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Kalwaniya DS, Gairola M, Gupta S, Pawan G. Ductal Carcinoma in Situ: A Detailed Review of Current Practices. Cureus 2023; 15:e37932. [PMID: 37220466 PMCID: PMC10200127 DOI: 10.7759/cureus.37932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2023] [Indexed: 05/25/2023] Open
Abstract
Ductal carcinoma in situ is a challenge for breast surgeons, beginning with its difficult radiological detection and continuing with its contentious multimodal treatment and management. It is becoming more common as a result of widespread screening mammography and usually manifests as a cluster of calcifications. Patients are usually asymptomatic or present with a small, palpable lump. It is, however, a premalignant lesion that has the potential to progress to invasive carcinoma and is treated similarly with multimodal therapy. Treatment options currently include total or simple mastectomy with sentinel lymph node biopsy or lumpectomy with radiation. Tamoxifen and human epidermal growth factor receptor two suppression therapy are examples of adjuvant therapy. A review of consensus guidelines and literature was performed, in which we included the available online literature on the concerned topic from 2000-2022. This article is not a complete review of all the available literature; rather, it is a comprehensive review of the topic and its current management guidelines.
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Affiliation(s)
- Dheer S Kalwaniya
- General Surgery, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, IND
| | - Madhur Gairola
- General Surgery, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, IND
| | - Sumedha Gupta
- Obstetrics and Gynaecology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, IND
| | - G Pawan
- General Surgery, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, IND
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2
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Aggarwal V, Miranda O, Johnston PA, Sant S. Three dimensional engineered models to study hypoxia biology in breast cancer. Cancer Lett 2020; 490:124-142. [PMID: 32569616 PMCID: PMC7442747 DOI: 10.1016/j.canlet.2020.05.030] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/13/2020] [Accepted: 05/22/2020] [Indexed: 12/14/2022]
Abstract
Breast cancer is the second leading cause of mortality among women worldwide. Despite the available therapeutic regimes, variable treatment response is reported among different breast cancer subtypes. Recently, the effects of the tumor microenvironment on tumor progression as well as treatment responses have been widely recognized. Hypoxia and hypoxia inducible factors in the tumor microenvironment have long been known as major players in tumor progression and survival. However, the majority of our understanding of hypoxia biology has been derived from two dimensional (2D) models. Although many hypoxia-targeted therapies have elicited promising results in vitro and in vivo, these results have not been successfully translated into clinical trials. These limitations of 2D models underscore the need to develop and integrate three dimensional (3D) models that recapitulate the complex tumor-stroma interactions in vivo. This review summarizes role of hypoxia in various hallmarks of cancer progression. We then compare traditional 2D experimental systems with novel 3D tissue-engineered models giving accounts of different bioengineering platforms available to develop 3D models and how these 3D models are being exploited to understand the role of hypoxia in breast cancer progression.
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Affiliation(s)
- Vaishali Aggarwal
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Oshin Miranda
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Paul A Johnston
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; UPMC-Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Shilpa Sant
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; UPMC-Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, 15261, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
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3
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Yang L, Lu D, Lai Y, Shen M, Yu Q, Lei T, Pu T, Bu H. Prognostic Score-Based Stratification Analysis Reveals Universal Benefits of Radiotherapy on Lowering the Risk of Ipsilateral Breast Event for Ductal Carcinoma In Situ Patients with Different Risk Levels. Ann Surg Oncol 2020; 28:975-984. [PMID: 32794031 DOI: 10.1245/s10434-020-09003-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 07/21/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND We aimed to analyze the effects of radiotherapy (RT) on the incidence rate of ipsilateral breast event (IBE) in ductal carcinoma in situ (DCIS) patients with lumpectomy after being stratified by prognostic score. METHODS We identified DCIS patients who received lumpectomy, from the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2015. Cumulative incidence functions for competing risk were used to evaluate the effects of RT on IBE risk over time. Three multivariate regression models (weighted, non-weighted, and Fine-Gray) were applied to compare the IBE risk between the RT and non-RT groups after stratifying patients by prognostic score. RESULTS Overall, 72,623 DCIS patients were identified from the SEER database and 49,206 (66.8%) patients received RT. During the follow-up period (ranging from 7 to 347 months), the cumulative probability of invasive and in situ IBE was significantly lower in the RT group than in the non-RT group (p < 0.001). After being stratified by prognostic score, the weighted IBE incidence rate increased as the risk level increased (p < 0.050). In multivariate regression models, RT lowered the IBE incidence rate by at least 30% in low-, moderate-, and high-risk DCIS (p < 0.010). In particular, the in situ and invasive IBE incidence rate decreased by over 50% in low-risk DCIS with RT (p < 0.001). CONCLUSIONS RT is associated with a lowered IBE incidence rate in DCIS patients, regardless of the assigned risk levels for patients. The significant reduction in the IBE incidence rate in low-risk DCIS patients also indicates the potential benefits for recommending RT to such a patient population in clinical practice.
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Affiliation(s)
- Libo Yang
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China
| | - Dongli Lu
- Department of Life Sciences, Imperial College London, London, UK
| | - Yutian Lai
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Mengjia Shen
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China
| | - Qiuxiao Yu
- Department of Pathology, Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Ting Lei
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China
| | - Tianjie Pu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Bu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China. .,Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China. .,Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China.
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Discordant Marker Expression Between Invasive Breast Carcinoma and Corresponding Synchronous and Preceding DCIS. Am J Surg Pathol 2020; 43:1574-1582. [PMID: 31206365 DOI: 10.1097/pas.0000000000001306] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Ductal carcinoma in situ (DCIS) is considered a potential precursor of invasive breast carcinoma (IBC). Studies aiming to find markers involved in DCIS progression generally have compared characteristics of IBC lesions with those of adjacent synchronous DCIS lesions. The question remains whether synchronous DCIS and IBC comparisons are a good surrogate for primary DCIS and subsequent IBC. In this study, we compared both primary DCIS and synchronous DCIS with the associated IBC lesion, on the basis of immunohistochemical marker expression. Immunohistochemical analysis of ER, PR, HER2, p53, and cyclo-oxygenase 2 (COX-2) was performed for 143 primary DCIS and subsequent IBC lesions, including 81 IBC lesions with synchronous DCIS. Agreement between DCIS and IBC was assessed using kappa, and symmetry tests were performed to assess the pattern in marker conversion. The primary DCIS and subsequent IBC more often showed discordant marker expression than synchronous DCIS and IBC. Strikingly, 18 of 49 (36%) women with HER2-positive primary DCIS developed an HER2-negative IBC. Such a difference in HER2 expression was not observed when comparing synchronous DCIS and IBC. The frequency of discordant marker expression did not increase with longer time between primary DCIS and IBC. In conclusion, comparison of primary DCIS and subsequent IBC yields different results than a comparison of synchronous DCIS and IBC, in particular with regard to HER2 status. To gain more insight into the progression of DCIS to IBC, it is essential to focus on the relationship between primary DCIS and subsequent IBC, rather than comparing IBC with synchronous DCIS.
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Van Bockstal MR, Agahozo MC, van Marion R, Atmodimedjo PN, Sleddens HFBM, Dinjens WNM, Visser LL, Lips EH, Wesseling J, van Deurzen CHM. Somatic mutations and copy number variations in breast cancers with heterogeneous HER2 amplification. Mol Oncol 2020; 14:671-685. [PMID: 32058674 PMCID: PMC7138394 DOI: 10.1002/1878-0261.12650] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 01/13/2020] [Accepted: 02/13/2020] [Indexed: 12/14/2022] Open
Abstract
Intratumour heterogeneity fuels carcinogenesis and allows circumventing specific targeted therapies. HER2 gene amplification is associated with poor outcome in invasive breast cancer. Heterogeneous HER2 amplification has been described in 5-41% of breast cancers. Here, we investigated the genetic differences between HER2-positive and HER2-negative admixed breast cancer components. We performed an in-depth analysis to explore the potential heterogeneity in the somatic mutational landscape of each individual tumour component. Formalin-fixed, paraffin-embedded breast cancer tissue of ten patients with at least one HER2-negative and at least one HER2-positive component was microdissected. Targeted next-generation sequencing was performed using a customized 53-gene panel. Somatic mutations and copy number variations were analysed. Overall, the tumours showed a heterogeneous distribution of 12 deletions, 9 insertions, 32 missense variants and 7 nonsense variants in 26 different genes, which are (likely) pathogenic. Three splice site alterations were identified. One patient had an EGFR copy number gain restricted to a HER2-negative in situ component, resulting in EGFR protein overexpression. Two patients had FGFR1 copy number gains in at least one tumour component. Two patients had an 8q24 gain in at least one tumour component, resulting in a copy number increase in MYC and PVT1. One patient had a CCND1 copy number gain restricted to a HER2-negative tumour component. No common alternative drivers were identified in the HER2-negative tumour components. This series of 10 breast cancers with heterogeneous HER2 gene amplification illustrates that HER2 positivity is not an unconditional prerequisite for the maintenance of tumour growth. Many other molecular aberrations are likely to act as alternative or collaborative drivers. This study demonstrates that breast carcinogenesis is a dynamically evolving process characterized by a versatile somatic mutational profile, of which some genetic aberrations will be crucial for cancer progression, and others will be mere 'passenger' molecular anomalies.
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Affiliation(s)
| | | | - Ronald van Marion
- Department of PathologyErasmus MC Cancer Institute RotterdamThe Netherlands
| | | | | | | | - Lindy L. Visser
- Division of Molecular PathologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
| | - Esther H. Lips
- Division of Molecular PathologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
| | - Jelle Wesseling
- Division of Molecular PathologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
- Department of PathologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
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Breast Ductal Carcinoma in Situ: Precursor to Invasive Breast Cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 189:942-945. [PMID: 31029232 DOI: 10.1016/j.ajpath.2019.03.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 03/12/2019] [Accepted: 03/12/2019] [Indexed: 02/06/2023]
Abstract
This Editorial introduces this month's special Breast Ductal Carcinoma in Situ Theme Issue, a series of reviews intended to highlight the relationship of ductal carcinoma in situ as a precursor to breast cancer and emphasize the need for appropriate treatment in hopes of minimizing the progression to invasive disease.
