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Molecular subtypes and imaging phenotypes of breast cancer 1Department of Radiology, Seoul National University Hospital, Seoul; 2Department of Radiology, Seoul National University College of Medicine, Seoul; 3Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Korea http://dx.doi.org/10.14366/usg.16030pISSN: 2288-5919 • eISSN: 2288-5943Ultrasonography 2016;35:281-288 During the last 15 years, traditional breast cancer classifications based on histopathology have been reorganized into the luminal A, luminal B, human epidermal growth factor receptor 2 (HER2), and basal-like subtypes based on gene expression profiling. Each molecular subtype has shown varying risk for progression, response to treatment, and survival outcomes. Research Received: June 23, 2016 linking the imaging phenotype with the molecular subtype has revealed that non-calcified, Revised: July 19, 2016 relatively circumscribed masses with posterior acoustic enhancement are common in the basal- Accepted: July 21, 2016 like subtype, spiculated masses with a poorly circumscribed margin and posterior acoustic Correspondence to:Nariya Cho, MD, Department of shadowing in the luminal subtype, and pleomorphic calcifications in the HER2-enriched subtype. Radiology, Seoul National University Understanding the clinical implications of the molecular subtypes and imaging phenotypes could College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea help radiologists guide precision medicine, tailoring medical treatment to patients and their Tel. +82-2-2072-1862 tumor characteristics. Fax. +82-2-743-6385E-mail: [email protected] Keywords: Breast neoplasms; Gene expression profiling; Ultrasonography; Diagnosis This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ Tumor size, lymph node status, histologic type, histologic grade, and estrogen receptor (ER), or licenses/by-nc/3.0/) which permits unrestricted non- progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) expression status commercial use, distribution, and reproduction in any medium, provided the original work is properly by immunohistochemistry (IHC) have been well established as prognostic and predictive factors for breast cancers. Yet the traditional classifications do not fully reflect the heterogeneity of breast Copyright 2016 Korean Society of cancer. For example, although women with ER-negative or HER2-negative tumors do not respond Ultrasound in Medicine (KSUM) to endocrine or HER2-targeted therapy, respectively, women with ER-positive or HER2-positive tumors tend to show varying responses to each targeted treatment [1]. Thus, there has long been investigation into better classifications to predict outcomes for breast cancer patients.
During the last 15 years, a reshuffling of breast cancer classifications has been underway, from the histopathologic type to the molecular subtype determined by microarray-based gene expression profiling. Today, we recognize that ER-positive breast cancers and ER-negative breast cancers constitute different diseases [1]. In addition, the existence of the four intrinsic subtypes of "luminal A," "luminal B," "HER2-enriched," and "basal-like" has been demonstrated by extensive profiling How to cite this article: Cho N. The molecular subtypes and imaging at the DNA, microRNA, and protein levels by The Cancer Genome Atlas (TCGA) Network [2]. The phenotypes of breast cancer. Ultrasonography. 2016 Oct;35(4):281-288.
intrinsic subtype is similar to the subtype based on mRNA gene expression profiling alone [3]. Ultrasonography 35(4), October 2016 Each subtype has shown different incidence, prognosis, response cancers, all the intrinsic subtypes exist [9]. There are six molecular to treatment, preferential metastatic organs, and recurrence or subtypes of TNBC, as follows: two basal-like (BL1 and BL2) subtypes, disease-free survival outcomes [3,4]. Since 2011, the St. Gallen an immunomodulatory (IM) subtype, a mesenchymal (M) subtype, a International Expert Consensus panel has used the subtype-based mesenchymal stem-like subtype, and a luminal androgen receptor recommendation for systemic therapies for breast cancer. As full subtype [10]. The M group shows the worst outcomes and the IM genetic analysis of breast cancer is not easily available in clinical group shows the best outcomes [8]. Rates of pathologic complete practice due to its high cost and the extensive resources required, response (pCR) following anthracycline/taxane chemotherapy are surrogate definitions of the subtype based on semiquantitative 25%-35%, and patients achieving pCR have better outcomes from IHC scoring of ER, PR, and in situ hybridization tests for HER2 among those patients with TNBC [11]. The distinction between overexpression have been proposed (Table 1) [5]. The most recent basal-like and non-basal-like subtypes within TNBC is important 2015 St. Gallen International Expert Consensus has suggested that for the