168 results on '"Yunn-Yi Chen"'
Search Results
2. Molecular analysis of TCGA breast cancer histologic types
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Aatish Thennavan, Francisco Beca, Youli Xia, Susana Garcia-Recio, Kimberly Allison, Laura C. Collins, Gary M. Tse, Yunn-Yi Chen, Stuart J. Schnitt, Katherine A. Hoadley, Andrew Beck, and Charles M. Perou
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breast cancer ,histologic type ,PAM50 ,molecular subtype ,claudin-low ,mucinous ,Genetics ,QH426-470 ,Internal medicine ,RC31-1245 - Abstract
Summary: Breast cancer is classified into multiple distinct histologic types, and many of the rarer types have limited characterization. Here, we extend The Cancer Genome Atlas Breast Cancer (TCGA-BRCA) dataset with additional histologic type annotations in a total of 1,063 breast cancers. We analyze this extended dataset to define transcriptomic and genomic profiles of six rare, special histologic types: cribriform, micropapillary, mucinous, papillary, metaplastic, and invasive carcinoma with medullary pattern. We show the broader applicability of our constructed special histologic type gene signatures in the TCGA Pan-Cancer Atlas dataset with a predictive model that detects mucinous histologic type across cancers of other organ systems. Using a normal mammary cell differentiation score analysis, we order histologic types into a continuum from stem cell-like to luminal progenitor-like to mature luminal-like. Finally, we classify TCGA-BRCA into 12 consensus groups based on integrated genomic and histological features. We present a rich, openly accessible resource of genomic, molecular, and histologic characterization of TCGA-BRCA to enable studies across the range of breast cancers.
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- 2021
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3. Low-grade endometrial stromal sarcoma metastatic to the breast: Immunohistochemical and molecular characterization of an unusual mimic of mammary myofibroblastoma
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Daffolyn Rachael Fels Elliott, Melike Pekmezci, Katherine B. Geiersbach, Gregor Krings, Joseph T. Rabban, Charles Zaloudek, and Yunn-Yi Chen
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Endometrial stromal sarcoma ,Metastasis ,Breast ,Myofibroblastoma ,Immunohistochemistry ,Pathology ,RB1-214 - Abstract
We present a case of low-grade endometrial stromal sarcoma (ESS) that metastasized to the breast 25 years after the original diagnosis, with clinical, radiographic and pathologic follow-up data. The diagnosis of metastatic ESS was supported by the morphologic features of the breast tumor and its immunohistochemical profile, which included positive staining for CD10, WT1, estrogen receptor (ER) and progesterone receptor (PR). The diagnosis of metastatic ESS was confirmed by fluorescence in situ hybridization (FISH) testing, which revealed a characteristic JAZF1 gene rearrangement. The unusual clinical presentation raised a differential diagnosis that included mammary myofibroblastoma of the breast. We compared the morphologic characteristics and immunohistochemical profile of 15 low-grade ESS cases (8 primary and 7 metastatic) to eight cases of mammary myofibroblastoma. Immunostains that differentiated between these entities included CD34, retinoblastoma protein (Rb) and FOXL2. The pathologist can play a key role in the recognition of uncommon metastases to breast, and although rare, metastatic low-grade ESS should be included in the differential diagnosis of spindle cell tumors of the breast.
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- 2020
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4. High throughput identification of monoclonal antibodies to membrane bound and secreted proteins using yeast and phage display.
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Lequn Zhao, Liang Qu, Jing Zhou, Zhengda Sun, Hao Zou, Yunn-Yi Chen, James D Marks, and Yu Zhou
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Medicine ,Science - Abstract
Antibodies are ubiquitous and essential reagents for biomedical research. Uses of antibodies include quantifying proteins, identifying the temporal and spatial pattern of expression in cells and tissue, and determining how proteins function under normal or pathological conditions. Specific antibodies are only available for a small portion of the proteome, limiting study of those proteins for which antibodies do not exist. The technologies to generate target-specific antibodies need to be improved to obtain high quality antibodies to the proteome at reasonable cost. Here we show that renewable, validated, and standardized monoclonal antibodies can be generated at high throughput, without the need for antigen production or animal immunizations. In this study, 60 protein domains from 24 selected secreted proteins were expressed on the surface of yeast and used for selection of phage antibodies, over 400 monoclonal antibodies were identified within 3 weeks. A subset of these antibodies was validated for binding to cancer cells that overexpress the target protein by flow cytometry or immunohistochemistry. This approach will be applicable to many of the membrane-bound and the secreted proteins, 20-40% of the proteome, accelerating the timeline for Ab generation while reducing the cost.
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- 2014
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5. Multiple cancer/testis antigens are preferentially expressed in hormone-receptor negative and high-grade breast cancers.
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Yao-Tseng Chen, Dara S Ross, Rita Chiu, Xi K Zhou, Yunn-Yi Chen, Peishan Lee, Syed A Hoda, Andrew J Simpson, Lloyd J Old, Otavia Caballero, and A Munro Neville
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Medicine ,Science - Abstract
BACKGROUND: Cancer/testis (CT) antigens are protein antigens normally expressed only in germ cells of testis, and yet are expressed in a proportion of a wide variety of human cancers. CT antigens can elicit spontaneous immune responses in cancer patients with CT-positive cancers, and CT antigen-based therapeutic cancer vaccine trials are ongoing for "CT-rich" tumors. Although some previous studies found breast cancer to be "CT-poor", our recent analysis identified increased CT mRNA transcripts in the ER-negative subset of breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we performed a comprehensive immunohistochemical study to investigate the protein expression of eight CT genes in 454 invasive ductal carcinomas, including 225 ER/PR/HER2-negative (triple-negative) carcinomas. We found significantly more frequent expression of all eight CT antigens in ER-negative cancers, and five of them--MAGEA, CT7, NY-ESO-1, CT10 and CT45, were expressed in 12-24% of ER-negative cancers, versus 2-6% of ER-positive cancers (p2 cm). CONCLUSIONS/SIGNIFICANCE: CT antigens are preferentially expressed in hormone receptor-negative and high-grade breast cancer. Considering the limited treatment options for ER/PR/HER2 triple-negative breast cancer, the potential of CT-based immunotherapy should be explored.
