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NPJ Breast Cancer

Benlong Yang, Jeff Chou, Yaozhong Tao, Dengbin Wu, Xinhong Wu, Xueqing Li, Yan Li, Yiwei Chu, Feng Tang, Yanxia Shi, Linlin Ma, Tong Zhou, William Kaufmann, Lisa A Carey, Jiong Wu, Zhiyuan Hu
Tumor-infiltrating lymphocytes (TIL) and immunity gene signatures have been reported to be significantly prognostic in breast cancer but have not yet been applied for calculation of risk of recurrence in clinical assays. A compact set of 17 immunity genes was derived herein from an Affymetrix-derived gene expression dataset including 1951 patients (AFFY1951). The 17 immunity genes demonstrated significant prognostic stratification of estrogen receptor (ER)-negative breast cancer patients with high proliferation gene expression...
2018: NPJ Breast Cancer
Kimberly S Keene, Tari King, E Shelley Hwang, Bo Peng, Kandace P McGuire, Coya Tapia, Hong Zhang, Sejong Bae, Faina Nakhlis, Nancy Klauber-Demore, Ingrid Meszoely, Michael S Sabel, Shawna C Willey, Agda Karina Eterovic, Cliff Hudis, Antonio C Wolff, Jennifer De Los Santos, Alastair Thompson, Gordon B Mills, Funda Meric-Bernstam
Breast cancer (BC) adjuvant therapy after mastectomy in the setting of 1-3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated molecular aberrations in primary cancers associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to non-recurrent controls. We identified 115 HER2 negative, therapy naïve, T 1-3 and N 0-1 BC patients treated with mastectomy but no post-mastectomy radiotherapy. This included 32 LRR, 34 DM, and 49 controls...
2018: NPJ Breast Cancer
Kevin H Kensler, Francisco Beca, Gabrielle M Baker, Yujing J Heng, Andrew H Beck, Stuart J Schnitt, Aditi Hazra, Bernard A Rosner, A Heather Eliassen, Susan E Hankinson, Myles Brown, Rulla M Tamimi
Sex steroid hormone signaling is critical in the development of breast cancers, although the role of the androgen receptor remains unclear. This study evaluated androgen receptor (AR) expression in normal breast tissue as a potential marker of breast cancer risk. We conducted a nested case-control study of women with benign breast disease (BBD) within the Nurses' Health Studies. Epithelial AR expression was assessed by immunohistochemistry in normal tissue from the BBD biopsy and the percent of positive nuclei was estimated in ordinal categories of 10% for 78 breast cancer cases and 276 controls...
2018: NPJ Breast Cancer
Rishi R Rawat, Daniel Ruderman, Paul Macklin, David L Rimm, David B Agus
In this pilot study, we introduce a machine learning framework to identify relationships between cancer tissue morphology and hormone receptor pathway activation in breast cancer pathology hematoxylin and eosin (H&E)-stained samples. As a proof-of-concept, we focus on predicting clinical estrogen receptor (ER) status-defined as greater than one percent of cells positive for estrogen receptor by immunohistochemistry staining-from spatial arrangement of nuclear features. Our learning pipeline segments nuclei from H&E images, extracts their position, shape and orientation descriptors, and then passes them to a deep neural network to predict ER status...
2018: NPJ Breast Cancer
Mark Jesus M Magbanua, Hope S Rugo, Louai Hauranieh, Ritu Roy, Janet H Scott, Jen Chieh Lee, Feng Hsiao, Eduardo V Sosa, Laura Van't Veer, Laura J Esserman, John W Park
Detection of disseminated tumor cells (DTCs) in bone marrow is an established negative prognostic factor. We isolated small pools of (~20) EPCAM-positive DTCs from early breast cancer patients for genomic profiling. Genome-wide copy number profiles of DTC pools ( n  = 45) appeared less aberrant than the corresponding primary tumors (PT, n  = 16). PIK3CA mutations were detected in 26% of DTC pools ( n  = 53), none of them were shared with matched PTs. Expression profiling of DTC pools ( n  = 30) confirmed the upregulation of EPCAM expression and certain oncogenes (e...
