated ductal carcinoma in situ (Table 3). Thirteen (65%) of the 20 patients with HER2-positive cancers with associated ductal carcinoma in situ had calcifications on mammograms compared with only six (26%) of the 23 patients with HER2-negative cancers with associated ductal carcinoma in situ. Twenty-six (79%) of 33 patients with ER-negative HER2-negative breast cancer, including 17 (74%) of 23 patients with ER-negative HER2-negative invasive breast cancer with associated ductal carcinoma in situ, had no visible calcifications on mammograms.

Cancer Stage
Breast cancer clinical stage at presentation was associated with HER2 status (P = .029). HER2-positive cancers were more likely than HER2-negative cancers to be stage II or III cancers (74% vs 58%) (Table 5).

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATION FOR PATIENT CARE... References

Our findings provide evidence that for confirmed ER-negative breast cancers, spiculated margins may enable one to predict HER2 status. On both mammograms and breast sonograms, ER-negative HER2-positive cancers were more likely to appear as spiculated masses across all tumor grades, while ER-negative HER2-negative cancers were more likely to appear as smooth or circumscribed masses. We found that nine (56%) of the 16 HER2-positive cancers that were identified as mammographic masses were spiculated, while none were circumscribed. On the other hand, only three (15%) of the 20 ER-negative HER2-negative tumors that were identified as mammographic masses were spiculated, while six (30%) were circumscribed.

Currently, clinicians view lesions with spiculated margins on mammograms and sonograms with a high degree of suspicion because more than 80% of spiculated lesions seen on mammograms and sonograms have been found to be histologically malignant (26,27). However, triple-negative breast cancers, some of which are associated with BRCA1 mutations, may show "pushing" margins (in contradistinction to spiculated margins) at radiography and histologic analysis (28,29). In fact, Kaas et al (28) and Hamilton et al (30) showed that 44%–72% of BRCA1-associated breast cancers had well-defined (ie, circumscribed) margins, while none had spiculated margins. In our study, 32 (97%) of 33 ER-negative HER2-negative tumors were triple-negative cancers. Three (9%) of these tumors had spiculated margins, six (18%) had circumscribed margins, and six (18%) were mammographically occult. This was in contrast to the 23 ER-negative HER2-negative tumors, of which nine (39%) were spiculated, none were circumscribed, and two (9%) were mammographically occult. These results imply that although HER2-positive cancers may be readily detected on mammograms because they appear as spiculated margins that are viewed with a high index of suspicion, HER2-negative cancers may be more likely to be dismissed as benign lesions because their margins may be circumscribed on mammograms. Thus, mammography has some limitations in the detection of ER-negative HER2-negative breast cancer, especially because these tumors are also more often mammographically occult (18% in the current study) than ER-negative HER2-positive cancers (9% in the current study).

We should note that while we found an association between spiculated margins and HER2 status among patients with ER-negative cancers, ER-positive tumors can also manifest as spiculated masses. In fact, Ildefonso et al (31) showed that 63% of spiculated masses were ER positive, and Alexander et al (32) showed that stellate tumors were better differentiated among tumors smaller than 1.5 cm. We analyzed our genomic data and noted that ER-negative HER2-positive breast cancers share some molecular features with ER-positive (luminal) breast cancers, irrespective of HER2 status (33), and speculated on whether features such as tumor margin may reflect such biologic features.

A study by Seo et al (34) also related HER2 status to mammographic features of invasive breast cancers and noninvasive ductal carcinoma in situ. Similar to us, Seo et al found that HER2-positive cancers were associated with calcifications at mammography. They did not, however, specify ER and progesterone receptor status or ductal carcinoma in situ–only status in their comparison of various mammographic features.

Tabar et al (35) and Thurfjell et al (36) found that the presence of pleomorphic calcifications in small cancers (<1.5 cm) was an independent predictor of poor prognosis. Given the general poor prognosis and survival rate for patients with HER2-positive cancer, it is not surprising that these patients would frequently have pleomorphic calcifica-tions at mammography, comprising 57% of ER-negative HER2-positive breast cancers and 87% of ER-negative HER2-positive cancers that had mammographic calcifications in the current study. However, because the targeted therapy (trastuzumab) has shown early success in the treatment of patients with HER2-positive cancer, patients with ER-negative HER2-positive cancer who classically have a poorer prognosis, including those with microcalcifications, may develop improved survival rates compared with the survival rates of patients with ER-negative HER2-negative cancer, for whom there are no targeted therapies. If that were to occur, one might speculate that the absence of calcifications in 79% of all patients with ER-negative HER2-negative cancer might bode for an even worse prognosis than the presence of calcifications in those patients with HER2-positive cancer who may be responsive to trastuzumab.