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- 2011
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6. Large Scale Semi-Automated Labeling of Routine Free-Text Clinical Records for Deep Learning.
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Hari Trivedi, Maryam Panahiazar, April Liang, Dmytro Lituiev, Peter Chang, Jae Ho Sohn, Yunn-Yi Chen, Benjamin L. Franc, Bonnie Joe, and Dexter Hadley
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- 2019
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7. HER2 IHC Expression and Gene Amplification in p53-aberrant High-grade Endometrial Endometrioid Carcinoma Suggests That This Population May Benefit From HER2 Testing and Targeted Therapy
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Amy S. Joehlin-Price, Miglena K. Komforti, Nicholas R. Ladwig, Patrick Devine, Carrie Hoyle, Lauren McCoy, Cathy Sprague, Caroline Astbury, Raza Hoda, Yunn-Yi Chen, and Karuna Garg
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Surgery ,Anatomy ,Pathology and Forensic Medicine - Published
- 2023
8. Loss of PPARγ activity characterizes early protumorigenic stromal reprogramming and dictates the therapeutic window of opportunity.
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Caruso, Joseph A., Xianhong Wang, Murrow, Lyndsay M., Rodriguez, Carlos Ivan, Chen-Tanyolac, Chira, Vu, Lisa, Yunn-Yi Chen, Gascard, Philippe, Gartner, Zev J., Kerlikowske, Karla, and Tlsty, Thea D.
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PEROXISOME proliferator-activated receptors ,CANCER cells ,CARCINOMA in situ ,ENDOTHELIAL cells ,DUCTAL carcinoma ,REMANUFACTURING ,NATURAL products - Abstract
Although robustly expressed in the disease-free (DF) breast stroma, CD36 is consistently absent from the stroma surrounding invasive breast cancers (IBCs). In this study, we primarily observed CD36 expression in adipocytes and intralobular capillaries within the DF breast. Larger vessels concentrated in interlobular regions lacked CD36 and were instead marked by the expression of CD31. When evaluated in perilesional capillaries surrounding ductal carcinoma in situ, a nonobligate IBC precursor, CD36 loss was more commonly observed in lesions associated with subsequent IBC. Peroxisome proliferator-activated receptor γ (PPARγ) governs the expression of CD36 and genes involved in differentiation, metabolism, angiogenesis, and inflammation. Coincident with CD36 loss, we observed a dramatic suppression of PPARγ and its target genes in capillary endothelial cells (ECs) and pericytes, which typically surround and support the stability of the capillary endothelium. Factors present in conditioned media from malignant cells repressed PPARγ and its target genes not only in cultured ECs and pericytes but also in adipocytes, which require PPARγ for proper differentiation. In addition, we identified a role for PPARγ in opposing the transition of pericytes toward a tumor-supportive myofibroblast phenotype. In mouse xenograft models, early intervention with rosiglitazone, a PPARγ agonist, demonstrated significant antitumor effects; however, following the development of a palpable tumor, the antitumor effects of rosiglitazone were negated by the repression of PPARγ in the mouse stroma. In summary, PPARγ activity in healthy tissues places several stromal cell types in an antitumorigenic state, directly inhibiting EC proliferation, maintaining adipocyte differentiation, and suppressing the transition of pericytes into tumor-supportive myofibroblasts. [ABSTRACT FROM AUTHOR]
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- 2023
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9. Supplementary Figures 1-8 from CD36 Repression Activates a Multicellular Stromal Program Shared by High Mammographic Density and Tumor Tissues
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Thea D. Tlsty, Bahram Parvin, Karla Kerlikowske, Maria Febbraio, Elad Ziv, Judy A. Tjoe, James J. Marx, Donglei Hu, Jianxin Zhao, Mona L. Gauthier, Hal K. Berman, Gerald V. Fontenay, Yunn-Yi Chen, Joseph T. Rabban, Nancy Dumont, Hang Chang, and Rosa Anna DeFilippis
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PDF file - 1.1MB, Figure S1: Image quantitation Figure S2: Histograms of Oil Red O quantitation in LDAFs and HDAFs Figure S3: Matrix protein immunofluorescent images of LDAFs and HDAFs Figure S4: Increased and decreased expression of CD36 in HMFs Figure S5: CD36 immunohistochemistry controls Figure S6: Histograms of CD36 immunohistochemistry quantitation Figure S7: CD36, CD31 and CD68 staining in serial sections Figure S8: Representative breast map
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- 2023
10. Supplementary Tables 1-9 from CD36 Repression Activates a Multicellular Stromal Program Shared by High Mammographic Density and Tumor Tissues
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Thea D. Tlsty, Bahram Parvin, Karla Kerlikowske, Maria Febbraio, Elad Ziv, Judy A. Tjoe, James J. Marx, Donglei Hu, Jianxin Zhao, Mona L. Gauthier, Hal K. Berman, Gerald V. Fontenay, Yunn-Yi Chen, Joseph T. Rabban, Nancy Dumont, Hang Chang, and Rosa Anna DeFilippis
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PDF file - 392K, Tables S1, S2, S5, S6, S7 and S8: Patient information Table S3: LDAFs vs HDAFs microarray analysis Table S4: CD36 expression in published microarrays Table S9: Association of CD36 levels with tumor characteristics
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- 2023
11. Supplementary Figures Legends 1-8, Table Legends 1-9, Methods from CD36 Repression Activates a Multicellular Stromal Program Shared by High Mammographic Density and Tumor Tissues