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Dessources K, Sebastiao APM, Pareja F, Weigelt B, Reis-Filho JS. How Did We Get There? The Progression from Ductal Carcinoma In Situ to Invasive Ductal Carcinoma. CURRENT BREAST CANCER REPORTS 2019. [DOI: 10.1007/s12609-019-00318-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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8
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Estrogen Receptor-positive Ductal Carcinoma In Situ Frequently Overexpresses HER2 Protein Without Gene Amplification. Am J Surg Pathol 2019; 43:1221-1228. [DOI: 10.1097/pas.0000000000001300] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Ductal Carcinoma In Situ Management: All or Nothing, or Something in between? CURRENT BREAST CANCER REPORTS 2019. [DOI: 10.1007/s12609-019-0306-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Goh CW, Wu J, Ding S, Lin C, Chen X, Huang O, Chen W, Li Y, Shen K, Zhu L. Invasive ductal carcinoma with coexisting ductal carcinoma in situ (IDC/DCIS) versus pure invasive ductal carcinoma (IDC): a comparison of clinicopathological characteristics, molecular subtypes, and clinical outcomes. J Cancer Res Clin Oncol 2019; 145:1877-1886. [PMID: 31089799 DOI: 10.1007/s00432-019-02930-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 05/06/2019] [Indexed: 12/26/2022]
Abstract
PURPOSE Ductal carcinoma in situ (DCIS) is widely recognized as the precursor of invasive ductal carcinoma (IDC). We aimed to analyze the clinicopathological characteristics and clinical outcomes of coexisting DCIS component in IDC and its clinical significance according to molecular subtypes. METHODS Data from 3001 patients with IDC (79.4%) and IDC/DCIS (20.6%) who underwent surgery from January 2009 to June 2016 were retrospectively assessed. The clinical outcomes of IDC with coexistent DCIS in different molecular subtypes were evaluated. RESULTS IDC/DCIS patients were more likely to be younger (P < 0.001), had low tumor grade (P = 0.001), had less lymph node involvement (P = 0.038) and received more mastectomy (P = 0.002) than IDC patients. In the comparison of molecular subtype prevalence, IDC/DCIS patients were more frequently presented with luminal B/HER2 positive (12.5% vs 11.0%, P < 0.001) and HER2 positive subtypes (20.9% vs 9.8%, P < 0.001). The 5-year disease-free survival (DFS, 90.9% vs 87.5%, P = 0.021) and 5-year overall survival (OS 96.1% vs 94.0%, P = 0.018) were significantly improved in IDC/DCIS patients compared to IDC patients. In multivariate analysis, the presence of coexisting DCIS (P = 0.048), tumor size (P < 0.001), lymph node status (P < 0.001), lymphovascular invasion (P = 0.007) and molecular subtypes (P < 0.001) were independent prognostic factors for DFS. Furthermore, coexistence of DCIS component in IDC significantly improved DFS in HER2 positive (94.8% vs 78.5%, P = 0.003), but had no association in luminal and triple negative subtypes. CONCLUSIONS IDC with coexisting DCIS was associated with improved prognosis. Patients with IDC/DCIS presented with more HER2 positive expression and might improve DFS in HER2 positive breast cancer.
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MESH Headings
- Breast Neoplasms/classification
- Breast Neoplasms/metabolism
- Breast Neoplasms/mortality
- Breast Neoplasms/pathology
- Carcinoma, Ductal, Breast/classification
- Carcinoma, Ductal, Breast/metabolism
- Carcinoma, Ductal, Breast/mortality
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Intraductal, Noninfiltrating/classification
- Carcinoma, Intraductal, Noninfiltrating/metabolism
- Carcinoma, Intraductal, Noninfiltrating/mortality
- Carcinoma, Intraductal, Noninfiltrating/pathology
- Female
- Humans
- Kaplan-Meier Estimate
- Lymphatic Metastasis
- Middle Aged
- Neoplasm Grading
- Neoplasm Staging
- Retrospective Studies
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Affiliation(s)
- Chih Wan Goh
- Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Jiayi Wu
- Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Shuning Ding
- Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Caijin Lin
- Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Xiaosong Chen
- Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Ou Huang
- Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Weiguo Chen
- Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Yafen Li
- Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Kunwei Shen
- Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Li Zhu
- Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
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Miligy IM, Toss MS, Gorringe KL, Lee AHS, Ellis IO, Green AR, Rakha EA. The clinical and biological significance of HER2 over-expression in breast ductal carcinoma in situ: a large study from a single institution. Br J Cancer 2019; 120:1075-1082. [PMID: 31065110 PMCID: PMC6738110 DOI: 10.1038/s41416-019-0436-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Revised: 03/04/2019] [Accepted: 03/07/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Previous studies have reported up to 50% of ductal carcinoma in situ (DCIS), is HER2 positive, but the frequency of HER2-positive invasive breast cancer (IBC) is lower. The aim of this study is to characterise HER2 status in DCIS and assess its prognostic value. METHODS HER2 status was evaluated in a large series of DCIS (n = 868), including pure DCIS and DCIS associated with IBC, prepared as tissue microarrays (TMAs). HER2 status was assessed using immunohistochemistry (IHC) and chromogenic in situ hybridisation (CISH). RESULTS In pure DCIS, HER2 protein was over-expressed in 9% of DCIS (3+), whereas 15% were HER2 equivocal (2+). Using CISH, the final HER2 status was positive in 20%. In mixed DCIS, HER2 amplification of the DCIS component was detected in 15% with amplification in the invasive component of only 12%. HER2-positive DCIS was associated with features of aggressiveness (p < 0.0001) and more frequent local recurrence (p = 0.03). On multivariate analysis, combined HER2+/Ki67+ profile was an independent predictor of local recurrence (p = 0.006). CONCLUSIONS The frequency of HER2 positivity in DCIS is comparable to IBC- and HER2-positive DCIS is associated with features of poor prognosis. The majority of HER2 over-expression in DCIS is driven by gene amplification.
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Affiliation(s)
- Islam M Miligy
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, Nottingham City Hospital, The University of Nottingham, Nottingham, UK.,Histopathology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Michael S Toss
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, Nottingham City Hospital, The University of Nottingham, Nottingham, UK.,Histopathology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Kylie L Gorringe
- Cancer Genomics Program, Peter MacCallum Cancer Centre, Melbourne, University of Melbourne, Parkville, Australia.,The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia
| | - Andrew H S Lee
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, Nottingham City Hospital, The University of Nottingham, Nottingham, UK
| | - Ian O Ellis
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, Nottingham City Hospital, The University of Nottingham, Nottingham, UK
| | - Andrew R Green
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, Nottingham City Hospital, The University of Nottingham, Nottingham, UK
| | - Emad A Rakha
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, Nottingham City Hospital, The University of Nottingham, Nottingham, UK. .,Histopathology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt.
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Lei JT, Gou X, Seker S, Ellis MJ. ESR1 alterations and metastasis in estrogen receptor positive breast cancer. ACTA ACUST UNITED AC 2019; 5. [PMID: 31106278 PMCID: PMC6519472 DOI: 10.20517/2394-4722.2019.12] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Endocrine therapy is essential for the treatment of patients with estrogen receptor positive (ER+) breast cancer, however, resistance and the development of metastatic disease is common. Understanding how ER+ breast cancer metastasizes is critical since the major cause of death in breast cancer is metastasis to distant organs. Results from many studies suggest dysregulation of the estrogen receptor alpha gene (ESR1 ) contributes to therapeutic resistance and metastatic biology. This review covers both pre-clinical and clinical evidence on the spectrum of ESR1 alterations including amplification, point mutations, and genomic rearrangement events driving treatment resistance and metastatic potential of ER+ breast cancer. Importantly, we describe how these ESR1 alterations may provide therapeutic opportunities to improve outcomes in patients with lethal, metastatic breast cancer.
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Affiliation(s)
- Jonathan T Lei
- Interdepartmental Graduate Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.,Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Xuxu Gou
- Interdepartmental Graduate Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.,Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sinem Seker
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Matthew J Ellis
- Interdepartmental Graduate Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.,Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.,Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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13
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Kader T, Hill P, Zethoven M, Goode DL, Elder K, Thio N, Doyle M, Semple T, Sufyan W, Byrne DJ, Pang JMB, Murugasu A, Miligy IM, Green AR, Rakha EA, Fox SB, Mann GB, Campbell IG, Gorringe KL. Atypical ductal hyperplasia is a multipotent precursor of breast carcinoma. J Pathol 2019; 248:326-338. [PMID: 30843206 DOI: 10.1002/path.5262] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 02/28/2019] [Accepted: 03/04/2019] [Indexed: 12/18/2022]
Abstract
The current model for breast cancer progression proposes independent 'low grade (LG)-like' and 'high grade (HG)-like' pathways but lacks a known precursor to HG cancer. We applied low-coverage whole-genome sequencing to atypical ductal hyperplasia (ADH) with and without carcinoma to shed light on breast cancer progression. Fourteen out of twenty isolated ADH cases harboured at least one copy number alteration (CNA), but had fewer aberrations than LG or HG ductal carcinoma in situ (DCIS). ADH carried more HG-like CNA than LG DCIS (e.g. 8q gain). Correspondingly, 64% (7/11) of ADH cases with synchronous HG carcinoma were clonally related, similar to LG carcinoma (67%, 6/9). This study represents a significant shift in our understanding of breast cancer progression, with ADH as a common precursor lesion to the independent 'low grade-like' and 'high grade-like' pathways. These data suggest that ADH can be a precursor of HG breast cancer and that LG and HG carcinomas can evolve from a similar ancestor lesion. We propose that although LG DCIS may be committed to a LG molecular pathway, ADH may remain multipotent, progressing to either LG or HG carcinoma. This multipotent nature suggests that some ADH cases could be more clinically significant than LG DCIS, requiring biomarkers for personalising management. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Tanjina Kader
- Peter MacCallum Cancer Centre, Melbourne, Australia.,The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
| | - Prue Hill
- Department of Anatomical Pathology, St Vincent's Hospital, Fitzroy, Australia
| | | | - David L Goode
- Peter MacCallum Cancer Centre, Melbourne, Australia.,The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
| | - Kenneth Elder
- The Breast Service, The Royal Women's Hospital, Melbourne, Australia
| | - Niko Thio
- Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Maria Doyle
- Peter MacCallum Cancer Centre, Melbourne, Australia
| | | | - Wajiha Sufyan
- Territory Pathology, Royal Darwin Hospital, Darwin, Australia
| | | | | | - Anand Murugasu
- The Breast Service, The Royal Women's Hospital, Melbourne, Australia
| | - Islam M Miligy
- Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.,Department of Histopathology, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham, UK
| | - Andrew R Green
- Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.,Department of Histopathology, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham, UK
| | - Emad A Rakha
- Division of Cancer and Stem Cells, Nottingham Breast Cancer Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.,Department of Histopathology, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham, UK
| | | | - G Bruce Mann
- The Breast Service, The Royal Women's Hospital, Melbourne, Australia
| | - Ian G Campbell
- Peter MacCallum Cancer Centre, Melbourne, Australia.,The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.,Department of Clinical Pathology, The University of Melbourne, Parkville, Australia
| | - Kylie L Gorringe
- Peter MacCallum Cancer Centre, Melbourne, Australia.,The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.,Department of Clinical Pathology, The University of Melbourne, Parkville, Australia
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14
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Brock EJ, Ji K, Shah S, Mattingly RR, Sloane BF. In Vitro Models for Studying Invasive Transitions of Ductal Carcinoma In Situ. J Mammary Gland Biol Neoplasia 2019; 24:1-15. [PMID: 30056557 PMCID: PMC6641861 DOI: 10.1007/s10911-018-9405-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 07/13/2018] [Indexed: 12/11/2022] Open
Abstract
About one fourth of all newly identified cases of breast carcinoma are diagnoses of breast ductal carcinoma in situ (DCIS). Since we cannot yet distinguish DCIS cases that would remain indolent from those that may progress to life-threatening invasive ductal carcinoma (IDC), almost all women undergo aggressive treatment. In order to allow for more rational individualized treatment, we and others are developing in vitro models to identify and validate druggable pathways that mediate the transition of DCIS to IDC. These models range from conventional two-dimensional (2D) monolayer cultures on plastic to 3D cultures in natural or synthetic matrices. Some models consist solely of DCIS cells, either cell lines or primary cells. Others are co-cultures that include additional cell types present in the normal or cancerous human breast. The 3D co-culture models more accurately mimic structural and functional changes in breast architecture that accompany the transition of DCIS to IDC. Mechanistic studies of the dynamic and temporal changes associated with this transition are facilitated by adapting the in vitro models to engineered microfluidic platforms. Ultimately, the goal is to create in vitro models that can serve as a reproducible preclinical screen for testing therapeutic strategies that will reduce progression of DCIS to IDC. This review will discuss the in vitro models that are currently available, as well as the progress that has been made using them to understand DCIS pathobiology.
