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Molecular Classification of Infiltrating Breast Cancer: Toward Personalized Therapy 1

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BREAST IMAGING 1178 Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at Molecular Classification of Infiltrating Breast Cancer: Toward Personalized Therapy 1 Isabelle Trop, MD, MPH Sophie M. LeBlanc, MD Julie David, MD Lucie Lalonde, MD Danh Tran-Thanh, MD Maude Labelle, MD Mona M. El Khoury, MD Abbreviations: ADC = apparent diffusion coefficient, BI-RADS = Breast Imaging Reporting and Data System, DCIS = ductal carcinoma in situ, ER = estrogen receptor, HER2 = human epidermal growth factor receptor 2, PR = progesterone receptor RadioGraphics 2014; 34: Published online /rg Content Codes: 1 From the Department of Radiology, Breast Imaging Center (I.T., S.M.L., J.D., L.L., M.L., M.M.E.), and the Department of Pathology (D.T.), Centre Hospitalier de l Université de Montréal (CHUM), 3840 rue Saint-Urbain, Montréal, QC, Canada H2W 1T8. Recipient of a Cum Laude award for an education exhibit at the 2012 RSNA Annual Meeting. Received August 10, 2013; revision requested October 23 and received November 14; accepted December 11. For this journal-based SA-CME activity, the authors, editor, and reviewers have disclosed no relevant relationships. Address correspondence to I.T. ( SA-CME LEARNING OBJECTIVES After completing this journal-based SA- CME activity, participants will be able to: Define the main molecular classes of infiltrating breast cancer. Describe the imaging findings characteristic of each major molecular subtype of breast cancer. Discuss the importance of the molecular classification of breast cancer in light of new targeted therapies. See Scan this code for access to supplemental material on our website. Breast cancer is a heterogeneous disease, which comprises several molecular and genetic subtypes, each with characteristic clinicobiologic behavior and imaging patterns. Traditional classification of breast cancer is based on the histopathologic features but offers limited prognostic value. Novel molecular characterization of breast cancer with cellular markers has allowed a new classification that offers prognostic value, with predictive categories of disease aggressiveness. These molecular signatures also open the door to personalized therapeutic options, with new receptor-targeted therapies. For example, invasive cancer subtypes such as the luminal A and B subtypes show better prognosis and response to hormone receptor targeted therapies compared with the triple-negative subtypes; on the other hand, triple-negative tumors respond better than luminal tumors to chemotherapy. Tumors that display amplification of the oncogene ERBB2 (also known as the HER2/neu oncogene) respond to drugs directed against this oncogene, such as trastuzumab. The imaging aspects of tumors correlate with molecular subgroups, as well as other pathologic features such as nuclear grade. Smooth tumor margins at mammography may be suggestive of a triple-negative breast cancer, and a human epidermal growth factor receptor 2 (HER2) positive tumor is characteristically a spiculated mass with calcifications. Low-grade ductal carcinoma in situ (DCIS) is better detected with mammography, although magnetic resonance (MR) imaging may allow better characterization of high-grade DCIS. MR imaging diffusion sequences show higher values for the apparent diffusion coefficient for triple-negative and HER2-positive subtypes, compared with luminal A and B tumors. MR imaging is also a useful tool in the prediction of tumor response after chemotherapy, especially for triple-negative and HER2-positive subtypes. RSNA, 2014 Introduction Breast cancer is the most common cancer in women, with a lifetime risk of 12% (one in eight) for average-risk women (1,2), and is the second most common cause of death from cancer in women. Mortality rates after a diagnosis of breast cancer began to decrease in 1991 as a result of improvements in early detection and refined treatment options (3,4). Specific drugs have had a substantial effect on the natural history of breast cancer, including a decreased disease incidence after the introduction of tamoxifen therapy and RG Volume 34 Number 5 Trop et al 1179 improved survival with trastuzumab administration (4); and such drugs have introduced into the field of breast cancer management a new relevance for understanding the molecular basis of breast cancer. Traditional classification of breast cancer is based on the clinicopathologic analysis of tumors, with classes of breast cancer defined by histopathologic features, including the pattern of architectural growth (eg, cribriform, papillary) and the nuclear grade (low, intermediate, or high). Treatment choices were then selected on the basis of tumor size, local invasion, and lymph node involvement or distant metastases, as defined by the American Joint Committee on Cancer s TNM staging classification (5). Survival rates correlate best with tumor size and the presence of axillary metastasis, but breast cancer patients at the same stage of disease can have markedly different clinical courses and clinical outcomes (2,6). Although this traditional classification remains relevant in clinical practice, it has been enriched in the past 2 decades by developments in the field of molecular biology, with tumors now also being analyzed in terms of their expression of specific biomarkers. The purpose of this article is to present the molecular classification of breast cancer, illustrate its added value in light of new targeted therapies, and discuss how mammographic and magnetic resonance (MR) imaging findings vary with the subgroups of breast cancer and how MR imaging can help in the evaluation of response to treatment. First, DNA microarray technology, molecular breast biomarkers, and the molecular subtypes of breast cancer are described, with a brief discussion of the molecular characterization of ductal carcinoma in situ (DCIS). The imaging characteristics of the molecular subtypes of breast cancer are detailed, and the role of diffusionweighted MR imaging is presented. Finally, the MR imaging assessment of chemotherapeutic tumor response and the imaging changes induced by specific drugs are discussed. DNA Microarray Technology Technical developments in DNA microarrays are at the root of the recent discoveries in the molecular characterization of disease (7,8). To determine the molecular signature of a breast cancer, scientists must first isolate the genetic material, generally messenger RNA, from the tumor of interest. This RNA can then be tested against specific complementary DNA microarrays to identify which genes the given cancer expresses and which other genes are lacking. DNA microarrays can be likened to a plate on which samples of several thousands of genes of interest can be placed. Incubating messenger RNA from the cancer to be analyzed with this plate containing as many as a million known short sequences from the genes commonly expressed by breast cancers allows one to determine the unique gene expression profile of the given cancer of interest (7). Practically, a small sample of a patient s breast cancer can be processed to isolate the messenger RNA fraction, which can then be incubated with a specific microarray that contains thousands of oligonucleotides that are encountered in breast cancer; sophisticated software can be used to analyze the data obtained from the microarray analysis and to provide a comprehensive and informative portrait of the patient s breast cancer. Molecular Breast Biomarkers It is on the basis of these types of experiments that researchers have been able to define the major subtypes of breast cancer used for classification today. In 2000, Perou and colleagues (9) were the first to propose a molecular classification of breast cancer on the basis of an analysis of 65 breast tumors tested against DNA microarrays representing 8102 genes. These investigators noted that the molecular portraits of the tumors, as revealed in the patterns of gene expression, disclosed some groupings; the tumors clustered in terms of growth rate, in terms of activity of specific signaling pathways, and in terms of their cellular composition. For example, the more proliferative tumors overexpressed genes such as the one for Ki-67, a marker of cellular proliferation; and this expression correlated with increased mitotic indexes at histopathologic examination. More generally, it was noted that breast cancers could be divided into two large categories, depending on the pattern of gene expression. When tumor cells manifested characteristics similar to the epithelial cells lining the milk ducts, expressing, for example, cytokeratin 8/18 and genes associated with the estrogen receptor (ER), the cancers were labeled luminal cancers. Alternatively, when cancer cells displayed characteristics more akin to the myoepithelial cells (also known as basal cells) that line the inner surface of the basement membranes, expressing, for example, cytokeratin 5/6 and laminin, the cancers were grouped into the basal category (9) (Fig 1). Thus, the two large categories of luminal breast cancers and basal breast cancers were defined and dichotomized on the basis of the presence or absence of ERs. ER biology was identified as a key player in breast carcinogenesis, defining the morphology and the clinical behavior of the final tumor, with other parameters, such as tumor grade, a distant second (10,11). Luminal tumors also were generally characterized by an absence 1180 September-October 2014 of overexpression of the gene ERBB2 (also known as the HER2/neu gene), a proto-oncogene that stimulates cellular growth. In addition to ER and HER2/neu expression, many more markers of cell proliferation and invasiveness have been described and analyzed in an effort to better characterize and understand breast cancer heterogeneity (6,11,12), including (a) the p53 gene, TP53, a tumor suppressor gene; (b) the Bcl-2 gene, BCL2, a proto-oncogene involved in the regulation of cell death, or apoptosis; (c) claudin, a protein involved in the harmonious formation of epithelium (13,14); and (d) UPA/PAI1 (urokinase plasminogen activator/plasminogen activator inhibitor 1), which is involved in tumor spread (15). During the past decade, research and clinical usage have led to the adoption of four major molecular subgroups of breast cancer (16). Molecular Subtypes of Breast Cancer Because cancers in each subgroup behave similarly in terms of disease evolution and prognosis, four subgroups of breast cancer have been adopted into routine clinical practice: (a) luminal A tumors, (b) luminal B tumors, (c) human epidermal growth factor receptor 2 (HER2) enriched tumors, and (d) basal-like breast cancer (6,9,10,16) (Table). Luminal A Breast Cancer Luminal A breast cancers are characterized by expression of both ERs and progesterone receptors (PRs). In addition, luminal A cancers are usually low-grade tumors, without amplification of the HER2/neu proto-oncogene and with a low Ki-67 proliferative index (17). Overall, luminal A breast cancer is associated with the most favorable prognosis, with a 5-year survival rate of more than 80% (10,18). This excellent prognosis is in part because expression of steroid hormone receptors is predictive of a favorable response to hormonal therapy. Fortunately, this breast cancer subtype is also the most common one, representing more than 50% of all breast cancers. Luminal B Breast Cancer Luminal B breast cancers also express ERs and PRs but have greater proliferative activity, as can be assessed through Ki-67 levels; these cancers are usually mid- to high-grade tumors (10,17,19). Luminal B breast cancers characteristically do not overexpress HER2/neu, but approximately 30% of them will be HER2-enriched. The prognosis of patients with luminal B breast cancer is often poorer than that for patients with luminal A tumors. Five-year survival rates were approximately 40% when this luminal B subclass Figure 1. Low-power photomicrograph (original magnification, 200; hematoxylin-phloxine-saffron stain) of normal breast tissue shows the two epithelial cell types of the normal duct and lobular system of the breast. Luminal cells line the ducts, and myoepithelial cells abut the basement membrane. From these two types of cells originate the various molecular subgroups of breast cancer. was defined in 2001 (10). Indeed, although ER status and PR status are predictors of response to tamoxifen-based therapies, the clinical outcome cannot reliably be predicted solely from the ER and PR status, and analysis of other cellular markers and tumor characteristics is required for optimal assessment of outcome. HER2-enriched Breast Cancer HER2-positive cancers are defined by overexpression of ERBB2, the gene that encodes one of the four homologous receptors of the epidermal growth factor receptor family the epidermal growth factor receptor type 2 (20). ERBB2 is also known as the HER2/neu gene, where the neu component of the name refers to the rat/ mouse homolog of HER2 (21). Because the HER2/neu gene is a proto-oncogene, its amplification results in increased cellular aggressiveness, with faster growth. The term HER2-enriched breast cancer refers to the molecular classification that groups together tumors most of which overexpress HER2/ neu and manifest features that distinguish them from the luminal and basal molecular subtypes of breast cancer (17). However, not all HER2- enriched breast cancers overexpress HER2/neu (approximately 66% do) (14,17). These tumors as a rule also overexpress genes in the ras pathway, which, like those in the neu pathway, are involved in cell signaling events and cell division and thereby favor tumorigenesis (8). As a result, HER2-enriched breast tumors are generally intermediate- to high-grade tumors, with an aggressive course; initial reports were associated RG Volume 34 Number 5 Trop et al 1181 Four Major Subtypes of Invasive Breast Cancer Used Clinically Subtype Luminal A Luminal B HER2- enriched Basal-like Standard Immunochemical Results and Cancer Grade ER+ PR+ HER2, usually low grade ER+ PR+ HER2, usually intermediate to high grade ER PR HER2+, usually mid to high grade ER PR HER2, high grade Overall 5-year Survival Rate (%)* Frequency (%) Comments Best prognosis, low Ki-67 levels Generally more proliferative (high Ki-67 levels) with less marked hormonal receptor expression than luminal A tumors, approximately 30% are HER2-positive Prognosis much improved since trastuzumab, 30% 40% of tumors also express ERs and PRs Often synonymous with triple negative Note. ER+ = tumor expresses ERs, ER = tumor does not express ERs, PR+ = tumor expresses PRs, PR = tumor does not express PRs, HER2+ = tumor overexpresses HER2/neu, HER2 = tumor does not overexpress HER2/neu. *Data from reference 10. Overall survival rates have improved with new treatment