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Thea D. Tlsty, Bahram Parvin, Karla Kerlikowske, Maria Febbraio, Elad Ziv, Judy A. Tjoe, James J. Marx, Donglei Hu, Jianxin Zhao, Mona L. Gauthier, Hal K. Berman, Gerald V. Fontenay, Yunn-Yi Chen, Joseph T. Rabban, Nancy Dumont, Hang Chang, and Rosa Anna DeFilippis
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PDF file - 131K
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- 2023
12. Standardizing Pathologic Evaluation of Breast Carcinoma After Neoadjuvant Chemotherapy
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Sunati Sahoo, Gregor Krings, Yunn-Yi Chen, Jodi M. Carter, Beiyun Chen, Hua Guo, Hanina Hibshoosh, Emily Reisenbichler, Fang Fan, Shi Wei, Laila Khazai, Ronald Balassanian, Molly E. Klein, Sonal Shad, Sara J. Venters, Alexander D. Borowsky, W. Fraser Symmans, and I. Tolgay Ocal
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Medical Laboratory Technology ,General Medicine ,Pathology and Forensic Medicine - Abstract
Context.— Neoadjuvant systemic therapy refers to the use of systemic agent(s) for malignancy prior to surgical treatment and has recently emerged as an option for most breast cancer patients eligible for adjuvant systemic therapy. Consequently, treated breast carcinomas have become routine specimens in pathology practices. A standard protocol has not yet been universally adopted for the evaluation and reporting of these specimens. The American Joint Committee on Cancer staging system recognizes the challenges in staging breast carcinomas after neoadjuvant treatment and provides important data points but does not currently provide detailed guidance in estimating the residual tumor burden in the breast and lymph nodes. The Residual Cancer Burden system is the only Web-based system that quantifies treatment response as a continuous variable using residual tumor burden in the breast and the lymph nodes. Objective.— To provide clarifications and guidance for evaluation and reporting of postneoadjuvant breast specimens, discuss issues with the current staging and reporting systems, and provide specific suggestions for future modifications to the American Joint Committee on Cancer system and the Residual Cancer Burden calculator. Data Sources.— English-language literature on the subject and the data from the I-SPY 2, a multicenter, adaptive randomization phase 2 neoadjuvant platform trial for early-stage, high-risk breast cancer patients. Conclusions.— This article highlights challenges in the pathologic evaluation and reporting of treated breast carcinomas and provides recommendations and clarifications for pathologists and clinicians. It also provides specific recommendations for staging and discusses future directions.
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- 2022
13. Data from Dense and Nondense Mammographic Area and Risk of Breast Cancer by Age and Tumor Characteristics
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Celine M. Vachon, Karla Kerlikowske, Steven R. Cummings, Andrew H. Beck, Lin Ma, Fang-Fang Wu, Bo Fan, Yunn-Yi Chen, John Shepherd, Fergus J. Couch, Daniel W. Visscher, Aaron D. Norman, V. Shane Pankratz, Matthew R. Jensen, Rulla M. Tamimi, Christopher G. Scott, and Kimberly A. Bertrand
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Background: Mammographic density (MD) is a strong breast cancer risk factor. We previously reported associations of percent mammographic density (PMD) with larger and node-positive tumors across all ages, and estrogen receptor (ER)–negative status among women ages Methods: Data were pooled from six studies including 4,095 breast cancers and 8,558 controls. DA and NDA were assessed from digitized film-screen mammograms and standardized across studies. Breast cancer odds by density phenotypes and age according to histopathologic characteristics and receptor status were calculated using polytomous logistic regression.Results: DA was associated with increased breast cancer risk [OR for quartiles: 0.65, 1.00 (Ref), 1.22, 1.55; Ptrend Ptrend Ptrend < 0.001) but no differences by nodal status. Among women + versus ER− tumors (Phet = 0.02), while NDA was more strongly associated with decreased risk of ER− versus ER+ tumors (Phet = 0.03).Conclusions: DA and NDA have differential associations with ER+ versus ER− tumors that vary by age.Impact: DA and NDA are important to consider when developing age- and subtype-specific risk models. Cancer Epidemiol Biomarkers Prev; 24(5); 798–809. ©2015 AACR.
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- 2023
14. Supplementary Figure S1 from Dense and Nondense Mammographic Area and Risk of Breast Cancer by Age and Tumor Characteristics
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Celine M. Vachon, Karla Kerlikowske, Steven R. Cummings, Andrew H. Beck, Lin Ma, Fang-Fang Wu, Bo Fan, Yunn-Yi Chen, John Shepherd, Fergus J. Couch, Daniel W. Visscher, Aaron D. Norman, V. Shane Pankratz, Matthew R. Jensen, Rulla M. Tamimi, Christopher G. Scott, and Kimberly A. Bertrand
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Distribution of dense area (DA) and non dense area (NDA) phenotypes prior to standardization. The age effect on DA and NDA as well as the differences in the distribution across the studies observed for breast cancer cases.
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- 2023
15. Supplementary Table S1 from Dense and Nondense Mammographic Area and Risk of Breast Cancer by Age and Tumor Characteristics
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Celine M. Vachon, Karla Kerlikowske, Steven R. Cummings, Andrew H. Beck, Lin Ma, Fang-Fang Wu, Bo Fan, Yunn-Yi Chen, John Shepherd, Fergus J. Couch, Daniel W. Visscher, Aaron D. Norman, V. Shane Pankratz, Matthew R. Jensen, Rulla M. Tamimi, Christopher G. Scott, and Kimberly A. Bertrand
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Characteristics of the study populations.