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MESH Headings
- Breast/pathology
- Breast Neoplasms/drug therapy
- Breast Neoplasms/pathology
- Carcinoma, Ductal, Breast/drug therapy
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Intraductal, Noninfiltrating/drug therapy
- Carcinoma, Intraductal, Noninfiltrating/pathology
- Cell Line, Tumor
- Coculture Techniques/methods
- Drug Screening Assays, Antitumor/methods
- Female
- Humans
- Neoplasm Invasiveness/pathology
- Neoplasm Invasiveness/prevention & control
- Primary Cell Culture/methods
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Affiliation(s)
- Ethan J Brock
- Program in Cancer Biology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Kyungmin Ji
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Seema Shah
- Program in Cancer Biology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Raymond R Mattingly
- Program in Cancer Biology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Bonnie F Sloane
- Program in Cancer Biology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
- Department of Pharmacology, Wayne State University, 540 E. Canfield, Detroit, MI, 48201, USA.
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15
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Hui Y, Lu S, Wang H, Resnick MB, Wang Y. Discordant HER2 immunohistochemical expression and gene amplification in ductal carcinoma in situ
- evaluating HER2 in synchronous in-situ
and invasive carcinoma. Histopathology 2018; 74:358-362. [DOI: 10.1111/his.13731] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Yiang Hui
- Department of Pathology; Rhode Island Hospital and Lifespan Medical Center; Providence RI USA
| | - Shaolei Lu
- Department of Pathology; Rhode Island Hospital and Lifespan Medical Center; Providence RI USA
| | - Hai Wang
- Department of Pathology; Rhode Island Hospital and Lifespan Medical Center; Providence RI USA
| | - Murray B. Resnick
- Department of Pathology; Rhode Island Hospital and Lifespan Medical Center; Providence RI USA
| | - Yihong Wang
- Department of Pathology; Rhode Island Hospital and Lifespan Medical Center; Providence RI USA
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16
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Shee K, Muller KE, Marotti J, Miller TW, Wells WA, Tsongalis GJ. Ductal Carcinoma in Situ Biomarkers in a Precision Medicine Era: Current and Future Molecular-Based Testing. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 189:956-965. [PMID: 30385093 DOI: 10.1016/j.ajpath.2018.08.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 08/09/2018] [Accepted: 08/30/2018] [Indexed: 12/18/2022]
Abstract
Historically, ductal carcinoma in situ (DCIS) of the breast has been managed aggressively with surgery and radiotherapy because of a risk of progression to invasive ductal carcinoma. However, this treatment paradigm has been challenged by overtreatment concerns and evidence that suggests that DCIS can be stratified according to risk of recurrence or risk of progression to invasive disease. Traditional methods of risk stratification include histologic grade and hormone receptor status. Recent technological advancements have enabled an era of precision medicine, where DCIS can be molecularly analyzed by tools, such as next-generation DNA and RNA sequencing, to identify molecular biomarkers for risk stratification. These findings have led to the development of tools such as the Oncotype DX Breast DCIS Score, a gene expression-based assay with the potential to prevent overtreatment in low-risk disease.
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Affiliation(s)
- Kevin Shee
- Department of Molecular & Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon
| | - Kristen E Muller
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
| | - Jonathan Marotti
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
| | - Todd W Miller
- Department of Molecular & Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon
| | - Wendy A Wells
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
| | - Gregory J Tsongalis
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire.
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17
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Kitamura M, Nakayama T, Mukaisho KI, Mori T, Umeda T, Moritani S, Kushima R, Tani M, Sugihara H. Progression Potential of Ductal Carcinoma in situ Assessed by Genomic Copy Number Profiling. Pathobiology 2018; 86:92-101. [PMID: 30332671 DOI: 10.1159/000492833] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 08/06/2018] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Ductal carcinoma in situ (DCIS) of the breast is heterogeneous in terms of the risk of progression to invasive ductal carcinoma (IDC). To treat DCIS appropriately for its progression risk, we classified individual DCIS by its profile of genomic changes into 2 groups and correlated them with clinicopathological progression factors. METHODS We used surgically resected, formalin-fixed, paraffin-embedded tissues of 22 DCIS and 30 IDC lesions. We performed immunohistochemical intrinsic subtyping, array-based comparative genomic hybridization, and unsupervised clustering. RESULTS The samples were divided into 2 major clusters, A and B. Cluster A showed a greater number of gene and chromosome copy number alterations, a larger IDC/DCIS ratio, a higher frequency of nonluminal subtype, a lower frequency of luminal subtype, and a higher nuclear grade, when compared with cluster B. However, there was no difference in the frequencies of lymph node metastasis between clusters A and B. We identified 9 breast-cancer-related genes, including TP53 and GATA3, that highly contributed to the discrimination of A and B clusters. CONCLUSION Classification of breast tumors into rapidly progressive cluster A and the other (cluster B) may contribute to select the treatment appropriate for their progression risk.
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Affiliation(s)
- Mina Kitamura
- Division of Molecular Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Otsu, Japan.,Division of Digestive, Breast and General Surgery, Department of Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Takahisa Nakayama
- Division of Molecular Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Ken-Ichi Mukaisho
- Division of Molecular Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Tsuyoshi Mori
- Division of Digestive, Breast and General Surgery, Department of Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Tomoko Umeda
- Division of Digestive, Breast and General Surgery, Department of Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Suzuko Moritani
- Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan
| | - Ryoji Kushima
- Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan
| | - Masaji Tani
- Division of Digestive, Breast and General Surgery, Department of Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Hiroyuki Sugihara
- Division of Molecular Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Otsu, Japan,
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18
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Vermeulen MA, Doebar SC, van Deurzen CHM, Martens JWM, van Diest PJ, Moelans CB. Copy number profiling of oncogenes in ductal carcinoma in situ of the male breast. Endocr Relat Cancer 2018; 25:173-184. [PMID: 29203614 DOI: 10.1530/erc-17-0338] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 12/04/2017] [Indexed: 01/09/2023]
Abstract
Characterizing male breast cancer (BC) and unraveling male breast carcinogenesis is challenging because of the rarity of this disease. We investigated copy number status of 22 BC-related genes in 18 cases of pure ductal carcinoma in situ (DCIS) and in 49 cases of invasive carcinoma (IC) with adjacent DCIS (DCIS-AIC) in males using multiplex ligation-dependent probe amplification (MLPA). Results were compared to female BC and correlated with survival. Overall, copy number ratio and aberration frequency including all 22 genes showed no significant difference between the 3 groups. Individual unpaired analysis revealed a significantly higher MTDH copy number ratio in IC compared to DCIS-AIC and pure DCIS (P = 0.009 and P = 0.038, respectively). ADAM9 showed a significantly lower copy number aberration frequency in male BC, compared to female BC (P = 0.020). In DCIS-AIC, MTDH, CPD, CDC6 and TOP2A showed a lower frequency of copy number increase in males compared to females (P < 0.001 for all 4 genes). In IC, CPD gain and CCNE1 gain were independent predictors of poor overall survival. In conclusion, male DCIS and IC showed a similar copy number profile for 21 out of 22 interrogated BC-related genes, illustrating their clonal relation and the genetically advanced state of male DCIS. MTDH showed a higher copy number ratio in IC compared to adjacent and pure DCIS and may therefore play a role in male breast carcinogenesis. Differences were detected between male and female DCIS for 4 genes pointing to differences in breast carcinogenesis between the sexes.
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Affiliation(s)
- Marijn A Vermeulen
- Department of PathologyUniversity Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Shusma C Doebar
- Department of PathologyErasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Carolien H M van Deurzen
- Department of PathologyErasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
- BOOG Study Center/Dutch Breast Cancer Research GroupAmsterdam, The Netherlands
| | - John W M Martens
- BOOG Study Center/Dutch Breast Cancer Research GroupAmsterdam, The Netherlands
- Department of Medical Oncology and Cancer Genomics NetherlandsErasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Paul J van Diest
- Department of PathologyUniversity Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Cathy B Moelans
- Department of PathologyUniversity Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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19
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Laird J, Lok B, Siu C, Cahlon O, Khan AJ, McCormick B, Powell SN, Cody H, Wen HY, Ho A, Braunstein LZ. Impact of an In Situ Component on Outcome After In-Breast Tumor Recurrence in Patients Treated with Breast-Conserving Therapy. Ann Surg Oncol 2017; 25:154-163. [PMID: 29094250 DOI: 10.1245/s10434-017-6209-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Indexed: 01/30/2023]
Abstract
BACKGROUND Among all in-breast tumor recurrences (IBTR) following breast-conserving therapy (BCT), some comprise metachronous new primaries (NPs) while others are true recurrences (TRs). Establishing this distinction remains a challenge. METHODS We studied 3932 women who underwent BCT for stage I-III breast cancer from 1998 to 2008. Of these, 115 (2.9%) had an IBTR. Excluding patients with inoperable/unresectable recurrences or simultaneous distant metastases, 81 patients with isolated IBTR comprised the study population. An IBTR was categorized as an NP rather than a TR if it included an in situ component. The log-rank test and Kaplan-Meier method were used to evaluate disease-free survival (DFS) and overall survival (OS), and univariate and multivariate analyses were performed using Cox proportional hazards regression models. RESULTS At a median of 64.5 months from IBTR diagnosis, 28 of 81 patients had DFS events. Five-year DFS was 43.1% in the TR group (p = 0.0001) versus 80.3% in the NP group, while 5-year OS was 59.7% in the TR group versus 91.7% among those with NPs (p = 0.0011). On univariate analysis, increasing tumor size, high grade, positive margins, lymphovascular invasion, node involvement, lack of axillary surgery, chemotherapy, radiation therapy, and IBTR type (TR vs. NP) were significantly associated with worse DFS. Controlling for tumor size and margin status, TRs remained significantly associated with lower DFS (hazard ratio 3.717, 95% confidence interval 1.607-8.595, p = 0.002). CONCLUSION The presence of an in situ component is associated with prognosis among patients with IBTR following BCT and may be useful in differentiating TRs and NPs.