2018: NPJ Breast Cancer
Heather D Couture, Lindsay A Williams, Joseph Geradts, Sarah J Nyante, Ebonee N Butler, J S Marron, Charles M Perou, Melissa A Troester, Marc Niethammer
RNA-based, multi-gene molecular assays are available and widely used for patients with ER-positive/HER2-negative breast cancers. However, RNA-based genomic tests can be costly and are not available in many countries. Methods for inferring molecular subtype from histologic images may identify patients most likely to benefit from further genomic testing. To identify patients who could benefit from molecular testing based on H&E stained histologic images, we developed an image analysis approach using deep learning...
2018: NPJ Breast Cancer
Patrick S Dischinger, Elizabeth A Tovar, Curt J Essenburg, Zachary B Madaj, Eve E Gardner, Megan E Callaghan, Ashley N Turner, Anil K Challa, Tristan Kempston, Bryn Eagleson, Robert A Kesterson, Roderick T Bronson, Megan J Bowman, Carrie R Graveel, Matthew R Steensma
The key negative regulatory gene of the RAS pathway, NF1 , is mutated or deleted in numerous cancer types and is associated with increased cancer risk and drug resistance. Even though women with neurofibromatosis (germline NF1 mutations) have a substantially increased breast cancer risk at a young age and NF1 is commonly mutated in sporadic breast cancers, we have a limited understanding of the role of NF1 in breast cancer. We utilized CRISPR-Cas9 gene editing to create Nf1 rat models to evaluate the effect of Nf1 deficiency on tumorigenesis...
2018: NPJ Breast Cancer
Kim R M Blenman, Ting-Fang He, Paul H Frankel, Nora H Ruel, Erich J Schwartz, David N Krag, Lee K Tan, John H Yim, Joanne E Mortimer, Yuan Yuan, Peter P Lee
Tumor invasion into draining lymph nodes, especially sentinel lymph nodes (SLNs), is a key determinant of prognosis and treatment in breast cancer as part of the TNM staging system. Using multicolor histology and quantitative image analysis, we quantified immune cells within SLNs from a discovery cohort of 76 breast cancer patients. We found statistically more in situ CD3+ T cells in tumor negative vs. tumor positive nodes (mean of 8878 vs. 6704, respectively, p  = 0.006), but no statistical difference in CD20+ B cells or CD1a+ dendritic cells...
2018: NPJ Breast Cancer
Eleftherios P Mamounas, Christy A Russell, Anna Lau, Michelle P Turner, Kathy S Albain
In contemporary management of early-stage breast cancer, clinical decisions regarding adjuvant systemic therapy are increasingly made after considering both genomic assay results and clinico-pathologic features. Genomic information augments the prognostic information gleaned from clinico-pathologic features by providing risk estimates for distant recurrence and/or breast cancer-specific survival based on individual tumor biology. The 21-gene Oncotype DX Breast Recurrence Score® (RS) assay is validated to be prognostic and predictive of chemotherapy benefit in patients with hormone receptor-positive (HR+), HER2-negative early-stage breast cancer, regardless of nodal status...
2018: NPJ Breast Cancer
Judy C Boughey, Michael D Alvarado, Rachael B Lancaster, W Fraser Symmans, Rita Mukhtar, Jasmine M Wong, Cheryl A Ewing, David A Potter, Todd M Tuttle, Tina J Hieken, Jodi M Carter, James W Jakub, Henry G Kaplan, Claire L Buchanan, Nora T Jaskowiak, Husain A Sattar, Jeffrey Mueller, Rita Nanda, Claudine J Isaacs, Paula R Pohlmann, Filipa Lynce, Eleni A Tousimis, Jay C Zeck, M Catherine Lee, Julie E Lang, Paulette Mhawech-Fauceglia, Roshni Rao, Bret Taback, Margaret Chen, Kevin M Kalinsky, Hanina Hibshoosh, Brigid Killelea, Tara Sanft, Gillian L Hirst, Smita Asare, Jeffrey B Matthews, Jane Perlmutter, Laura J Esserman
Advances in the surgical management of the axilla in patients treated with neoadjuvant chemotherapy, especially those with node positive disease at diagnosis, have led to changes in practice and more judicious use of axillary lymph node dissection that may minimize morbidity from surgery. However, there is still significant confusion about how to optimally manage the axilla, resulting in variation among practices. From the viewpoint of drug development, assessment of response to neoadjuvant chemotherapy remains paramount and appropriate assessment of residual disease-the primary endpoint of many drug therapy trials in the neoadjuvant setting-is critical...