There is even a report of several patients with ER-negative HER2-positive cancer and advanced breast cancer who reverted to ER-positive HER2-positive status after they were administered trastuzumab and became responsive to hormonal therapy (37). Clearly, the field of breast cancer therapies is changing rapidly. In this study, we showed that tumor phenotype could be associated with imaging findings, which we speculate will have the potential to assist in the prediction of responsiveness to various therapies. This means that in the future, breast imagers may assist clinicians in their treatment planning by helping to determine, for example, whether patients with HER2-positive cancer with specific morphologic types of calcifications or other mammographic findings might be more or less likely to respond to trastuzumab therapy.

Given the prevailing hypothesis that the outcomes of different breast cancer subtypes may be influenced by their underlying biologic features (38), efforts have been directed at the identification of specific gene expression profiles in subsets of breast cancer. Comprehensive analyses of breast cancer tissues with DNA microarrays have enabled identification of at least five subtypes of breast cancer with distinct gene expression patterns (39–45). When clinical outcomes of these subtypes are studied, both the basal-like group and the ER-negative HER2-positive group (previously called the ERBB2-overexpressing group) are associated with the poorest short-term survival rates (40,41,43). Basal-like breast cancers are characterized by the expression of markers expressed in normal basal and myoepithelial cells, and they form 56%–85% of the triple-negative group (29,46). As all but one of the ER-negative HER2-negative breast cancers included in this study were triple-negative cancers, it is likely that many corresponded to the basal-like phenotype. We also suspect that our ER-negative HER2-positive tumors reflected the ER-negative HER2-positive genomic phenotype. We are in the process of correlating genomic phenotypes with imaging findings.

An important limitation of our study, the small number of patients in each HER2 subgroup, may have two consequences: First, because the mean mammographic sizes of tumors were relatively large (2.4 cm for HER2-positive tumors, 2.2 cm for HER2-negative tumors) and because we analyzed relatively few tumors smaller than 1 cm, we did not have the statistical power to determine whether smaller tumors have different mammographic features, sonographic features, or both. Second, our sample size may have affected the significance of associations between specific imaging or clinicohistopathologic features and HER2 status. Moreover, the dataset consisted of multiple mammographic features, all of which were examined for association with HER2 status. This means that there were multiple testing issues. Thus, while the P values reported here were significant for each test, they were not corrected for multiple testing. Therefore, our findings should be considered preliminary results and require further investigation in future larger studies. By describing imaging features of two biologically distinct breast cancer subtypes, radiologists may be able to identify the imaging patterns that will enable them to differentiate biologically diverse breast cancers. For ER-negative tumors of a specific molecular subtype, imaging characteristics may add prognostic or predictive information. We are currently exploring this possibility.

In the future, breast cancer will be treated on the basis of the molecular features of the patient's tumor. Studying the range of imaging features of cancers may help refine our current molecular phenotypes. Developing a unified classification schema that incorporates imaging findings, molecular subtype, and predictive biomarkers should help to more precisely predict patient outcome and those individuals who will be responsive to a specific therapeutic regimen. This should facilitate prognostic assessment and potentially guide the therapeutic approach.

	ADVANCES IN KNOWLEDGE

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATION FOR PATIENT CARE... References

 

• Our study results show that the human epidermal growth factor receptor type 2 (HER2) status of patients with estrogen receptor (ER)-negative breast cancer is associated with the presence of calcifications, almost all of which are pleomorphic, at mammography (P = .003) and with lesion margins at mammography (P = .028) and breast sonography (P = .023).
  
• Our results suggest that underlying biologic differences are associated with distinctive imaging features for ER-negative HER2-negative tumors and ER-negative HER2-positive tumors.
  

	IMPLICATION FOR PATIENT CARE

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATION FOR PATIENT CARE... References

 

• The range of imaging features of breast cancers may help refine current molecular phenotypes and lead to the development of better targeted and more individualized therapies for patients with breast cancer.
  

	FOOTNOTES

 

Abbreviations: ER = estrogen receptor • HER2 = human epidermal growth factor receptor type 2

Guarantors of integrity of entire study, Y.W., S.S.J.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, Y.W., D.M.I., T.A.L., R.J.B., S.S.J.; clinical studies, Y.W., D.M.I., T.A.L., S.P., R.J.J.; statistical analysis, Y.W., B.N., S.S.J.; and manuscript editing, all authors

Authors stated no financial relationship to disclose.