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Affiliation(s)
- James Laird
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,New York University School of Medicine, New York, NY, USA
| | - Benjamin Lok
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Chun Siu
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Oren Cahlon
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Atif J Khan
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Beryl McCormick
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Simon N Powell
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hiram Cody
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hannah Yong Wen
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alice Ho
- Department of Radiation Oncology, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Lior Z Braunstein
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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20
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Gorringe KL, Fox SB. Ductal Carcinoma In Situ Biology, Biomarkers, and Diagnosis. Front Oncol 2017; 7:248. [PMID: 29109942 PMCID: PMC5660056 DOI: 10.3389/fonc.2017.00248] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 10/02/2017] [Indexed: 12/21/2022] Open
Abstract
Ductal carcinoma in situ (DCIS) is an often-diagnosed breast disease and a known, non-obligate, precursor to invasive breast carcinoma. In this review, we explore the clinical and pathological features of DCIS, fundamental elements of DCIS biology including gene expression and genetic events, the relationship of DCIS with recurrence and invasive breast cancer, and the interaction of DCIS with the microenvironment. We also survey how these various elements are being used to solve the clinical conundrum of how to optimally treat a disease that has potential to progress, and yet is also likely over-treated in a significant proportion of cases.
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Affiliation(s)
- Kylie L. Gorringe
- Cancer Genomics Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
| | - Stephen B. Fox
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
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21
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Guo P, Pu T, Chen S, Qiu Y, Zhong X, Zheng H, Chen L, Bu H, Ye F. Breast cancers with EGFR and HER2 co-amplification favor distant metastasis and poor clinical outcome. Oncol Lett 2017; 14:6562-6570. [PMID: 29181099 PMCID: PMC5696709 DOI: 10.3892/ol.2017.7051] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 02/28/2017] [Indexed: 02/05/2023] Open
Abstract
ErbB signaling serves essential roles in invasive ductal carcinoma (IDC). The aim of the present study was to assess gene amplification in ErbB family members in IDC with clinical implications. Quantitative polymerase chain reaction and fluorescence in situ hybridization were performed on formalin-fixed paraffin-embedded tumor samples for gene amplification detection. The clinical and histopathological characteristics, as well as the prognostic significance, were analyzed. Among the 119 IDC patients evaluated, epidermal growth factor receptor [EGFR; also known as human epidermal growth factor receptor (HER)1], HER2, HER3 and HER4 gene amplification was observed in 30 (25.2%), 44 (36.9%), 0 (0.0%) and 1 (0.8%) patients, respectively. EGFR amplification was associated with estrogen receptor status (P=0.028) and higher possibilities of recurrence (P=0.015) and distant metastasis (following initial surgery) (P=0.011). In survival analysis, EGFR amplification was also associated with disease-free survival (DFS) (P=0.001) and overall survival (OS) (P=0.003). HER2 amplification was associated with larger tumor size (P=0.006), later clinical stage (P=0.003) and distant metastasis (following initial surgery) (P=0.006). In survival analysis, HER2 amplification was also associated with DFS (P=0.011). Notably, the present study identified a group of patients in whom EGFR and HER2 were co-amplified. This group of patients appeared to have a higher possibility of metastasis (when diagnosed) (P=0.014) and distant metastasis (following initial surgery) (P<0.001). In survival analysis, these patients were noticed to be associated with DFS (P<0.001) and OS (P=0.002). With respect to treatment regimen, this was also true for the DFS association with chemotherapy (P<0.001), radiotherapy (P<0.001) and hormonal therapy (P=0.001). The present results suggest that EGFR and HER2 amplification favor distant metastasis following initial surgery and are significantly associated with poor clinical outcome in breast cancer patients.
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Affiliation(s)
- Peng Guo
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Tianjie Pu
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.,Department of Pathology, State Key Laboratory of Biotherapy, National Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Shinan Chen
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yan Qiu
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.,Department of Pathology, State Key Laboratory of Biotherapy, National Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiaorong Zhong
- Cancer Center, State Key Laboratory of Biotherapy, National Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.,Laboratory of Molecular Diagnosis of Cancer, State Key Laboratory of Biotherapy, National Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hong Zheng
- Cancer Center, State Key Laboratory of Biotherapy, National Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.,Laboratory of Molecular Diagnosis of Cancer, State Key Laboratory of Biotherapy, National Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lina Chen
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hong Bu
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.,Department of Pathology, State Key Laboratory of Biotherapy, National Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Feng Ye
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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22
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Lambein K, Van Bockstal M, Vandemaele L, Van den Broecke R, Cocquyt V, Geenen S, Denys H, Libbrecht L. Comparison of HER2 amplification status among breast cancer subgroups offers new insights in pathways of breast cancer progression. Virchows Arch 2017; 471:575-587. [PMID: 28567637 DOI: 10.1007/s00428-017-2161-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 05/09/2017] [Accepted: 05/22/2017] [Indexed: 12/21/2022]
Abstract
Although the prognostic and predictive significance of human epidermal growth factor receptor 2 (HER2) in invasive breast cancer is well established, its role in ductal carcinoma in situ (DCIS) remains unclear. Reports on combined evaluation of both HER2 protein expression and HER2 amplification status in pure DCIS and DCIS adjacent to invasive ductal carcinoma (i.e., admixed DCIS) are scarce. In this study, immunohistochemistry and fluorescence in situ hybridization (FISH) were used to assess HER2 status in 72 cases of pure DCIS, 73 cases of DCIS admixed with invasive ductal carcinoma (IDC), and 60 cases of pure IDC. HER2 copy number-based amplification was present in 49% of pure DCIS, 16% of admixed DCIS, 18% of admixed IDC, and 8% of pure IDC. Amplified pure DCIS with clusters of HER2 signals showed a significantly lower HER2 copy number than amplified admixed DCIS with clusters. Whereas pure DCIS and admixed DCIS presented significant differences, the in situ and invasive component of admixed tumors showed striking similarities regarding mean HER2 and chromosome 17 centromere (CEP17) copy number, grade, and estrogen and progesterone receptor expression. The discrepant prevalence of HER2 amplification among breast cancer subgroups indirectly suggests that HER2 may not play a crucial role in the transition of in situ to invasive breast cancer. The similarities in HER2 amplification status between the in situ and invasive component of admixed tumors hint at a common biological pathway for both components. Our data support the theory that pure DCIS, pure IDC, and admixed lesions have a common progenitor, but can progress as separate lineages.
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MESH Headings
- Adult
- Aged
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/genetics
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Intraductal, Noninfiltrating/genetics
- Carcinoma, Intraductal, Noninfiltrating/pathology
- Disease Progression
- Female
- Gene Amplification
- Humans
- Middle Aged
- Receptor, ErbB-2/genetics
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Affiliation(s)
- Kathleen Lambein
- Department of Pathology, AZ St Lucas Hospital, Groenebriel 1, 9000, Ghent, Belgium
- Department of Oncology, KU Leuven, Surgical Oncology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium
| | - Mieke Van Bockstal
- Department of Medical and Forensic Pathology, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Lies Vandemaele
- Department of Medical and Forensic Pathology, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium
| | - Rudy Van den Broecke
- Department of Gynaecology, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium
| | - Veronique Cocquyt
- Department of Medical Oncology, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium
| | - Sofie Geenen
- Department of Medical and Forensic Pathology, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium
| | - Hannelore Denys
- Department of Medical Oncology, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium
| | - Louis Libbrecht
- Department of Medical and Forensic Pathology, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium.
- Department of Pathology, University Clinics St Luc, Hippokrateslaan 10, 1200, Sint-Lambrechts-Woluwe, Belgium.
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23
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Groen EJ, Elshof LE, Visser LL, Rutgers EJT, Winter-Warnars HA, Lips EH, Wesseling J. Finding the balance between over- and under-treatment of ductal carcinoma in situ (DCIS). Breast 2017; 31:274-283. [DOI: 10.1016/j.breast.2016.09.001] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 08/19/2016] [Accepted: 09/01/2016] [Indexed: 12/21/2022] Open
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24
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Shah V, Nowinski S, Levi D, Shinomiya I, Kebaier Ep Chaabouni N, Gillett C, Grigoriadis A, Graham TA, Roylance R, Simpson MA, Pinder SE, Sawyer EJ. PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression. Breast Cancer Res 2017; 19:7. [PMID: 28095868 PMCID: PMC5240238 DOI: 10.1186/s13058-016-0789-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 12/01/2016] [Indexed: 11/17/2022] Open
Abstract
Background Lobular carcinoma in situ (LCIS) is a non-invasive breast lesion that is typically found incidentally on biopsy and is often associated with invasive lobular carcinoma (ILC). LCIS is considered by some to be a risk factor for future breast cancer rather than a true precursor lesion. The aim of this study was to identify genetic changes that could be used as biomarkers of progression of LCIS to invasive disease using cases of pure LCIS and comparing their genetic profiles to LCIS which presented contemporaneously with associated ILC, on the hypothesis that the latter represents LCIS that has already progressed. Methods Somatic copy number aberrations (SCNAs) were assessed by SNP array in three subgroups: pure LCIS, LCIS associated with ILC and the paired ILC. In addition exome sequencing was performed on seven fresh frozen samples of LCIS associated with ILC, to identify recurrent somatic mutations. Results The copy number profiles of pure LCIS and LCIS associated with ILC were almost identical. However, four SCNAs were more frequent in ILC than LCIS associated with ILC, including gain/amplification of CCND1. CCND1 protein over-expression assessed by immunohistochemical analysis in a second set of samples from 32 patients with pure LCIS and long-term follow up, was associated with invasive recurrence (P = 0.02, Fisher’s exact test). Exome sequencing revealed that PIK3CA mutations were as frequent as CDH1 mutations in LCIS, but were not a useful biomarker of LCIS progression as they were as frequent in pure LCIS as in LCIS associated with ILC. We also observed heterogeneity of PIK3CA mutations and evidence of sub-clonal populations in LCIS irrespective of whether they were associated with ILC. Conclusions Our data shows that pure LCIS and LCIS co-existing with ILC have very similar SCNA profiles, supporting the hypothesis that LCIS is a true precursor lesion. We have provided evidence that over-expression of CCND1 may identify a subgroup of patients with pure LCIS who are more likely to develop invasive disease, in contrast to PIK3CA mutations, which occur too early in lobular tumorigenesis to be informative. Electronic supplementary material The online version of this article (doi:10.1186/s13058-016-0789-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Vandna Shah
- Division of Cancer Studies, Guy's Hospital, King's College London, London, SE1 9RT, UK
| | - Salpie Nowinski
- Division of Cancer Studies, Guy's Hospital, King's College London, London, SE1 9RT, UK
| | - Dina Levi
- Division of Cancer Studies, Guy's Hospital, King's College London, London, SE1 9RT, UK
| | - Irek Shinomiya
- Division of Cancer Studies, Guy's Hospital, King's College London, London, SE1 9RT, UK
| | | | - Cheryl Gillett
- Division of Cancer Studies, Guy's Hospital, King's College London, London, SE1 9RT, UK
| | - Anita Grigoriadis
- Breast Cancer Now Unit, Research Oncology & Cancer Epidemiology, Guy's Hospital, King's College London, London, SE1 9RT, UK
| | - Trevor A Graham
- Evolution and Cancer laboratory, Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Rebecca Roylance
- Department of Oncology, UCLH Foundation Trust, London, NW1 2PG, UK
| | - Michael A Simpson
- Medical and Molecular Genetics, Guy's Hospital, King's College London, London, UK
| | - Sarah E Pinder
- Division of Cancer Studies, Guy's Hospital, King's College London, London, SE1 9RT, UK
| | - Elinor J Sawyer
- Division of Cancer Studies, Guy's Hospital, King's College London, London, SE1 9RT, UK.