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- 2023
16. Supplementary Data from Protein Acetylation and Histone Deacetylase Expression Associated with Malignant Breast Cancer Progression
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E. Shelley Hwang, Frederic M. Waldman, Christopher C. Benz, Koei Chin, Sandy DeVries, Gary K. Scott, Yunn-Yi Chen, and Junko Suzuki
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Supplementary Data from Protein Acetylation and Histone Deacetylase Expression Associated with Malignant Breast Cancer Progression
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- 2023
17. Data from Protein Acetylation and Histone Deacetylase Expression Associated with Malignant Breast Cancer Progression
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E. Shelley Hwang, Frederic M. Waldman, Christopher C. Benz, Koei Chin, Sandy DeVries, Gary K. Scott, Yunn-Yi Chen, and Junko Suzuki
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Purpose: Excess histone deacetylase (HDAC) activity can induce hypoacetylation of histone and nonhistone protein substrates, altering gene expression patterns and cell behavior potentially associated with malignant transformation. However, HDAC expression and protein acetylation have not been studied in the context of breast cancer progression.Experimental Design: We assessed expression levels of acetylated histone H4 (ac-H4), ac-H4K12, ac-tubulin, HDAC1, HDAC2, and HDAC6 in 22 reduction mammoplasties and in 58 specimens with synchronous normal epithelium, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) components. Differences among groups were tested for significance using nonparametric tests.Results: From normal epithelium to DCIS, there was a marked reduction in histone acetylation (P < 0.0001). Most cases showed similar levels of acetylation in DCIS and IDC, although some showed further reduction of ac-H4 and ac-H4K12 from DCIS to IDC. Expression of HDAC1, HDAC2, and HDAC6 was also significantly reduced but by a smaller magnitude. Greater reductions of H4 acetylation and HDAC1 levels were observed from normal to DCIS in estrogen receptor–negative compared with estrogen receptor–positive, and in high-grade compared with non–high-grade tumors.Conclusion: Overall, there was a global pattern of hypoacetylation associated with progression from normal to DCIS to IDC. These findings suggest that the reversal of this hypoacetylation in DCIS and IDC could be an early measure of HDAC inhibitor activity.
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- 2023
18. Supplementary Figure Legends from Dense and Nondense Mammographic Area and Risk of Breast Cancer by Age and Tumor Characteristics
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Celine M. Vachon, Karla Kerlikowske, Steven R. Cummings, Andrew H. Beck, Lin Ma, Fang-Fang Wu, Bo Fan, Yunn-Yi Chen, John Shepherd, Fergus J. Couch, Daniel W. Visscher, Aaron D. Norman, V. Shane Pankratz, Matthew R. Jensen, Rulla M. Tamimi, Christopher G. Scott, and Kimberly A. Bertrand
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Supplementary Figure Legends from Dense and Nondense Mammographic Area and Risk of Breast Cancer by Age and Tumor Characteristics
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- 2023
19. Supplemental Methods, References and Figure Legends from Force Engages Vinculin and Promotes Tumor Progression by Enhancing PI3K Activation of Phosphatidylinositol (3,4,5)-Triphosphate
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Valerie M. Weaver, Yunn-Yi Chen, Michael W. Davidson, Matthew J. Paszek, Guanqing Ou, Yoshihiro Yui, Christopher C. DuFort, Russell Bainer, Luke Cassereau, and Matthew G. Rubashkin
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Supplemental Methods, References, and Figure Legends
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- 2023
20. Supplemental Figure 5 from Force Engages Vinculin and Promotes Tumor Progression by Enhancing PI3K Activation of Phosphatidylinositol (3,4,5)-Triphosphate
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Valerie M. Weaver, Yunn-Yi Chen, Michael W. Davidson, Matthew J. Paszek, Guanqing Ou, Yoshihiro Yui, Christopher C. DuFort, Russell Bainer, Luke Cassereau, and Matthew G. Rubashkin
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Vinculin is localized to cell-ECM borders in invasive breast cancer and adhesome proteins are upregulated across human cancers.
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- 2023
21. Supplemental Figure 4 from Force Engages Vinculin and Promotes Tumor Progression by Enhancing PI3K Activation of Phosphatidylinositol (3,4,5)-Triphosphate
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Valerie M. Weaver, Yunn-Yi Chen, Michael W. Davidson, Matthew J. Paszek, Guanqing Ou, Yoshihiro Yui, Christopher C. DuFort, Russell Bainer, Luke Cassereau, and Matthew G. Rubashkin
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Scanning angle interference microscopy - validation experiments.
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- 2023
22. Supplemental Figure 2 from Force Engages Vinculin and Promotes Tumor Progression by Enhancing PI3K Activation of Phosphatidylinositol (3,4,5)-Triphosphate
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Valerie M. Weaver, Yunn-Yi Chen, Michael W. Davidson, Matthew J. Paszek, Guanqing Ou, Yoshihiro Yui, Christopher C. DuFort, Russell Bainer, Luke Cassereau, and Matthew G. Rubashkin
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MECs remodel 3D collagen gels for cell invasion. Individual collagen fibers are stiff and >500nm in diameter.
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- 2023
23. Supplemental Figure 3 from Force Engages Vinculin and Promotes Tumor Progression by Enhancing PI3K Activation of Phosphatidylinositol (3,4,5)-Triphosphate
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Valerie M. Weaver, Yunn-Yi Chen, Michael W. Davidson, Matthew J. Paszek, Guanqing Ou, Yoshihiro Yui, Christopher C. DuFort, Russell Bainer, Luke Cassereau, and Matthew G. Rubashkin
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Vinculin nanoscale localization reflects altered molecular activity.