2018: NPJ Breast Cancer
Kathleen Van Dyk, Julienne E Bower, Catherine M Crespi, Laura Petersen, Patricia A Ganz
Cognitive changes after breast cancer treatment are often attributed to chemotherapy, without considering other important factors such as other treatments (e.g., surgery, radiation, endocrine therapy (ET)). We compared neuropsychological functioning in the domains of learning, memory, attention, visuospatial, executive function, and processing speed according to primary breast cancer treatment exposures in early survivorship, before the initiation of ET ( n  = 189). We were also interested in the association of neuropsychological functioning with select clinical, psychological, and behavioral factors...
2018: NPJ Breast Cancer
Shih-Ying Huang, Benjamin L Franc, Roy J Harnish, Gengbo Liu, Debasis Mitra, Timothy P Copeland, Vignesh A Arasu, John Kornak, Ella F Jones, Spencer C Behr, Nola M Hylton, Elissa R Price, Laura Esserman, Youngho Seo
Radiomics is an emerging technology for imaging biomarker discovery and disease-specific personalized treatment management. This paper aims to determine the benefit of using multi-modality radiomics data from PET and MR images in the characterization breast cancer phenotype and prognosis. Eighty-four features were extracted from PET and MR images of 113 breast cancer patients. Unsupervised clustering based on PET and MRI radiomic features created three subgroups. These derived subgroups were statistically significantly associated with tumor grade ( p  = 2...
2018: NPJ Breast Cancer
Esther Holgado, Jose Perez-Garcia, Maria Gion, Javier Cortes
Although the prognosis and prediction of therapeutic benefit for breast cancer patients overexpressing the human epidermal growth factor receptor 2 (HER2) have dramatically changed with the administration of anti-HER2-targeted therapies, HER2-positive metastatic breast cancer is still an incurable disease. Thus, new and better therapeutic options are urgently needed. Among them, are the agents stemming from the field of immunology that have been the focus of impressive scientific progress and new therapeutic opportunities seem to emerge "every day" in a variety of tumor types...
2018: NPJ Breast Cancer
Bastien Nguyen, David Venet, Hatem A Azim, David Brown, Christine Desmedt, Matteo Lambertini, Samira Majjaj, Giancarlo Pruneri, Fedro Peccatori, Martine Piccart, Françoise Rothé, Christos Sotiriou
Breast cancer diagnosed during pregnancy (BCP) is a rare and highly challenging disease. To investigate the impact of pregnancy on the biology of breast cancer, we conducted a comparative analysis of a cohort of BCP patients and non-pregnant control patients by integrating gene expression, copy number alterations and whole genome sequencing data. We showed that BCP exhibit unique molecular characteristics including an enrichment of non-silent mutations, a higher frequency of mutations in mucin gene family and an enrichment of mismatch repair deficiency mutational signature...
2018: NPJ Breast Cancer
Yuan-Ke Liang, Hao-Yu Lin, Xiao-Wei Dou, Min Chen, Xiao-Long Wei, Yong-Qu Zhang, Yang Wu, Chun-Fa Chen, Jing-Wen Bai, Ying-Sheng Xiao, Yu-Zhu Qi, Frank A E Kruyt, Guo-Jun Zhang
Basal-like breast cancer (BLBC) is an aggressive subtype with a strong tendency to metastasize. Due to the lack of effective chemotherapy, BLBC has a poor prognosis compared with luminal subtype breast cancer. MicroRNA-221 and -222 (miR-221/222) are overexpressed in BLBC and associate with metastasis as well as poor prognosis; however, the mechanisms by which miR-221/222 function as oncomiRs remain unknown. Here, we report that miR-221/222 expression is inversely correlated with Notch3 expression in breast cancer cell lines...