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Casasent AK, Edgerton M, Navin NE. Genome evolution in ductal carcinoma in situ: invasion of the clones. J Pathol 2016; 241:208-218. [PMID: 27861897 DOI: 10.1002/path.4840] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 10/21/2016] [Accepted: 10/26/2016] [Indexed: 12/21/2022]
Abstract
Ductal carcinoma in situ (DCIS) is the most frequently diagnosed early-stage breast cancer. Only a subset of patients progress to invasive ductal carcinoma (IDC), and this presents a formidable clinical challenge for determining which patients to treat aggressively and which patients to monitor without therapeutic intervention. Understanding the molecular and genomic basis of invasion has been difficult to study in DCIS cancers due to several technical obstacles, including low tumour cellularity, lack of fresh-frozen tissues, and intratumour heterogeneity. In this review, we discuss the role of intratumour heterogeneity in the progression of DCIS to IDC in the context of three evolutionary models: independent lineages, evolutionary bottlenecks, and multiclonal invasion. We examine the evidence in support of these models and their relevance to the diagnosis and treatment of patients with DCIS. We also discuss how emerging technologies, such as single-cell sequencing, STAR-FISH, and imaging mass spectrometry, are likely to provide new insights into the evolution of this enigmatic disease. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Anna K Casasent
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mary Edgerton
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nicholas E Navin
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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26
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Pang JMB, Gorringe KL, Fox SB. Ductal carcinoma in situ - update on risk assessment and management. Histopathology 2016; 68:96-109. [PMID: 26768032 DOI: 10.1111/his.12796] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 07/31/2015] [Indexed: 12/20/2022]
Abstract
Ductal carcinoma in situ (DCIS) accounts for ~20-25% of breast cancers. While DCIS is not life-threatening, it may progress to invasive carcinoma over time, and treatment intended to prevent invasive progression may itself cause significant morbidity. Accurate risk assessment is therefore necessary to avoid over- or undertreatment of an individual patient. In this review we will outline the evidence for current management of DCIS, discuss approaches to DCIS risk assessment and challenges facing identification of novel DCIS biomarkers.
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Affiliation(s)
- Jia-Min B Pang
- Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Vic., Australia.,Department of Pathology, University of Melbourne, Melbourne, Vic., Australia
| | - Kylie L Gorringe
- Department of Pathology, University of Melbourne, Melbourne, Vic., Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic., Australia.,Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Vic., Australia
| | - Stephen B Fox
- Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Vic., Australia.,Department of Pathology, University of Melbourne, Melbourne, Vic., Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic., Australia
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27
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Abstract
PURPOSE OF REVIEW Ductal carcinoma in situ (DCIS) accounts for approximately 20% of mammographically diagnosed breast cancers. Currently, there is a trend to consider DCIS as a lesion for which treatment deescalation is advocated to avoid overtreatment, that is, radiotherapy in addition to breast-conserving surgery or even surgery at all. RECENT FINDINGS The long-term follow-up updates of the four first-generation randomized trials comparing lumpectomy with and without radiation therapy have confirmed that radiation halves the local failure rates. However, radiotherapy is not associated with a survival benefit just as affirmed by the recently published evaluation of the Surveillance, Epidemiology, and End Results registries database, including 108,196 women with DCIS. Nevertheless, the risk of dying of breast cancer increases about factor 18 after experience of an invasive local recurrence. That means at least some DCIS have the potential to progress to a life threatening disease. At the same time, none of the recently updated prospective trials that tested the outcome after excision alone in low-risk DCIS achieved a 10-year local failure rate below 10%. SUMMARY DCIS is not a uniform disease. Its clinical behaviour is heterogeneous, but up to date no citeria are available that allow a precise identification of patients with low or very low progression risk who do not need irradiation. Therefore, excision followed by radiotherapy is still the standard of care in patients undergoing breast conservation. Promising new approaches for risk estimation have to be validated prospectively before their use in daily practice can be recommended.
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28
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Holst F. Estrogen receptor alpha gene amplification in breast cancer: 25 years of debate. World J Clin Oncol 2016; 7:160-173. [PMID: 27081639 PMCID: PMC4826962 DOI: 10.5306/wjco.v7.i2.160] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 01/05/2016] [Accepted: 02/16/2016] [Indexed: 02/06/2023] Open
Abstract
Twenty-five years ago, Nembrot and colleagues reported amplification of the estrogen receptor alpha gene (ESR1) in breast cancer, initiating a broad and still ongoing scientific debate on the prevalence and clinical significance of this genetic aberration, which affects one of the most important genes in breast cancer. Since then, a multitude of studies on this topic has been published, covering a wide range of divergent results and arguments. The reported prevalence of this alteration in breast cancer ranges from 0% to 75%, suggesting that ESR1 copy number analysis is hampered by technical and interpreter issues. To date, two major issues related to ESR1 amplification remain to be conclusively addressed: (1) The extent to which abundant amounts of messenger RNA can mimic amplification in standard fluorescence in situ hybridization assays in the analysis of strongly expressed genes like ESR1, and (2) the clinical relevance of ESR1 amplification: Such relevance is strongly disputed, with data showing predictive value for response as well as for resistance of the cancer to anti-estrogen therapies, or for subsequent development of cancers in the case of precursor lesions that display amplification of ESR1. This review provides a comprehensive summary of the various views on ESR1 amplification, and highlights explanations for the contradictions and conflicting data that could inform future ESR1 research.
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29
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Rane SU, Mirza H, Grigoriadis A, Pinder SE. Selection and evolution in the genomic landscape of copy number alterations in ductal carcinoma in situ (DCIS) and its progression to invasive carcinoma of ductal/no special type: a meta-analysis. Breast Cancer Res Treat 2015; 153:101-21. [PMID: 26255059 DOI: 10.1007/s10549-015-3509-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 07/18/2015] [Indexed: 12/18/2022]
Abstract
Ductal carcinoma in situ (DCIS) is a pre-invasive malignancy detected with an increasing frequency through screening mammography. One of the primary aims of therapy is to prevent local recurrence, as in situ or as invasive carcinoma, the latter arising in half of the recurrent cases. Reliable biomarkers predictive of its association with recurrence, particularly as invasive disease, are however lacking. In this study, we perform a meta-analysis of 26 studies which report somatic copy number aberrations (SCNAs) in 288 cases of 'pure' DCIS and 328 of DCIS associated with invasive carcinoma, along with additional unmatched cases of 145 invasive carcinoma of ductal/no special type (IDC) and 50 of atypical ductal hyperplasia (ADH). SCNA frequencies across the genome were calculated at cytoband resolution (UCSC genome build 19) to maximally utilize the available information in published literature. Fisher's exact test was used to identify significant differences in the gain-loss distribution in each cytoband in different group comparisons. We found synchronous DCIS to be at a more advanced stage of genetic aberrations than pure DCIS and was very similar to IDC. Differences in gains and losses in each disease process (i.e. invasive or in situ) at each cytoband were used to infer evidence of selection and conservation for each cytoband and to define an evolutionary conservation scale (ECS) as a tool to identify and distinguish driver SCNA from the passenger SCNA. Using ECS, we have identified aberrations that show evidence of selection from the early stages of neoplasia (i.e. in ADH and pure DCIS) and persist in IDC; we postulate these to be driver aberrations and that their presence may predict progression to invasive disease.
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Affiliation(s)
- Swapnil Ulhas Rane
- Department of Research Oncology, King's Health Partners AHSC, King's College London, London, UK,
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30
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Pang JMB, Gorringe KL, Wong SQ, Dobrovic A, Campbell IG, Fox SB. Appraisal of the technologies and review of the genomic landscape of ductal carcinoma in situ of the breast. Breast Cancer Res 2015; 17:80. [PMID: 26078038 PMCID: PMC4469314 DOI: 10.1186/s13058-015-0586-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Ductal carcinoma in situ is a biologically diverse entity. Whereas some lesions are cured by local surgical excision, others recur as in situ disease or progress to invasive carcinoma with subsequent potential for metastatic spread. Reliable prognostic biomarkers are therefore desirable for appropriate clinical management but remain elusive. In common with invasive breast cancer, ductal carcinoma in situ exhibits many genomic changes, predominantly copy number alterations. Although studies have revealed the genomic heterogeneity within individual ductal carcinoma in situ lesions and the association of certain copy number alterations with nuclear grade, none of the genomic changes defined so far is consistently associated with invasive transformation or recurrence risk in pure ductal carcinoma in situ. This article will review the current landscape of genomic alterations in ductal carcinoma in situ and their potential as prognostic biomarkers together with the technologies used to define these.
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Affiliation(s)
- Jia-Min B Pang
- Department of Pathology, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia. .,Department of Pathology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, 3010, Australia.
| | - Kylie L Gorringe
- Department of Pathology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, 3010, Australia. .,Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, 3010, Australia. .,Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia.
| | - Stephen Q Wong
- Department of Pathology, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia. .,Translational Research Laboratory, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia.
| | - Alexander Dobrovic
- Department of Pathology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, 3010, Australia. .,Translational Genomics & Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Studley Road, Heidelberg, VIC, 3084, Australia.
| | - Ian G Campbell
- Department of Pathology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, 3010, Australia. .,Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, 3010, Australia. .,Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia.
| | - Stephen B Fox
- Department of Pathology, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC, 3002, Australia. .,Department of Pathology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, 3010, Australia. .,Sir Peter MacCallum Department of Oncology, University of Melbourne, Grattan Street, Parkville, Melbourne, VIC, 3010, Australia.