	References

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATION FOR PATIENT CARE... References

 

1. Putti TC, El-Rehim DM, Rakha EA, et al. Estrogen receptor-negative breast carcinomas: a review of morphology and immunophenotypical analysis. Mod Pathol 2005;18:26–35. [CrossRef][Medline]
2. Parl FF, Schmidt BP, Dupont WD, Wagner RK. Prognostic significance of estrogen receptor status in breast cancer in relation to tumor stage, axillary node metastasis, and histopathologic grading. Cancer 1984;54:2237–2242. [CrossRef][Medline]
3. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007;13:2329–2334. [Abstract/Free Full Text]
4. Pichon MF, Broet P, Magdelenat H, et al. Prognostic value of steroid receptors after long-term follow-up of 2257 operable breast cancers. Br J Cancer 1996;73:1545–1551. [Medline]
5. Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005;365:60–62. [CrossRef][Medline]
6. Paone JF, Abeloff MD, Ettinger DS, Arnold EA, Baker RR. The correlation of estrogen and progesterone receptor levels with response to chemotherapy for advanced carcinoma of the breast. Surg Gynecol Obstet 1981;152:70–74. [Medline]
7. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707–712. [Abstract/Free Full Text]
8. Pegram M, Slamon D. Biological rationale for HER2/neu (c-erbB2) as a target for monoclonal antibody therapy. Semin Oncol 2000;27:13–19. [Medline]
9. Konecny G, Pauletti G, Pegram M, et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 2003;95:142–153. [Abstract/Free Full Text]
10. Stefano R, Agostara B, Calabro M, et al. Expression levels and clinical-pathological correlations of HER2/neu in primary and metastatic human breast cancer. Ann N Y Acad Sci 2004;1028:463–472. [CrossRef][Medline]
11. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–792. [Abstract/Free Full Text]
12. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719–726. [Abstract/Free Full Text]
13. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–1684. [Abstract/Free Full Text]
14. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354:809–820. [Abstract/Free Full Text]
15. Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007;369:29–36. [CrossRef][Medline]
16. Siziopikou KP, Ariga R, Proussaloglou KE, Gattuso P, Cobleigh M. The challenging estrogen receptor–negative/progesterone receptor–negative/HER-2-negative patient: a promising candidate for epidermal growth factor receptor-targeted therapy? Breast J 2006;12:360–362. [CrossRef][Medline]
17. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006;295:2492–2502. [Abstract/Free Full Text]
18. Kim MJ, Ro JY, Ahn SH, Kim HH, Kim SB, Gong G. Clinicopathologic significance of the basal-like subtype of breast cancer: a comparison with hormone receptor and Her2/neu-overexpressing phenotypes. Hum Pathol 2006;37:1217–1226. [CrossRef][Medline]
19. Jeffrey SS, Lonning PE, Hillner BE. Genomics-based prognosis and therapeutic prediction in breast cancer. J Natl Compr Canc Netw 2005;3:291–300. [Medline]
20. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991;19:403–410.
21. Choi DH, Shin DB, Lee MH, et al. A comparison of five immunohistochemical biomarkers and HER-2/neu gene amplification by fluorescence in situ hybridization in white and Korean patients with early-onset breast carcinoma. Cancer 2003;98:1587–1595. [CrossRef][Medline]
22. Dybdal N, Leiberman G, Anderson S, et al. Determination of HER2 gene amplification by fluorescence in situ hybridization and concordance with the clinical trials immunohistochemical assay in women with metastatic breast cancer evaluated for treatment with trastuzumab. Breast Cancer Res Treat 2005;93:3–11. [Medline]
23. American College of Radiology. Breast Imaging and Reporting Data System (BIRADS). Reston, Va: American College of Radiology, 2003.
24. R Development Core Team. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2006.
25. Yu D, Hung MC. Overexpression of ErbB2 in cancer and ErbB2-targeting strategies. Oncogene 2000;19:6115–6121. [CrossRef][Medline]
26. Hong AS, Rosen EL, Soo MS, Baker JA. BI-RADS for sonography: positive and negative predictive values of sonographic features. AJR Am J Roentgenol 2005;184:1260–1265. [Abstract/Free Full Text]