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- 2023
24. Supplemental Table 1 from Force Engages Vinculin and Promotes Tumor Progression by Enhancing PI3K Activation of Phosphatidylinositol (3,4,5)-Triphosphate
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Valerie M. Weaver, Yunn-Yi Chen, Michael W. Davidson, Matthew J. Paszek, Guanqing Ou, Yoshihiro Yui, Christopher C. DuFort, Russell Bainer, Luke Cassereau, and Matthew G. Rubashkin
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List of Adhesome, Oncogene and Control Genes used in Bioinformatics Analysis.
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- 2023
25. Supplemental Figure 1 from Force Engages Vinculin and Promotes Tumor Progression by Enhancing PI3K Activation of Phosphatidylinositol (3,4,5)-Triphosphate
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Valerie M. Weaver, Yunn-Yi Chen, Michael W. Davidson, Matthew J. Paszek, Guanqing Ou, Yoshihiro Yui, Christopher C. DuFort, Russell Bainer, Luke Cassereau, and Matthew G. Rubashkin
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ECM cues, malignant transformation, and integrin signaling, promote cell spreading and invasion.
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- 2023
26. Supplemental Table 2 from Force Engages Vinculin and Promotes Tumor Progression by Enhancing PI3K Activation of Phosphatidylinositol (3,4,5)-Triphosphate
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Valerie M. Weaver, Yunn-Yi Chen, Michael W. Davidson, Matthew J. Paszek, Guanqing Ou, Yoshihiro Yui, Christopher C. DuFort, Russell Bainer, Luke Cassereau, and Matthew G. Rubashkin
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List of Cancer Tissue with Unbiased Matched Normal Tissue used in Bioinformatics Analysis.
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- 2023
27. Genetic and immunohistochemical profiling of small cell and large cell neuroendocrine carcinomas of the breast
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Gregory R. Bean, Saleh Najjar, Sandra J. Shin, Elizabeth M. Hosfield, Jennifer L. Caswell-Jin, Anatoly Urisman, Kirk D. Jones, Yunn-Yi Chen, and Gregor Krings
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Class I Phosphatidylinositol 3-Kinases ,Carcinoma ,Intraductal ,Clinical Trials and Supportive Activities ,Breast Neoplasms ,Cell Cycle Proteins ,Large Cell ,Medical and Health Sciences ,Noninfiltrating ,Pathology and Forensic Medicine ,Carcinoma, Neuroendocrine ,Neuroendocrine Tumors ,Carcinoma, Intraductal, Noninfiltrating ,Neuroendocrine ,Clinical Research ,Proto-Oncogene Proteins ,Breast Cancer ,Pathology ,Carcinoma, Large Cell ,Humans ,Female ,Tumor Suppressor Protein p53 ,Carrier Proteins ,Cancer - Abstract
Neuroendocrine carcinomas (NEC) of the breast are exceedingly rare tumors, which are classified in the WHO system as small cell (SCNEC) and large cell (LCNEC) carcinoma based on indistinguishable features from their lung counterparts. In contrast to lung and enteropancreatic NEC, the genomics of breast NEC have not been well-characterized. In this study, we examined the clinicopathologic, immunohistochemical, and genetic features of 13 breast NEC (7 SCNEC, 4 LCNEC, 2 NEC with ambiguous small versus large cell morphology [ANEC]). Co-alterations of TP53 and RB1 were identified in 86% (6/7) SCNEC, 100% (2/2) ANEC, and 50% (2/4) LCNEC. The one SCNEC without TP53/RB1 alteration had other p53 pathway aberrations (MDM2 and MDM4 amplification) and was immunohistochemically RB negative. PIK3CA/PTEN pathway alterations and ZNF703 amplifications were each identified in 46% (6/13) NEC. Two tumors (1 SCNEC, 1 LCNEC) were CDH1 mutated. By immunohistochemistry, 100% SCNEC (6/6) and ANEC (2/2) and 50% (2/4) LCNEC (83% NEC) showed RB loss, compared to 0% (0/8) grade 3 neuroendocrine tumors (NET) (p
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- 2022
28. Triple-Negative Apocrine Carcinomas: Toward a Unified Group With Shared Molecular Features and Clinical Behavior
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Christopher J. Schwartz, Jeanette Ruiz, Gregory R. Bean, Deepika Sirohi, Nancy M. Joseph, Elizabeth M. Hosfield, Timothy W. Jacobs, Rita A. Mukhtar, Yunn-Yi Chen, and Gregor Krings
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Pathology and Forensic Medicine - Published
- 2023
29. Correction to: Genetic and immunohistochemical profiling of small cell and large cell neuroendocrine carcinomas of the breast
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Gregory R. Bean, Saleh Najjar, Sandra J. Shin, Elizabeth M. Hosfield, Jennifer L. Caswell-Jin, Anatoly Urisman, Kirk D. Jones, Yunn-Yi Chen, and Gregor Krings
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Pathology and Forensic Medicine - Published