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Orzalesi L, Casella D, Criscenti V, Gjondedaj U, Bianchi S, Vezzosi V, Nori J, Cecconi L, Meattini I, Livi L, Bernini M. Microinvasive breast cancer: pathological parameters, cancer subtypes distribution, and correlation with axillary lymph nodes invasion. Results of a large single-institution series. Breast Cancer 2015; 23:640-8. [DOI: 10.1007/s12282-015-0616-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 05/05/2015] [Indexed: 01/04/2023]
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Histopathological characterization of ductal carcinoma in situ (DCIS) of the breast according to HER2 amplification status and molecular subtype. Virchows Arch 2014; 465:275-89. [PMID: 24973889 DOI: 10.1007/s00428-014-1609-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 05/15/2014] [Accepted: 06/16/2014] [Indexed: 12/29/2022]
Abstract
This study aimed to characterize ductal carcinoma in situ (DCIS) according to human epidermal growth factor receptor 2 (HER2) amplification status and molecular subtype. In addition, we performed a detailed HER2 and CEP17 copy number analysis and we assessed the impact of recent changes in the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines on HER2 immunohistochemical (IHC) scores in DCIS. Nuclear grade, extensive comedonecrosis, stromal architecture, stromal inflammation, and progesterone receptor (PR) expression were significantly associated with HER2 amplification status. In multivariate analysis, stromal inflammation and extensive comedonecrosis were the only two features that remained significantly related to HER2 amplification status. The recent changes in ASCO/CAP guidelines resulted in significant upgrading of HER2 IHC score. Remarkably, about one in five non-amplified DCIS presented a 3+ IHC score, regardless of the scoring method. The biological significance of this phenomenon is presently unknown. After categorization according to molecular subtype, luminal A DCIS mainly presented histopathological features associated with good prognosis, whereas luminal B/HER2+ and HER2+ categories displayed a more aggressive phenotype. Overall, our results demonstrate that HER2-amplified DCIS constitute a clearly distinct subgroup which is characterized by histopathological features associated with poor prognosis. Further studies are required to elucidate the biological significance of a 3+ IHC score in non-amplified DCIS, as well as its mechanism.
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33
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Burandt E, Grünert M, Lebeau A, Choschzick M, Quaas A, Jänicke F, Müller V, Scholz U, Bokemeyer C, Petersen C, Geist S, Paluchowski P, Wilke C, Heilenkötter U, Simon R, Sauter G, Wilczak W. Cyclin D1 gene amplification is highly homogeneous in breast cancer. Breast Cancer 2014; 23:111-119. [PMID: 24862872 DOI: 10.1007/s12282-014-0538-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Accepted: 05/09/2014] [Indexed: 01/30/2023]
Abstract
BACKGROUND Cyclin D1 (CCND1) gene amplification is a molecular key alteration in breast cancer and was suggested to predict resistance to antihormonal therapy. As tissue heterogeneity may affect diagnostic accuracy of predictive biomarkers, CCND1 genetic heterogeneity was assessed in this study. A novel tissue microarray (TMA) platform was manufactured for this purpose. METHODS Primary breast carcinomas from 147 patients were sampled in a "heterogeneity-TMA" by taking eight different tissue cores from 4 to 8 tumor-containing blocks per case. Additional tissue samples were taken from 1 to 4 corresponding nodal metastases in 35 of these patients. CCND1 amplification was assessed by fluorescence in situ hybridization (FISH). RESULTS CCND1 amplification was seen in 28 of 133 (21.05 %) informative patients. Amplification was significantly associated with high tumor grade (p = 0.042), but unrelated to tumor type (p = 0.307), stage (p = 0.540) and ER (p = 0.061) or PR (p = 0.871) expression. A discordant Cyclin D1 amplification status was detected in 6 out of 28 (21.43 %) amplified tumors by heterogeneity-TMA analysis. Re-testing on large sections revealed three patients with true heterogeneity of high-level CCND1 amplification and another three patients with variable interpretation of borderline FISH ratios ranging between 1.7 and 2.3. No discrepancies were detected between 22 primary tumors and their matched lymph node metastases. CONCLUSIONS The high degree of homogeneity seen for CCND1 amplification suggests that this alteration is an early event in the development of a small subset of breast cancers.
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Affiliation(s)
- Eike Burandt
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
| | - Martin Grünert
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Annette Lebeau
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Matthias Choschzick
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Alexander Quaas
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Fritz Jänicke
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Volkmar Müller
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Ursula Scholz
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Carsten Bokemeyer
- Department of Internal Medicine II, Oncology Center, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Cordula Petersen
- Department of Radiotherapy and Radio-Oncology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Stefan Geist
- Department of Gynecology, Regio Clinic Pinneberg, 25421, Pinneberg, Germany
| | - Peter Paluchowski
- Department of Gynecology, Regio Clinic Pinneberg, 25421, Pinneberg, Germany
| | - Christian Wilke
- Department of Gynecology, Regio Clinic Elmshorn, 25337, Elmshorn, Germany
| | - Uwe Heilenkötter
- Department of Gynecology, Clinical Centre Itzehoe, 25524, Itzehoe, Germany
| | - Ronald Simon
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Guido Sauter
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Waldemar Wilczak
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
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Sakr RA, Weigelt B, Chandarlapaty S, Andrade VP, Guerini-Rocco E, Giri D, Ng CKY, Cowell CF, Rosen N, Reis-Filho JS, King TA. PI3K pathway activation in high-grade ductal carcinoma in situ--implications for progression to invasive breast carcinoma. Clin Cancer Res 2014; 20:2326-37. [PMID: 24634376 PMCID: PMC4015460 DOI: 10.1158/1078-0432.ccr-13-2267] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
PURPOSE To assess the prevalence of phosphoinositide 3-kinase (PI3K) pathway alterations in pure high-grade ductal carcinoma in situ (DCIS) and DCIS associated with invasive breast cancer (IBC), and to determine whether DCIS and adjacent IBCs harbor distinct PI3K pathway aberrations. EXPERIMENTAL DESIGN Eighty-nine cases of pure high-grade DCIS and 119 cases of high-grade DCIS associated with IBC were characterized according to estrogen receptor (ER) and HER2 status, subjected to immunohistochemical analysis of PTEN, INPP4B, phosphorylated (p)AKT and pS6 expression, and to microdissection followed by Sequenom genotyping of PIK3CA and AKT1 hotspot mutations. RESULTS Alterations affecting the PI3K pathway were found in a subset of pure DCIS and DCIS adjacent to IBC. A subtype-matched comparison of pure DCIS and DCIS adjacent to IBC revealed that PIK3CA hotspot mutations and pAKT expression were significantly more prevalent in ER-positive/HER2-negative DCIS adjacent to IBC (P values, 0.005 and 0.043, respectively), and that in ER-negative/HER2-positive cases INPP4B loss of expression was more frequently observed in pure DCIS (a P value of 0.013). No differences in the parameters analyzed were observed in a pairwise comparison of the in situ and invasive components of cases of DCIS and adjacent IBC. Analysis of the PIK3CA-mutant allelic frequencies in DCIS and synchronous IBC revealed cases in which PIK3CA mutations were either restricted to the DCIS or to the invasive components. CONCLUSION Molecular aberrations affecting the PI3K pathway may play a role in the progression from high-grade DCIS to IBC in a subset of cases (e.g., a subgroup of ER-positive/HER2-negative lesions).
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Affiliation(s)
- Rita A. Sakr
- Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Britta Weigelt
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Sarat Chandarlapaty
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Victor P. Andrade
- Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Elena Guerini-Rocco
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Dilip Giri
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Charlotte K. Y. Ng
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Catherine F. Cowell
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Neal Rosen
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Jorge S. Reis-Filho
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Tari A. King
- Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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Chen JR, Hsieh TY, Chen HY, Yeh KY, Chen KS, ChangChien YC, Pintye M, Chang LC, Hwang CC, Chien HP, Hsu YC. Absence of estrogen receptor alpha (ESR1) gene amplification in a series of breast cancers in Taiwan. Virchows Arch 2014; 464:689-99. [PMID: 24756215 DOI: 10.1007/s00428-014-1576-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Revised: 03/18/2014] [Accepted: 03/21/2014] [Indexed: 11/28/2022]
Abstract
Immunohistochemical expression of ERα, encoded by the ESR1 (estrogen receptor 1) gene located at 6q25.1, is the most important determinant of responsiveness to endocrine therapy in breast cancer. The prevalence and significance of ESR1 amplification in breast cancer remain controversial. We set out to assess ESR1 status and its relevance in breast cancer in Taiwan. We tested tissue samples from 311 invasive carcinomas in a tissue microarray for ESR1 status by fluorescent in situ hybridization (FISH) and chromogenic in situ hybridization (CISH). In order to examine its association with ERα and ESR1 status, HER2 status was determined by FISH. Of the carcinomas, 58.8 % (183/311) was ERα positive. None of the carcinomas showed amplification of ESR1 by either method, whereas 24.1 % (75/311) of the carcinomas harbored HER2 amplification. Of the carcinomas, 9.6 % (26/301) showed ESR1 gain (1.3 ≤ ratio ESR1/chromosome 6 < 2) by FISH and 10 % (24/299) by CISH. FISH and CISH results showed a good correlation (κ-coefficient = 0.786). ESR1 gain by FISH and CISH was significantly associated with high-grade (P = 0.0294 and 0.0417, respectively) but not with ERα expression, HER2 status, or overall survival. ERα positivity was significantly associated with better overall survival (P = 0.039). HER2 amplification was significantly related with poor overall survival (P = 0.002). Our data confirm that in breast cancer, HER2 amplification is a frequent genetic aberration and a negative prognostic factor, and show that ESR1 amplification is not a key genetic abnormality in the tumorigenesis of breast cancer in Taiwan.
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Affiliation(s)
- Jim-Ray Chen
- Department of Pathology, Keelung Chang Gung Memorial Hospital, 222 Maijin Road, Keelung, 204, Taiwan,
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Takagi K, Moriguchi T, Miki Y, Nakamura Y, Watanabe M, Ishida T, Yamamoto M, Sasano H, Suzuki T. GATA4 immunolocalization in breast carcinoma as a potent prognostic predictor. Cancer Sci 2014; 105:600-7. [PMID: 24862985 PMCID: PMC4317835 DOI: 10.1111/cas.12382] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 02/13/2014] [Accepted: 02/14/2014] [Indexed: 12/23/2022] Open
Abstract
Transcriptional GATA factors are known lineage selector genes and regulate a variety of biological processes including specification and differentiation of tissues. In the present study, we examined expression profiles of six GATA factor genes in invasive ductal carcinomas (IDC) of the breast using microarray analysis (n = 20) and found that GATA4 expression was closely correlated with recurrence in patients. Because the significance of GATA4 has remained largely unknown in breast carcinoma, we further immunolocalized GATA4 in ductal carcinoma in situ (DCIS) of the breast (n = 48) and IDC (n = 163). GATA4 immunoreactivity was detected in the nuclei of carcinoma cells and was positive in 27% of DCIS and 31% of IDC cases. GATA4 status was significantly associated with nuclear grade and van Nuys classification in DCIS and was positively associated with distant metastasis, histological grade and HER2 status, but negatively correlated with progesterone receptor labeling index in IDC. Subsequent multivariate analysis demonstrated that GATA4 status was an independent prognostic factor for both disease-free and breast cancer-specific survival of IDC patients. All of these results indicate that GATA4 plays important roles in the progression of breast carcinoma from an early stage and that immunohistochemical GATA4 status is considered a potent prognostic factor in human breast cancer patients.