27. Liberman L, Abramson AF, Squires FB, Glassman JR, Morris EA, Dershaw DD. The breast imaging reporting and data system: positive predictive value of mammographic features and final assessment categories. AJR Am J Roentgenol 1998;171:35–40. [Abstract/Free Full Text]
28. Kaas R, Kroger R, Peterse JL, Hart AA, Muller SH. The correlation of mammographic-and histologic patterns of breast cancers in BRCA1 gene mutation carriers, compared to age-matched sporadic controls. Eur Radiol 2006;16:2842–2848. [CrossRef][Medline]
29. Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO. Prognostic markers in triple-negative breast cancer. Cancer 2007;109:25–32. [CrossRef][Medline]
30. Hamilton LJ, Evans AJ, Wilson AR, et al. Breast imaging findings in women with BRCA1- and BRCA2-associated breast carcinoma. Clin Radiol 2004;59:895–902. [CrossRef][Medline]
31. Ildefonso C, Vazquez J, Guinea O, et al. The mammographic appearance of breast carcinomas of invasive ductal type: relationship with clinicopathological parameters, biological features and prognosis. Eur J Obstet Gynecol Reprod Biol doi:10.1016/j.ejogrb.2006.10.025. Published online November 20, 2006. Accessed April 25, 2007.
32. Alexander MC, Yankaskas BC, Biesemier KW. Association of stellate mammographic pattern with survival in small invasive breast tumors. AJR Am J Roentgenol 2006;187:29–37. [Abstract/Free Full Text]
33. Nicolau M, Tibshirani R, Borresen-Dale AL, Jeffrey SS. Disease-specific genomic analysis: identifying the signature of pathologic biology. Bioinformatics 2007;23:957–965. [Abstract/Free Full Text]
34. Seo BK, Pisano ED, Kuzimak CM, et al. Correlation of HER-2/neu overexpression with mammography and age distribution in primary breast carcinomas. Acad Radiol 2006;13:1211–1218. [CrossRef][Medline]
35. Tabar L, Tony Chen HH, Amy Yen MF, et al. Mammographic tumor features can predict long-term outcomes reliably in women with 1–14-mm invasive breast carcinoma. Cancer 2004;101:1745–1759. [CrossRef][Medline]
36. Thurfjell E, Thurfjell MG, Lindgren A. Mammographic finding as predictor of survival in 1–9 mm invasive breast cancers: worse prognosis for cases presenting as calcifications alone. Breast Cancer Res Treat 2001;67:177–180. [CrossRef][Medline]
37. Munzone E, Curigliano G, Rocca A, et al. Reverting estrogen-receptor-negative phenotype in HER-2-overexpressing advanced breast cancer patients exposed to trastuzumab plus chemotherapy. Breast Cancer Res 2006;8:R4. [Published correction appears in Breast Cancer Res 2006;8:407.] [CrossRef][Medline]
38. Fan C, Oh DS, Wessels L, et al. Concordance among gene-expression-based predictors for breast cancer. N Engl J Med 2006;355:560–569. [Abstract/Free Full Text]
39. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000;406:747–752. [CrossRef][Medline]
40. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001;98:10869–10874. [Abstract/Free Full Text]
41. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 2003;100:8418–8423. [Abstract/Free Full Text]
42. Hu Z, Fan C, Oh DS, et al. The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics 2006;7:96. [CrossRef][Medline]
43. Sotiriou C, Neo SY, McShane LM, et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A 2003;100:10393–10398. [Abstract/Free Full Text]
44. Yu K, Lee CH, Tan PH, Tan P. Conservation of breast cancer molecular subtypes and transcriptional patterns of tumor progression across distinct ethnic populations. Clin Cancer Res 2004;10:5508–5517. [Abstract/Free Full Text]
45. Zhao H, Langerod A, Ji Y, et al. Different gene expression patterns in invasive lobular and ductal carcinomas of the breast. Mol Biol Cell 2004;15:2523–2536. [Abstract/Free Full Text]
46. Livasy CA, Karaca G, Nanda R, et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 2006;19:264–271. [CrossRef][Medline]

This article has been cited by other articles:

				T. Uematsu, M. Kasami, and S. Yuen Triple-Negative Breast Cancer: Correlation between MR Imaging and Pathologic Findings Radiology, March 1, 2009; 250(3): 638 - 647. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Supplemental Tables All Versions of this Article: 2462070169v1 246/2/367    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, Y. Articles by Jeffrey, S. S. Search for Related Content PubMed PubMed Citation Articles by Wang, Y. Articles by Jeffrey, S. S.