- 2022
30. Abstract PS4-09: Pathologic features of the inter-regimen biopsy predict response to neoadjuvant therapy in the I-SPY 2 TRIAL
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Molly Klein, Alexander D. Borowsky, Gregor Krings, Ronald Balassanian, I Tolgay Ocal, Sunati Sahoo, Denise M. Wolf, Kimberley Cole, Shuko Harada, Amy L. Delson, Laura van 't Veer, Kamaljeet Singh, Kimmie Rabe, W. Fraser Symmans, Sara J. Venters, Sonal Shad, Yunn-Yi Chen, Laura J. Esserman, Malini Harigopal, Lamorna Brown-Swigart, Jodi M. Carter, and Laila Khazai
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Cancer Research ,Regimen ,medicine.medical_specialty ,Oncology ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Biopsy ,medicine ,Radiology ,business ,Neoadjuvant therapy - Abstract
Background: I-SPY 2 is a neoadjuvant platform trial open to patients with locally advanced, molecular high-risk breast cancer. In a concerted pursuit of mid-therapy response biomarkers, we evaluated inter-regimen biopsies, to identify patients who may be candidates for treatment de-escalation. In a pilot study, we observed that absence of carcinoma in an inter-regimen biopsy may predict pathologic complete response (pCR). In this expanded study of 100 participants, we sought to confirm that finding and assess pathologic features of the inter-regimen biopsy as predictors of tumor response to neoadjuvant therapy. Methods: Digital H&E images of 100 inter-regimen (12 week) image-guided breast biopsies +/- ancillary immunohistochemistry (p63 and/or cytokeratin) were reviewed by 9 I-SPY affiliated pathologists to record 1) tumor bed and 2) presence/absence of residual invasive carcinoma (IC) (with tumor cellularity scored as 0-100%). The data set included 393 cores (mean 3.9 (2-4) cores/biopsy). Fisher’s exact t-test was used for association of presence/absence of IC with pCR, and tumoral hormone receptor (HR) and HER2 status. Association between biopsy tumor cellularity and residual cancer burden (RCB) indices used Pearson’s correlation. Results: In the biopsy set, 84 (84%) had ≥80% inter-observer diagnostic agreement on both 1) presence of tumor bed and 2) presence/absence of IC (53 IC+ /31 IC-). IC+/IC- biopsies had equal numbers of evaluable tissue cores. The primary tumors were 63% HR+/37% HR-. The presence of IC in the biopsy correlated with tumoral HR/HER2 status (p=0.0014: 74%: HR+HER2-; 62%: TN; 60%: HR+HER2+; 10%: HR-HER2+). Of 31 patients with IC- biopsies, 25 (80%) went on to pCR, whereas only 7/53 (13%) of patients with IC+ biopsies had pCR, conferring an odds ratio for pCR of 26, Fisher p=7.5E-10. Overall, IC- biopsies had a positive predictive value (PPV) for pCR of 81%, with a PPV for HR- tumors of 94% vs. 67% for HR+ tumors (Table 1). In the 6 IC- biopsies from patients with non-pCR (“false-negatives”), most were HR+ (5/6, Table 1), and tumor bed size in the resection specimen was smaller than for IC+ biopsies with non-pCR: 276 mm2 (0.4-1000 mm2) vs. 1166 mm2 (1-11960 mm2). In contrast, the 46/53 IC+ biopsies in patients with non-pCR had a PPV for predicting non-pCR of 86%, (PPV for HR+ tumors: 94% vs. PPV for HR- tumors: 66%. Tumor cellularity in the biopsy (mean 37%, [2.5-93%]) did not correlate with RCB index (p=0.57) or RCB breast-only index (p = 0.17) at resection. Conclusion: In this 100 biopsy set from the I-SPY2 trial, the absence of residual carcinoma in inter-regimen biopsies was highly predictive of pCR, particularly for HR- tumors. The “false-negative” biopsies (IC-/non-pCR) were predominantly HR+ tumors with small residual tumor beds at resection. Conversely, the presence of carcinoma in inter-regimen biopsies was highly predictive of non-pCR, particularly for HR+ tumors. These data demonstrate the utility, and the limitations, of the inter-regimen biopsy as one tool to identify patients who may benefit from therapeutic de-escalation. Table 1: PPV for pCR/non-PCR by Inter-regimen Biopsy StatusInter-regimen biopsy with or without Invasive carcinoma (IC+/-)pCRnon-pCRPPV (Sensitivity) for pCR(IC- Biopsies)PPV (Sensitivity) for non-pCR(IC+ biopsies)IC- biopsiesAll25681% (78%)-HR+10567% (83%)-HR-15194% (75%)-IC+ biopsiesAll746-86% (88%)HR+236-94% (88%)HR-510-66% (91%) Citation Format: Jodi M Carter, Molly E Klein, Sara J Venters, Kimmie Rabe, I Tolgay Ocal, Kamaljeet Singh, Denise M Wolf, Sunati Sahoo, Shuko Harada, Laila Khazai, Malini Harigopal, Alexander D Borowsky, Gregor Krings, Ronald Balassanian, Yunn-Yi Chen, Kimberley Cole, Sonal Shad, Amy Delson, Lamorna Brown-Swigart, I-SPY 2 TRIAL Consortium, Laura Esserman, Laura van ‘t Veer, W Fraser Symmans. Pathologic features of the inter-regimen biopsy predict response to neoadjuvant therapy in the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-09.