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Affiliation(s)
- Kiyoshi Takagi
- Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Cowell CF, Weigelt B, Sakr RA, Ng CKY, Hicks J, King TA, Reis-Filho JS. Progression from ductal carcinoma in situ to invasive breast cancer: revisited. Mol Oncol 2013; 7:859-69. [PMID: 23890733 DOI: 10.1016/j.molonc.2013.07.005] [Citation(s) in RCA: 175] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Accepted: 07/04/2013] [Indexed: 12/21/2022] Open
Abstract
Ductal carcinoma in situ (DCIS) is an intraductal neoplastic proliferation of epithelial cells that is separated from the breast stroma by an intact layer of basement membrane and myoepithelial cells. DCIS is a non-obligate precursor of invasive breast cancer, and up to 40% of these lesions progress to invasive disease if untreated. Currently, it is not possible to predict accurately which DCIS would be more likely to progress to invasive breast cancer as neither the significant drivers of the invasive transition have been identified, nor has the clinical utility of tests predicting the likelihood of progression been demonstrated. Although molecular studies have shown that qualitatively, synchronous DCIS and invasive breast cancers are remarkably similar, there is burgeoning evidence to demonstrate that intra-tumor genetic heterogeneity is observed in a subset of DCIS, and that the process of progression to invasive disease may constitute an 'evolutionary bottleneck', resulting in the selection of subsets of tumor cells with specific genetic and/or epigenetic aberrations. Here we review the clinical challenge posed by DCIS, the contribution of the microenvironment and genetic aberrations to the progression from in situ to invasive breast cancer, the emerging evidence of the impact of intra-tumor genetic heterogeneity on this process, and strategies to combat this heterogeneity.
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Affiliation(s)
- Catherine F Cowell
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
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Nie X, He J, Li Y, Pan DZ, Pan HX, Weng MX, Yang XP, Liu CP, Huang T. Accurate assessment of HER2 gene status for invasive component of breast cancer by combination of immunohistochemistry and chromogenic In Situ hybridization. ACTA ACUST UNITED AC 2013; 33:379-384. [PMID: 23771664 DOI: 10.1007/s11596-013-1128-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Indexed: 11/25/2022]
Abstract
The specimens of ductal carcinoma in situ (DCIS) with early invasion, and specimens collected by core needle biopsy (CNB) tend to contain limited amount of invasive component, so it is imperative to explore a new technique which can assess HER2 gene status accurately for the limited invasive cancer component in these specimens. Dual staining technique of combining immunohistochemistry (IHC) for myoepithelial cells and single or dual probe chromogenic in situ hybridization (CISH) for HER2 gene was performed on routinely processed paraffin sections from 20 cases diagnosed as having DCIS with invasive cancer. Among them, 10 had fluorescence in situ hybridization (FISH)-confirmed amplification of HER2 and 10 had FISH-confirmed non-amplification of HER2. We successfully detected HER2 genetic signals and myoepithelial IHC markers (SMM-HC or CK5/6) simultaneously on a single section in all 20 specimens. Myoepithelial markers and HER2 signals detected by dual staining assay were consistent with those by individual technique performed alone. HER2 gene amplification results determined by dual staining assay were 100% consistent with those of FISH. Dual staining technique which allows simultaneous detection of myoepithelial marker protein and cancerous HER2 gene is feasible, and it has potential to be used in clinical practice for effective determination of HER2 amplification in limited invasive component.
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Affiliation(s)
- Xiu Nie
- Department of Pathology, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jun He
- Department of Pathology, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yan Li
- Department of Pathology, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Dan-Zhen Pan
- Department of Pathology, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hua-Xiong Pan
- Department of Pathology, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Mi-Xia Weng
- Department of Pathology, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiu-Ping Yang
- Department of Pathology, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chun-Ping Liu
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Tao Huang
- Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Droog M, Beelen K, Linn S, Zwart W. Tamoxifen resistance: from bench to bedside. Eur J Pharmacol 2013; 717:47-57. [PMID: 23545365 DOI: 10.1016/j.ejphar.2012.11.071] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Revised: 11/20/2012] [Accepted: 11/23/2012] [Indexed: 01/09/2023]
Abstract
Although tamoxifen is a classical example of a targeted drug, a substantial proportion of estrogen receptor alpha positive breast cancer patients does not benefit from the drug. Over the last few decades, many potential biomarkers have been discovered in cell biological studies that may aid in the prediction of tamoxifen sensitivity and guide in treatment selection. Nonetheless, the transition of such a biomarker from the scientific community towards a diagnostic test that can be used in daily clinical practice has been far from ideal, and such markers seldom face clinical introduction. From a large number of potential predictive biomarkers as described in cell biological literature, the clinical (translational) scientist has to make a decision which of these biomarkers should be tested in clinical material to determine their clinical validity. This problem is not trivial, since patient samples with clinical follow-up are a valuable asset that should therefore be cherished. In this review, we will describe a number of 'cell biological biomarkers' for tamoxifen resistance and their possible clinical implications. This may guide the clinical scientist in choosing what potential biomarkers to test on tumour samples, which may catalyse the translation of scientific discoveries into daily clinical practice of breast cancer medicine.
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Affiliation(s)
- Marjolein Droog
- Department of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Modulation of estrogen receptor alpha activity and expression during breast cancer progression. VITAMINS AND HORMONES 2013; 93:135-60. [PMID: 23810005 DOI: 10.1016/b978-0-12-416673-8.00004-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Seventy percent of breast tumors express the estrogen receptor (ER), which is generally considered to predict a better outcome relative to ER-negative tumors, as they often respond to antiestrogen therapies. During cancer progression, mammary tumors can escape from estrogen control, resulting in the acquisition of invasive properties and resistance to treatment. ER expression is a dynamic phenomenon and is finely regulated at numerous levels, including the gene, mRNA, and protein levels. As a consequence, many molecular mechanisms have been implicated in modulating ER activity and estrogen signaling in mammary cancer. In fact, one-third of ER-positive breast cancer cells do not respond to first-line endocrine therapies, and a large subset of relapsing tumors retain ER expression. Increased knowledge of these mechanisms has led to the development of better prognostic methods and targeted therapies for patients; however, additional research is still needed to improve patient survival. In this chapter, we focus on the signaling pathways leading to changes in or loss of ER activity in breast cancer progression.
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Jang M, Kim E, Choi Y, Lee H, Kim Y, Kim J, Kang E, Kim SW, Kim I, Park S. FGFR1 is amplified during the progression of in situ to invasive breast carcinoma. Breast Cancer Res 2012; 14:R115. [PMID: 22863309 PMCID: PMC3680930 DOI: 10.1186/bcr3239] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Accepted: 08/03/2012] [Indexed: 12/17/2022] Open
Abstract
Introduction Gene amplification is an important mechanism for activating oncogenes in malignant tumors. Although amplification of HER2, C-MYC, CCND1 and FGFR1 has been reported in breast cancers, their role in the progression of in situ to invasive breast carcinoma is unclear. To investigate this question we compared the amplification frequencies of these genes in pure ductal carcinoma in situ (DCIS), DCIS associated with invasive carcinoma, and invasive carcinoma. Methods We performed fluorescence in situ hybridization of the selected genes on tissue microarrays composed of 179 pure DCIS and 438 invasive carcinomas. Two hundred and sixteen of the latter had DCIS components, and in those cases we compared gene amplification in the intraductal and invasive components of each carcinoma. Results The rate of amplification of FGFR1 was higher in invasive carcinomas than in the pure DCIS, but the opposite was true for HER2 amplification. These findings applied consistently to high-grade tumors, but not to low/intermediate-grade tumors. The amplification status of HER2, C-MYC, CCND1 and FGFR1 was generally similar in the matched invasive and DCIS components of the same tumors. However, FGFR1 amplification was more common in the invasive components than in the DCIS components. In survival analyses, FGFR1 amplification was found to be an independent prognostic factor for poor disease-free survival for all patients with invasive carcinoma and for the hormone receptor-positive subgroup. Conclusion Amplification of HER2, C-MYC and CCND1 seems to play a role in the early development of breast cancer, but not in its progression. However, the increased frequency of FGFR1 amplification in invasive carcinomas compared with pure DCIS and in the invasive components of individual tumors, and its association with decreased disease-free survival, suggests a role for FGFR1 amplification in the progression of breast cancer including in situ-to-invasive transition, as well as initiation.
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Ebata A, Suzuki T, Takagi K, Miki Y, Onodera Y, Nakamura Y, Fujishima F, Ishida K, Watanabe M, Tamaki K, Ishida T, Ohuchi N, Sasano H. Oestrogen-induced genes in ductal carcinoma in situ: their comparison with invasive ductal carcinoma. Endocr Relat Cancer 2012; 19:485-96. [PMID: 22569827 DOI: 10.1530/erc-11-0345] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
It is well known that oestrogens play important roles in both the pathogenesis and development of invasive ductal carcinoma (IDC) of human breast. However, molecular features of oestrogen actions have remained largely unclear in pure ductal carcinoma in situ (pDCIS), regarded as a precursor lesion of many IDCs. This is partly due to the fact that gene expression profiles of oestrogen-responsive genes have not been examined in pDCIS. Therefore, we first examined the profiles of oestrogen-induced genes in oestrogen receptor (ER)-positive pDCIS and DCIS (DCIS component (DCIS-c)) and IDC (IDC component (IDC-c)) components of IDC cases (n=4 respectively) by microarray analysis. Oestrogen-induced genes identified in this study were tentatively classified into three different groups in the hierarchical clustering analysis, and 33% of the genes were predominantly expressed in pDCIS rather than DCIS-c or IDC-c cases. Among these genes, the status of MYB (C-MYB), RBBP7 (RBAP46) and BIRC5 (survivin) expressions in carcinoma cells was significantly higher in ER-positive pDCIS (n=53) than that in ER-positive DCIS-c (n=27) or IDC-c (n=27) by subsequent immunohistochemical analysis of the corresponding genes (P<0.0001, P=0.03 and P=0.0003 respectively). In particular, the status of C-MYB immunoreactivity was inversely (P=0.006) correlated with Ki67 in the pDCIS cases. These results suggest that expression profiles of oestrogen-induced genes in pDCIS may be different from those in IDC; and C-MYB, RBAP46 and survivin may play important roles particularly among oestrogen-induced genes in ER-positive pDCIS.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Ductal, Breast/metabolism
- Carcinoma, Intraductal, Noninfiltrating/genetics
- Carcinoma, Intraductal, Noninfiltrating/metabolism
- Estrogens/pharmacology
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic/drug effects
- Genes, Neoplasm/drug effects
- Humans
- Microarray Analysis
- Middle Aged
- Up-Regulation/drug effects
- Up-Regulation/genetics
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Affiliation(s)
- Akiko Ebata
- Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aobaku, Sendai, Japan
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Laenkholm AV, Knoop A, Ejlertsen B, Rudbeck T, Jensen MB, Müller S, Lykkesfeldt AE, Rasmussen BB, Nielsen KV. ESR1 gene status correlates with estrogen receptor protein levels measured by ligand binding assay and immunohistochemistry. Mol Oncol 2012; 6:428-36. [PMID: 22626971 DOI: 10.1016/j.molonc.2012.04.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Accepted: 04/30/2012] [Indexed: 01/13/2023] Open
Abstract
The Estrogen Receptor (ER) is an established predictive marker for the selection of adjuvant endocrine treatment in early breast cancer. During the 1990s Immunohistochemistry (IHC) replaced cytosol based assays for determination of ER status. This study examined the association between ER protein level determined by two different methods and ESR1 gene copy number. From 289 primary high-risk breast cancer patients, randomized in the Danish Breast Cancer Cooperative Group (DBCG) 77C trial, results from cytosolic ER levels were available from ligand binding assays. Archival tumor tissue was retrieved from 257 patients. ESR1/CEN-6 ratio was analyzed successfully by Fluorescence In Situ Hybridization (FISH) in 220 (86%) patients. ESR1 amplification (ESR1/CEN-6 ≥ 2.00) was observed in 23% of the patients and ESR1 deletion (ESR1/CEN-6 < 0.80) was observed in 32%. Further, we identified ESR1 gain (ratio ESR1/CEN-6 from 1.30 to 1.99) in 19% of the patients. A positive correlation of ESR1 FISH with both ER-cytosol and ER IHC was found (p < 0.0001). Amplification and gain of the ESR1 gene are associated with higher ER protein content measured by ligand binding assay and a more intense nuclear staining by IHC compared to tumors with normal ESR1 gene status. Major variations in ER measured by ligand binding assay and IHC are observed within all ESR1 copy number subgroups and other mechanisms than gene copy number seem to contribute to the ER protein content in the tumors.