choice of chemotherapy, in that carboplatin is as effective discrimination between patients who will or will not benefit from as docetaxel in basal-like subtypes, but less so in other intrinsic particular therapies is the key question (Table 2) [6]. subtypes in the metastatic setting [6]. In this article, the clinical implications of breast cancer subtypes Tumor infiltrating lymphocytes are most often found in TNBC or and the imaging phenotypes of each subtype are reviewed to help HER2-positive cancers, and other highly proliferative breast cancers radiologists understand breast cancer biology and identify their roles are associated with increased pCR, longer disease-free survival, and in translational research. improved overall survival outcomes [6]. It has also been suggested that genes involved in immune, inflammatory, and/or chemokine Basal-like Subtype pathways might be related to the prognosis of hormone receptor (HR)-negative tumors, and that proliferation-associated genes are Analysis based on TCGA has confirmed that the basal-like subtype related to the prognosis of HR-positive tumors [1]. is a unique subtype among breast cancers. Basal-like tumors have the worst prognosis, while luminal A tumors have the best. Possible explanations for the differentiation include distinct cell-of-origin (e.g., cancer stem cells) and tumor subtype-specific genetic and Approximately 70% of breast cancers are HR-positive breast epigenetic events for each tumor subtype [7]. As the majority (86%) cancers, and they show a more favorable prognosis than HR-of triple negative breast cancers (TNBC)-those that show as ER- negative breast cancers. Within HR-positive/HER2-negative breast negative, PR-negative, and HER2-negative-correspond to the cancer, 90%-95% of tumors are luminal A and B subtypes [8]. basal-like subtype [8], the terms TNBC and basal-like have been Compared to luminal A tumors, the luminal B subtype tends to show used interchangeably to refer to a tumor subtype. However, within higher expression of proliferation genes [3] and worse baseline the set of TNBC tumors, which make up 10%-20% of all breast distant recurrence-free survival at 5 years and 10 years, regardless Table 1. Surrogate definitions of intrinsic subtypes of breast cancer classification from the St. Gallen Consensus 2013 Clinicopathologic surrogate definition Intrinsic subtype Recurrence riska) Low (if available) Endocrine therapy is often used aloneCytotoxic therapy may be added Luminal B-likec) High (if available) Endocrine therapy for all patients, cytotoxic therapy for most Modified from Goldhirsch A et al. Ann Oncol 2013;24:2206-2223 [5], according to the Creative Commons license.
ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; NA, not applicable.
a)Based on multi-gene-expression assay. b)Between luminal A-like and luminal B-like subtype, PR cut-point of ≥20% best corresponds to luminal A subtype. c)ER-positive and HER2-negative and at least one of: Ki-67 high, PR-negative or low, or recurrence risk high.
Ultrasonography 35(4), October 2016 Molecular subtype of breast cancer of adjuvant systemic therapy, although luminal B tumors do show of HR-positive/HER2-negative tumors [8]. The non-luminal subtypes a higher pCR rate following neoadjuvant chemotherapy [1,8]. In of early breast cancers showed worse outcomes compared to the addition, at 5-year follow-up, basal-like tumors show a worse luminal A subtype when they were treated with 5 years of adjuvant outcome than luminal B tumors, and at around 10-year follow- tamoxifen-only [13]. This study suggests that tumors of the ER- up, the survival curves of luminal B tumors tend to cross those of positive but non-luminal subtype might not benefit from endocrine basal-like tumors [8]. Thus, stratification of luminal A and B tumors, treatment. One study reported that 80% of ER-positive tumors with combined with tumor size and nodal status, allow us to predict low expression (1%-9%) belonged to non-luminal subtypes [14]. resistance to endocrine therapy or to decide the length of endocrine The most influential contribution of microarray-based technology treatment (5 years vs. 10 years) [8]. Numerous studies have has been to the development of commercially available prognostic reported that there are 30% to 44% discordance rates between the signatures, including the 70-gene MammaPrint microarray assay classifications based on gene expression predictors and surrogate (Agendia, Amsterdam, The Netherlands), the 21-gene Oncotype DX classifications using IHC scoring of monoclonal antibody Ki-67 and assay (Genomic Health, Redwood City, CA, USA), and the 50-gene PR status [8,12]. Distinguishing between luminal A-like and luminal PAM50 assay (Prosigna, NanoString Technologies, Seattle, WA, USA) B-like tumors using conventional pathology has proven impractical, [1]. These signatures composed of different gene lists have been as it might not provide a clinically useful threshold [6].