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- 2021
31. Abstract PS4-10: Serial MRI and pathology combined to select candidates for therapy de-escalation in the I-SPY 2 TRIAL
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Sonal Shad, Nola M. Hylton, Alexander D. Borowsky, David C. Newitt, Shuko Harada, Sara J. Venters, Ronald Balassanian, Molly Klein, I Tolgay Ocal, Sunati Sahoo, Wen Li, Kamaljeet Singh, Kimmie Rabe, Amy L. Delson, Laura van 't Veer, Christina Yau, Gregor Krings, W. Fraser Symmans, Natsuko Onishi, Kimberley Cole, Jessica Gibbs, Jodi M. Carter, Laila Khazai, Malini Harigopal, Barbara LeStage, Yunn-Yi Chen, Denise M. Wolf, Sandra Finestone, Laura J. Esserman, and Lamorna Brown-Swigart
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Cancer Research ,medicine.medical_specialty ,Oncology ,business.industry ,medicine ,Radiology ,business ,De-escalation - Abstract
Background: The I-SPY 2 TRIAL, open to patients with locally advanced, molecular high-risk breast cancer, aims to bring each patient to pathologic complete response (pCR) with a minimum of toxicity. Here we test the hypothesis that imaging (MR volume predictors) combined with core biopsy may be used to accurately select candidates who show early response and provide an option of treatment de-escalation at mid-therapy (12 weeks). Methods: Of 100 I-SPY 2 patients with pathologist-assessed core biopsies at the inter-regimen time point (~12 weeks through treatment) and pCR data, 87 also had serial MR images and were considered in this study. Eleven I-SPY 2 TRIAL pathologists independently provided a digital assessment of the presence or absence of residual invasive cancer from H&E stained, and any requested ancillary IHC, images from imaging-guided core biopsies. Pathology predicts pCR if there is a consensus of no invasive residual disease. We generated predictions for all (55) unique pairs over the 11 pathologists, where pCR is predicted if both pathologists find no invasive cells. MRI pCR prediction models were previously developed on an independent dataset of ~990 I-SPY 2 patients, and applied to this cohort. Volume-based prediction models were previously optimized within each subtype and predicted probability thresholds were selected over a range of positive predictive value (PPV). In this study, MR predicts pCR (positive test) if the predicted probability is above a threshold that yields a given PPV value. For each pathologist pair, we combined pathology-based and MR-based predictors into a predictive-RCB (pre-RCB); and pre-RCB predicts a patient as pCR (RCB0) if both MR and pathology predicts pCR. Predictive performance is assessed by calculating the mean and range of PPV and sensitivity.Results: 39% (34/87) of the patients in this study achieved pCR. Over all pairs of pathologists, on average 80% of pathology-only predicted pCRs were true pCRs (mean PPV = 80% [range: 69-92%]), and 74% of patients who achieved pCR were predicted pCR by pathology alone (mean sensitivity = 74% [65-82%]). We assessed combinations with MR probability thresholds at PPV levels 50%-70%; and observed the best balance of PPV and sensitivity for the pre-RCB when MR thresholds were set at 50% PPV level. At this threshold setting, the pre-RCB achieved a PPV = 92% [83-100%], meaning on average 92% of predicted pCRs were true pCRs, and this improvement in positive predictive performance over pathology alone is achieved with a lower but still-reasonable 53% sensitivity [33-62%]. Conclusion: Pre-RCB, which predicts a patient as pCR if both MR and inter-regimen pathology predicts pCR, provides clinically actionable accuracy for treatment de-escalation for early responders (PPV>90%). Adding a final MR review at the time of early surgery may further improve performance. Resulting from data presented in this abstract, the pre-RCB algorithm, including the final MR review, has been operationalized and will be used prospectively to identify patients who are highly likely to have already achieved pCR by the inter-regimen timepoint. Citation Format: Sara J Venters, Wen Li, Denise M Wolf, Jodi M Carter, Molly E Klein, Kamaljeet Singh, Kimmie Rabe, I Tolgay Ocal, David Newitt, Christina Yau, Natsuko Onishi, Jessica Gibbs, Sunati Sahoo, Shuko Harada, Laila Khazai, Malini Harigopal, Alexander D Borowsky, Gregor Krings, Ronald Balassanian, Yunn-Yi Chen, Kimberley Cole, Sonal Shad, Barbara LeStage, Amy Delson, Sandra Finestone, Lamorna Brown-Swigart, I-SPY 2 Imaging Working Group, I-SPY 2 TRIAL Consortium, Laura Esserman, Laura van ‘t Veer, W Fraser Symmans, Nola M Hylton. Serial MRI and pathology combined to select candidates for therapy de-escalation in the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-10.
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- 2021
32. Association of mammographic density measures and breast cancer 'intrinsic' molecular subtypes
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Aaron D. Norman, Rulla M. Tamimi, Christopher G. Scott, Celine M. Vachon, Kimberly A. Bertrand, Yunn Yi Chen, Fergus J. Couch, Steven R. Cummings, John A. Shepherd, Fang Fang Wu, V. Shane Pankratz, Matthew R. Jensen, Karla Kerlikowske, Kathleen R. Brandt, Stacey J. Winham, Geffen Kleinstern, and Daniel W. Visscher
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Receptor, ErbB-2 ,Estrogen receptor ,Breast Neoplasms ,Logistic regression ,Article ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Risk Factors ,Internal medicine ,Progesterone receptor ,Biomarkers, Tumor ,medicine ,Humans ,Aged ,Breast Density ,business.industry ,MAMMOGRAPHIC DENSITY ,Odds ratio ,Middle Aged ,medicine.disease ,Confidence interval ,030104 developmental biology ,Receptors, Estrogen ,Case-Control Studies ,030220 oncology & carcinogenesis ,Female ,Receptors, Progesterone ,business ,Body mass index - Abstract