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Hashimoto K, Yamamoto H, Shiratsuchi H, Nakashima T, Tamiya S, Nishiyama KI, Higaki Y, Komune S, Tsuneyoshi M, Oda Y. HER-2/neu gene amplification in carcinoma ex pleomorphic adenoma in relation to progression and prognosis: a chromogenic in-situ hybridization study. Histopathology 2012; 60:E131-42. [PMID: 22486195 DOI: 10.1111/j.1365-2559.2012.04201.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIMS The aim of this study was to investigate the potential role of HER-2/neu in the stepwise progression of carcinoma ex pleomorphic adenoma (CXPA) and to evaluate its prognostic significance in CXPA. METHODS AND RESULTS We examined HER2 overexpression and HER2 amplification by immunohistochemistry and chromogenic in-situ hybridization in 31 cases of CXPA with ductal differentiation (eight intraductal, five intracapsular, and 18 extracapsular) and seven cases of atypical pleomorphic adenoma (PA). HER2 overexpression and HER2 amplification were found in 17 (54.8%) and 12 (38.7%) of the 31 CXPA cases, respectively. HER2 amplification was more prevalent in extracapsular CXPAs (9/18 cases; 50%) than intracapsular CXPAs (1/5 cases; 20%), intraductal CXPAs (2/8 cases; 25%), or atypical PAs (0/7 case; 0%). The status of HER2 amplification was essentially retained from the intraductal to the extracapsular component in individual extracapsular CXPAs. In addition, HER2 amplification was significantly associated with a worse prognosis (shorter disease-free survival time and shorter overall survival time) among extracapsular CXPAs (each P < 0.05). CONCLUSIONS These results suggest that HER2 may play an important role in the progression of CXPA, and that HER2 amplification may be an additional prognostic indicator of CXPA.
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Affiliation(s)
- Kazuki Hashimoto
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Identification of copy number alterations associated with the progression of DCIS to invasive ductal carcinoma. Breast Cancer Res Treat 2011; 133:889-98. [PMID: 22052326 DOI: 10.1007/s10549-011-1835-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2011] [Accepted: 10/11/2011] [Indexed: 12/16/2022]
Abstract
Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive ductal carcinoma (IDC). Annotation of the genetic differences between the two lesions may assist in the identification of genes that promote the invasive phenotype. Synchronous DCIS and IDC cells were microdissected from FFPE tissue and analysed by molecular inversion probe (MIP) copy number arrays. Matched IDC and DCIS showed highly similar copy number profiles (average of 83% of the genome shared) indicating a common clonal origin although there is evidence that the DCIS continues to evolve in parallel with the co-existing IDC. Four chromosomal regions of loss (3q, 6q, 8p and 11q) and four regions of gain (5q, 16p, 19q and 20) were recurrently affected in IDC but not in DCIS. CCND1 and MYC showed increased amplitude of gain in IDC. One region of loss (17p11.2) was specific to DCIS. IDC-specific regions include genes with previous links to breast cancer progression and potential therapeutic targets such as AXL, SPHK1 and PLAUR.
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Yu KD, Shao ZM. ESR1 gene amplification: another mechanism regulating the cellular levels of ERα. Nat Rev Cancer 2011; 11:823; author reply 823. [PMID: 22020208 DOI: 10.1038/nrc3093-c1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Guenthoer J, Diede SJ, Tanaka H, Chai X, Hsu L, Tapscott SJ, Porter PL. Assessment of palindromes as platforms for DNA amplification in breast cancer. Genome Res 2011; 22:232-45. [PMID: 21752925 DOI: 10.1101/gr.117226.110] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
DNA amplification, particularly of chromosomes 8 and 11, occurs frequently in breast cancer and is a key factor in tumorigenesis, often associated with poor prognosis. The mechanisms involved in the amplification of these regions are not fully understood. Studies from model systems have demonstrated that palindrome formation can be an early step in DNA amplification, most notably seen in the breakage-fusion-bridge (BFB) cycle. Therefore, palindromes might be associated with gene amplicons in breast cancer. To address this possibility, we coupled high-resolution palindrome profiling by the Genome-wide Analysis of Palindrome Formation (GAPF) assay with genome-wide copy-number analyses on a set of breast cancer cell lines and primary tumors to spatially associate palindromes and copy-number gains. We identified GAPF-positive regions distributed nonrandomly throughout cell line and tumor genomes, often in clusters, and associated with copy-number gains. Commonly amplified regions in breast cancer, chromosomes 8q and 11q, had GAPF-positive regions flanking and throughout the copy-number gains. We also identified amplification-associated GAPF-positive regions at similar locations in subsets of breast cancers with similar characteristics (e.g., ERBB2 amplification). These shared positive regions offer the potential to evaluate the utility of palindromes as prognostic markers, particularly in premalignant breast lesions. Our results implicate palindrome formation in the amplification of regions with key roles in breast tumorigenesis, particularly in subsets of breast cancers.
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Affiliation(s)
- Jamie Guenthoer
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
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Association between c-myc amplification and pathological complete response to neoadjuvant chemotherapy in breast cancer. Eur J Cancer 2011; 47:1779-88. [PMID: 21741827 DOI: 10.1016/j.ejca.2011.06.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2011] [Revised: 06/07/2011] [Accepted: 06/07/2011] [Indexed: 11/21/2022]
Abstract
BACKGROUND The aim of this study was to investigate whether c-myc amplification in human breast cancer is associated with response to neoadjuvant chemotherapy comprising paclitaxel followed by 5-FU/epirubicin/cyclophosphamide (P-FEC). METHODS Tumour tissue samples were obtained before neoadjuvant chemotherapy (P-FEC) from 100 primary breast cancer patients (stage II/III). C-myc and HER2 amplification were examined by FISH, and oestrogen receptor (ER), progesterone receptor (PR), Ki67, and topoisomerase 2α (TOP2A) expression were examined immunohistochemically. Pathological complete response (pCR) was defined by a complete loss of tumour cells in the breast without any lymph node metastasis. RESULTS C-myc amplification was observed in 40% (40/100) of breast tumours, and was significantly associated with ER-negative tumours (23/40 for ER(-) versus 17/60 for ER(+), P=0.004), high histological grade tumours (11/18 for grade 3 versus 29/82 for grades 1+2, P=0.043) and TOP2A-positive tumours (28/51 for TOP2A(+) versus 12/49 for TOP2A(-), P=0.002). pCR rate was 20% for total patients (10.0% for ER(+) and 35.0% for ER(-)). Further, breast tumours with c-myc amplification (c-myc(+)) showed a significantly (P=0.041) higher pCR rate (12/40) than those without such amplification (c-myc(-)) (8/60). This association between pCR and c-myc amplification was observed in ER-positive tumours (4/17 for c-myc(+) versus 2/43 for c-myc(-), P=0.048) but not in ER-negative tumours (8/23 for c-myc(+) versus 6/17 for c-myc(-), P=0.973). CONCLUSION Our results suggest that c-myc amplification is significantly associated with a high pCR rate to P-FEC in breast tumours, especially in ER-positive tumours.
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Brown J, Bothma H, Veale R, Willem P. Genomic imbalances in esophageal carcinoma cell lines involve Wnt pathway genes. World J Gastroenterol 2011; 17:2909-2923. [PMID: 21734802 PMCID: PMC3129505 DOI: 10.3748/wjg.v17.i24.2909] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Revised: 10/30/2010] [Accepted: 11/06/2010] [Indexed: 02/06/2023] Open
Abstract
AIM To identify molecular markers shared across South African esophageal squamous cell carcinoma (ESCC) cell lines using cytogenetics, fluorescence in situ hybridization (FISH) and single nucleotide polymorphism (SNP) array copy number analysis. METHODS We used conventional cytogenetics, FISH, and multicolor FISH to characterize the chromosomal rearrangements of five ESCC cell lines established in South Africa. The whole genome copy number profile was established from 250K SNP arrays, and data was analyzed with the CNAT 4.0 and GISTIC software. RESULTS We detected common translocation breakpoints involving chromosomes 1p11-12 and 3p11.2, the latter correlated with the deletion, or interruption of the EPHA3 gene. The most significant amplifications involved the following chromosomal regions and genes: 11q13.3 (CCND1, FGF3, FGF4, FGF19, MYEOV), 8q24.21(C-MYC, FAM84B), 11q22.1-q22.3 (BIRC2, BIRC3), 5p15.2 (CTNND2), 3q11.2-q12.2 (MINA) and 18p11.32 (TYMS, YES1). The significant deletions included 1p31.2-p31.1 (CTH, GADD45α, DIRAS3), 2q22.1 (LRP1B), 3p12.1-p14.2 (FHIT), 4q22.1-q32.1 (CASP6, SMAD1), 8p23.2-q11.1 (BNIP3L) and 18q21.1-q21.2 (SMAD4, DCC). The 3p11.2 translocation breakpoint was shared across four cell lines, supporting a role for genes involved at this site, in particular, the EPHA3 gene which has previously been reported to be deleted in ESCC. CONCLUSION The finding that a significant number of genes that were amplified (FGF3, FGF4, FGF19, CCND1 and C-MYC) or deleted (SFRP2 gene) are involved in the Wnt and fibroblast growth factor signaling pathways, suggests that these pathways may be activated in these cell lines.
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