implemented to identify breast cancer patients with good or poor Within HR-positive/HER2-negative tumors, occurrence rates of prognosis based on the expression levels of proliferation-associated the non-luminal subtypes (HER2-enriched and basal-like tumors) genes [1]. Al signatures show the highest discriminatory power by gene expression profiling are as follows: the HER2-enriched for ER-positive tumors, but they have limited use for ER-negative type exists in 5.5%-11.0% and the basal-like type in 1% to 5% tumors, since more than 95% of ER-negative tumors show high Table 2. Treatment-oriented classification of subgroups of breast cancer from the St. Gallen Consensus 2015 Clinical grouping Negative ER, PR, and HER2 Cytotoxic chemotherapy including anthracycline and taxane HR (-) and HER2 (+) ASCO/CAP guidelinesa) T1a node negative: no chemotherapyT1b, c node negative: chemotherapy+trastuzumabHigher T or N stage: anthracycline → taxane with HR (+) and HER2 (+) ASCO/CAP guidelinesa) As above+endocrine therapy HR (+) and HER2 (-) ER and/or PR (+) ≥ 1%b) Multiparameter molecular marker ‘favorable Endocrine therapy alone according to menopausal low proliferation, prognosis' if available High ER/PR and clearly low Ki-67c)Low or absent nodal involvement (N 0-3), smaller T size (T1, T2) Multiparameter molecular marker ‘intermediate' if availablec)Uncertainty persists about degree of risk and responsiveness to endocrine and cytotoxic therapies Multiparameter molecular marker ‘unfavorable Endocrine therapy+adjuvant cytotoxic high proliferation, prognosis' if available; lower ER/PR with clearly chemotherapy in many cases high tumor burden high Ki-67c); more extensive nodal involvement, histological grade 3, extensive lymphovascular invasion, larger T size (T3) Modified from Coates AS et al. Ann Oncol 2015;26:1533-1546 [6], according to the Creative Commons license.
ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; ASCO, American Society of Clinical Oncology; CAP, College of American Pathologists; IHC, immunohistochemistry.
a)IHC of c-erbB-2 staining 3+ score was defined as HER2 positive, and the 0 or 1+ score was negative. For tumors with 2+ score, HER-2 gene copies to the centromeric region of chromosome 17 ratios of 2.2 or more on fluorescence in situ hybridization was interpreted as amplified. b)ER values between 1% and 9% were considered equivocal. Thus, endocrine therapy alone cannot be relied upon for patients with these values. ER (-), ER (+) (1%-10%) tumors were clinicopathologically more similar to ER (-) than ER (+) tumors, but they would be classified as ER (+). c)Ki-67 scores should be interpreted in the light of local laboratory values: as an example, if a laboratory has a median Ki-67 score in receptor-positive disease of 20%, values of 30% or above could be considered clearly high; those of 10% or less clearly low.
Ultrasonography 35(4), October 2016 Table 3. Imaging phenotypes according to the molecular subtypes Clinical grouping A mass with a relatively A distinct mass with a circumscribed margin A mass with rim enhancement and internal circumscribed margin without and posterior acoustic enhancement high signal intensity on T2-weighted MRI Presence of intratumoral necrosis and irregular mass associated with nonresponse to neoadjuvant chemotherapyPeritumoral edema on T2-weighted MRI associated with worse recurrence free survival HR (-) and HER2 (+) Microcalcifications, branching Irregular mass with a not-circumscribed A washout or fast initial kinetics or fine linear calcifications margin (circumscribed margin showing Multicentric and/or multifocal disease were High suspicion for malignancy decreased possibility of HER2 type) more frequently found in HER2 type or luminal High suspicion for malignancy HR (+) and HER2 (-) A mass with a poorly circumscribed margin and posterior acoustic shadowing MRI, magnetic resonance imaging; HR, hormone receptor; HER2, human epidermal growth factor receptor 2.
expression levels of proliferation-related genes [1,15]. been increasingly used, the definition of molecular subtype in the earlier imaging studies has changed from the alternate classification using IHC [20-29] to the intrinsic subtype classification using gene HER2-Enriched Subtype expression profiling techniques [30]. In addition, imaging parameters Tumors with HER2 overexpression are found in 15% to 25% of have changed from the Breast Imaging Reporting and Data System invasive breast cancers and they show a worse prognosis but lexicon [20,24,26-29] to the quantitative parameters derived from respond well to HER2-targeted therapies [16]. Heterogeneous texture analysis using computer-aided analysis software [30]. The intrinsic subtypes exist within HER2-positive tumors, which indicates primary outcome has also changed from distinguishing each subtype the potential for predicting the degree of a patient's response to [20-29] to identifying an association between imaging parameters trastuzumab [6]. Within the HER2 subtype of breast cancer, HR- with response to a treatment [31,32] or recurrence-free survival positive tumors were associated with increased disease-free survival outcomes [32].