options, particularly trastuzumab therapy for HER2-enriched cancers and new chemotherapy regimens for triple-negative tumors. with a 5-year survival rate of 31% and a high recurrence rate (10). When metastases of HER2- enriched breast cancers occur, they are more likely to involve the brain, compared with luminal breast cancer, in which bone metastatic involvement is most common (22). Approximately 15% 30% of all breast cancers overproduce HER2/neu, including 30% 40% of ER-negative breast cancers (1,23). Fortunately, the development and availability of targeted therapy for HER2-positive cancers have reversed much of the adverse prognostic effect of HER2 overexpression; the introduction of trastuzumab therapy has resulted in a 52% reduction in disease recurrence and a 33% reduction in the death rate (24). In 2006, the U.S. Food and Drug Administration approved trastuzumab for treatment of all HER2-positive breast cancers (1). All invasive breast cancers are now tested for HER2 gene amplification or protein overexpression to identify women who would benefit from this therapy. HER2-enriched cancers may express the steroid hormone receptors ER and PR in approximately 30% 40% of cases (14,17). Compared with women who have tumors that are ER positive and PR positive, women with tumors lacking ER and PR expression have an estimated 1.5-fold to twofold higher risk of death (25,26). Basal-like Breast Cancer The most common basal-type gene signature is the triple-negative (ER-negative, PR-negative, and HER2-negative) type. Biologically, basallike breast cancer is defined not only by the absence of ER, PR, and HER2/neu markers but also by the overexpression of oncogenes that favor cell proliferation and carcinogenesis, for example, c-kit, c-myc, and the epidermal growth factor receptor gene, EGFR (8,27); a high incidence of mutation in the p53 gene is also encountered. There is no universally accepted definition of basal-like breast cancers. Because most basal-like breast cancers are also triple-negative cancers and a majority of triplenegative cancers (approximately 80%) are also basal-like breast cancers, the two terms are often used interchangeably (28), although they are not synonyms. In most clinical studies, investigators describe triple-negative breast cancer, rather than the pure basal-like subtype. It is estimated that 12% 17% of women diagnosed with breast cancer have triple-negative cancer (28). Basal-like breast cancer is more common in BRCA1 mutation carriers and in young black women (8,28,29). Clinically, the basal-like phenotype indicates the possible presence of a germline BRCA1 mutation, particularly when diagnosed in younger women; as they age, the proportion of ER-positive cancer in women with the BRCA1 mutation increases (28). In comparison, BRCA2-related breast cancers are more akin to nonhereditary breast cancer, including the fact that they are less often ER negative than are BRCA1-related breast cancers (28,30). Medullary carcinoma and metaplastic carcinoma are strongly associated with triplenegative breast cancer (31), and their diagnosis 1182 September-October 2014 may also suggest an underlying genetic susceptibility, especially if diagnosed in young women. The increased frequency of triple-negative breast cancer among women of African American origin triple-negative cancer represents 27% of the cancer burden in this group (32) at least partly explains the divergence in breast cancer mortality between African American and white women, with death rates 41% higher in black women compared with white women (1,32). On the other hand, some rare histologic types of breast cancer, such as adenoid cystic and secretory carcinomas, are also characteristically triplenegative cancers yet are associated with a better prognosis than the more common triple-negative infiltrating ductal carcinoma (33). Dent and colleagues (29) reported the findings in a cohort of 1601 women, 180 of whom harbored triple-negative tumors. Compared with other breast cancer subtypes, triple-negative tumors were often larger at the time of diagnosis (64% 2 cm vs 37% 2 cm for other subtypes), involved lymph nodes more frequently (54% vs 46%), and were more often high-grade tumors (66% vs 28%). Interestingly, unlike non triple-negative cancers, there was no linear correlation between tumor size and the likelihood of lymph node involvement for the triple-negative subgroup (28,29,34), and some researchers have even noted a decreased incidence of lymph node involvement in triple-negative cancers compared with other cancer subtypes (28,35). The importance of lymph node involvement appears to be diminished in triple-negative tumors that display a propensity toward node-negative progression and early systemic involvement (28,34,35). Triple-negative cancers also differed from other breast cancer subtypes in their clinical course: Triple-negative cancers had a higher proportion of distant recurrence (34% vs 20%),
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