2018: NPJ Breast Cancer
Yanan Kuang, Bilal Siddiqui, Jiani Hu, Matthew Pun, MacIntosh Cornwell, Gilles Buchwalter, Melissa E Hughes, Nikhil Wagle, Paul Kirschmeier, Pasi A Jänne, Cloud P Paweletz, Nancy U Lin, Ian E Krop, William T Barry, Eric P Winer, Myles Brown, Rinath Jeselsohn
ESR1 mutations were recently found to be an important mechanism of endocrine resistance in ER-positive (ER + ) metastatic breast cancer. To determine the clinicopathological features driving the emergence of the ESR1 mutations we studied plasma cfDNA and detailed clinical data collected from patients with metastatic breast cancer. Droplet Digital PCR was performed for the detection of the most common ESR1 mutations and PIK3CA mutations. Among the patients with ER + /HER2- disease, ESR1 mutations were detected in 30% of the patients...
2018: NPJ Breast Cancer
Yoon-Sim Yap, Angad P Singh, John H C Lim, Jin-Hee Ahn, Kyung-Hae Jung, Jeongeun Kim, Rebecca A Dent, Raymond C H Ng, Sung-Bae Kim, Derek Y Chiang
Breast cancer is an increasing problem in Asia, with a higher proportion of premenopausal patients who are at higher risk of recurrence. Targeted sequencing was performed on DNA extracted from primary tumor specimens of 63 premenopausal Asian patients who relapsed after initial diagnosis of non-metastatic breast cancer. The most prevalent alterations included: TP53 (65%); PIK3CA (32%); GATA3 (29%); ERBB2 (27%); MYC (25%); KMT2C (21%); MCL1 (17%); PRKDC, TPR, BRIP1 (14%); MDM4, PCDH15, PRKAR1A, CDKN1B (13%); CCND1, KMT2D, STK11 , and MLH1 (11%)...
2018: NPJ Breast Cancer
Gábor Valcz, Edit Irén Buzás, Zoltán Szállási, Alexandra Kalmár, Tibor Krenács, Zsolt Tulassay, Péter Igaz, Béla Molnár
Carcinomas are complex structures composed of hierarchically organized distinct cell populations such as cancer stem cells and non-stem (bulk) cancer cells. Their genetic/epigenetic makeup and the dynamic interplay between the malignant cell populations and their stromal fibroblasts are important determinants of metastatic tumor invasion. Important mediators of these interactions are the small, membrane-enclosed extracellular vesicles, in particular exosomes. Both cancer cell and fibroblast-derived exosomes carry a set of regulatory molecules, including proteins and different species of RNA, which cooperatively support metastatic tumor spread...
2018: NPJ Breast Cancer
Valentina I Petkov, Dave P Miller, Nadia Howlader, Nathan Gliner, Will Howe, Nicola Schussler, Kathleen Cronin, Frederick L Baehner, Rosemary Cress, Dennis Deapen, Sally L Glaser, Brenda Y Hernandez, Charles F Lynch, Lloyd Mueller, Ann G Schwartz, Stephen M Schwartz, Antoinette Stroup, Carol Sweeney, Thomas C Tucker, Kevin C Ward, Charles Wiggins, Xiao-Cheng Wu, Lynne Penberthy, Steven Shak
[This corrects the article DOI: 10.1038/npjbcancer.2016.17.].
2018: NPJ Breast Cancer
Zsofia Sztupinszki, Miklos Diossy, Marcin Krzystanek, Lilla Reiniger, István Csabai, Francesco Favero, Nicolai J Birkbak, Aron C Eklund, Ali Syed, Zoltan Szallasi
The first genomic scar-based homologous recombination deficiency (HRD) measures were produced using SNP arrays. As array-based technology has been largely replaced by next generation sequencing approaches, it has become important to develop algorithms that derive the same type of genomic scar scores from next generation sequencing (whole exome "WXS", whole genome "WGS") data. In order to perform this analysis, we introduce here the scarHRD R package and show that using this method the SNP array-based and next generation sequencing-based derivation of HRD scores show good correlation (Pearson correlation between 0...
2018: NPJ Breast Cancer
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