and overal survival compared to HR-negative tumors-regardless Imaging phenotypes according to the molecular subtypes of clinicopathologic factors-in the 4-year follow-up to the National are summarized in Table 3. TNBC tends to present as a mass Surgical Adjuvant Breast and Bowel Project B-31 trials [17]. In the with a relatively circumscribed margin, without calcifications first 5-year follow-up results from the National Comprehensive (Fig. 1A) [20]. Absence of associated calcifications and lower Cancer Network centers, more cancer recurrences were reported associated ductal carcinoma in situ suggest rapid progression of from the HR-negative tumor group than the HR-positive tumor malignant transformation, bypassing the stage of in situ [20]. On group [14]. Women with HR-negative/HER2-positive tumors showed ultrasonography (US), a distinct mass with a circumscribed margin less first recurrence in bone and more recurrence in the brain [18]. and posterior acoustic enhancement is frequently reported in TNBC In addition, women with HR-negative/HER2-positive tumors had (Fig. 1B). TNBC showed greater stiffness than ER-positive tumors in a higher pCR rate than those with HR-positive/HER2-positive tumors one study [21], although such stiffness was not consistently found [19]. The pCR rate could be increased to over 70% using a double- in other studies [22,23]. On magnetic resonance imaging (MRI), HER2 blockade treatment either with trastuzumab plus lapatinib a mass with rim enhancement (Fig. 1C) and internal high signal or trastuzumab plus pertuzumab in addition to an anthracycline/ intensity on T2-weighted magnetic resonance (MR) image (Fig. 1D) taxane-based chemotherapy [6]. was frequently reported in TNBC [24-26]. For the prediction of response to a treatment or the survival outcome of TNBC, presence of intratumoral necrosis and irregular mass on MRI were reported to Imaging Phenotype of Breast Cancer Subtypes be associated with nonresponse to neoadjuvant chemotherapy [31] A number of studies regarding imaging features according to the and peritumoral edema on T2-weighted MR image has also been molecular subtypes have been published during the last 15 years. reported to be associated with worse recurrence-free survival [32]. As commercially available microarray-based genetic analysis has With regard to the HR-positive tumor, a poorly circumscribed Ultrasonography 35(4), October 2016

Molecular subtype of breast cancer Fig. 1. A 59-year-old woman with a basal-like breast cancer. A. Mammography shows an irregular mass with an indistinct margin without calcifications. B. Sonograms shows an irregular mass with a circumscribed margin and a posterior acoustic enhancement. C. Gadolinium-enhanced T1-weighted magnetic resonance (MR) image shows an irregular mass with rim-enhancement. D. T2-weighted MR image shows an irregular mass with internal high signal intensity. Histopathology revealed an invasive ductal carcinoma with high histologic grade. Immunohistochemistry analysis showed estrogen receptor -negative, progesterone receptor-negative, human epidermal growth factor receptor 2-negative, cytokeratin 5/6-positive, and Ki-67-30% positive. margin, and posterior acoustic shadowing were associated with enhancement ratio of lesion to background parenchyma on MRI was HR-positive tumors and lower-grade tumors (Fig. 2A, B), whereas a associated with the luminal B subtype [30].
posterior enhancement and a circumscribed margin were associated According to a meta-analysis of the imaging features of with HR-negative or higher-grade tumors [29-31]. Recently, a tumors with HER2 overexpression, several imaging features were study using the TCGA Imaging Archive reported that a higher associated with HER2 overexpression, as follows: presence of Ultrasonography 35(4), October 2016 Fig. 2. A 45-year-old woman with a luminal A-like breast cancer. A. Mammography shows a spiculated mass with calcifications. B. Sonogram shows an irregular mass with spiculated margin and posterior acoustic shadowing. Histopathology revealed an invasive ductal carcinoma with low histologic grade. Immunohistochemistry analysis showed estrogen receptor-85% positive, progesterone receptor-90% positive, and human epidermal growth factor receptor 2-negative. Fig. 3. A 35-year-old woman with a human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A. Mammography shows segmental, pleomorphic, linear branching microcalcifications. B. Songogram shows an il -defined, irregular mass with calcifications within surrounding ductal changes. Histopathology revealed an invasive ductal carcinoma with high histologic grade. Immunohistochemistry analysis showed estrogen receptor-negative and progesterone receptor-negative. HER2 was positive on fluorescence in situ hybridization. microcalcifications, branching or fine linear calcifications, extremely luminal A or basal-like subtype [34].
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Ultrasonography 35(4), October 2016

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