We evaluated the association of percent mammographic density (PMD), absolute dense area (DA), and non-dense area (NDA) with risk of “intrinsic” molecular breast cancer (BC) subtypes. We pooled 3492 invasive BC and 10,148 controls across six studies with density measures from prediagnostic, digitized film-screen mammograms. We classified BC tumors into subtypes [63% Luminal A, 21% Luminal B, 5% HER2 expressing, and 11% as triple negative (TN)] using information on estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and tumor grade. We used polytomous logistic regression to calculate odds ratio (OR) and 95% confidence intervals (CI) for density measures (per SD) across the subtypes compared to controls, adjusting for age, body mass index and study, and examined differences by age group. All density measures were similarly associated with BC risk across subtypes. Significant interaction of PMD by age (P = 0.001) was observed for Luminal A tumors, with stronger effect sizes seen for younger women
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- 2021
33. Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression
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Johnathon N. Lakins, Thanh T. Pham, Ori Maller, Irene Acerbi, Andrew C. Nelson, Travis Nemkov, Hellen Kuasne, Allison P. Drain, Olöf Bjarnadottir, Igor Zakharevich, Morag Park, Brian Ruffell, J. Matthew Barnes, Kirk C. Hansen, Aastha Chauhan, E. Shelley Hwang, Valerie M. Weaver, Lisa M. Coussens, Aqsa Nasir, Alexander S. Barrett, Signe Borgquist, Jessica Gruenberg, Tina Gruosso, Peter Kabos, Zena Werb, and Yunn Yi Chen
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Breast Neoplasms/immunology ,Biopsy ,02 engineering and technology ,01 natural sciences ,Metastasis ,Protein-Lysine 6-Oxidase ,chemistry.chemical_compound ,Tumor-Associated Macrophages ,2.1 Biological and endogenous factors ,General Materials Science ,Cancer ,Tumor ,biology ,Chemistry ,Tumor-Associated Macrophages/metabolism ,Middle Aged ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,Protein-Lysine 6-Oxidase/metabolism ,Mechanics of Materials ,cardiovascular system ,Immunohistochemistry ,Female ,Collagen ,0210 nano-technology ,Adult ,Stromal cell ,Lysyl hydroxylase ,Stromal Cells/metabolism ,Breast Neoplasms ,Lysyl oxidase ,macromolecular substances ,010402 general chemistry ,Article ,Cell Line ,Stroma ,Cell Line, Tumor ,Collagen/metabolism ,Breast Cancer ,medicine ,Humans ,Nanoscience & Nanotechnology ,Mechanical Engineering ,technology, industry, and agriculture ,General Chemistry ,medicine.disease ,0104 chemical sciences ,Hydroxylysine ,biology.protein ,Cancer research ,Stromal Cells - Abstract
Stromal stiffening accompanies malignancy, compromises treatment and promotes tumour aggression. Clarifying the molecular nature and the factors that regulate stromal stiffening in tumours should identify biomarkers to stratify patients for therapy and interventions to improve outcome. We profiled lysyl hydroxylase-mediated and lysyl oxidase-mediated collagen crosslinks and quantified the greatest abundance of total and complex collagen crosslinks in aggressive human breast cancer subtypes with the stiffest stroma. These tissues harbour the highest number of tumour-associated macrophages, whose therapeutic ablation in experimental models reduced metastasis, and decreased collagen crosslinks and stromal stiffening. Epithelial-targeted expression of the crosslinking enzyme, lysyl oxidase, had no impact on collagen crosslinking in PyMT mammary tumours, whereas stromal cell targeting did. Stromal cells in microdissected human tumours expressed the highest level of collagen crosslinking enzymes. Immunohistochemical analysis of biopsies from a cohort of patients with breast cancer revealed that stromal expression of lysyl hydroxylase 2, an enzyme that induces hydroxylysine aldehyde-derived collagen crosslinks and stromal stiffening, correlated significantly with disease specific mortality. The findings link tissue inflammation, stromal cell-mediated collagen crosslinking and stiffening to tumour aggression and identify lysyl hydroxylase 2 as a stromal biomarker.
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- 2020
34. Invasive Lobular Carcinoma
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Eliah R. Shamir, Helena Hwang, and Yunn-Yi Chen
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- 2022
35. Atypical Lobular Hyperplasia and Lobular Carcinoma In Situ
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Gregor Krings, Helena Hwang, and Yunn-Yi Chen
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- 2022
36. Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer:a multicentre pooled analysis of 5161 patients
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Christina Yau, Marie Osdoit, Marieke van der Noordaa, Sonal Shad, Jane Wei, Diane de Croze, Anne-Sophie Hamy, Marick Laé, Fabien Reyal, Gabe S Sonke, Tessa G Steenbruggen, Maartje van Seijen, Jelle Wesseling, Miguel Martín, Maria del Monte-Millán, Sara López-Tarruella, Judy C Boughey, Matthew P Goetz, Tanya Hoskin, Rebekah Gould, Vicente Valero, Stephen B Edge, Jean E Abraham, John M S Bartlett, Carlos Caldas, Janet Dunn, Helena Earl, Larry Hayward, Louise Hiller, Elena Provenzano, Stephen-John Sammut, Jeremy S Thomas, David Cameron, Ashley Graham, Peter Hall, Lorna Mackintosh, Fang Fan, Andrew K Godwin, Kelsey Schwensen, Priyanka Sharma, Angela M DeMichele, Kimberly Cole, Lajos Pusztai, Mi-Ok Kim, Laura J van 't Veer, Laura J Esserman, W Fraser Symmans, Kathi Adamson, Kathy S. Albain, Adam L. Asare, Smita M. Asare, Ron Balassanian, Heather Beckwith, Scott M. Berry, Donald A. Berry, Judy C. Boughey, Meredith B. Buxton, Yunn-Yi Chen, Beiyun Chen, A. Jo Chien, Stephen Y. Chui, Amy S. Clark, Julia L. Clennell, Brian Datnow, Angela M. DeMichele, Xiuzhen Duan, Kirsten K. Edmiston, Anthony D. Elias, Erin D. Ellis, Laura L. Esserman, David M. Euhus, Oluwole Fadare, Michael D Feldman, Andres Forero-Torres, Barbara B. Haley, Hyo S. Han, Shuko Harada, Patricia Haugen, Teresa Helsten, Gillian L. Hirst, Nola M. Hylton, Claudine Isaacs, Kathleen Kemmer, Qamar J. Khan, Laila Khazai, Molly E. Klein, Gregor Krings, Julie E. Lang, Lauren G. LeBeau, Brian Leyland-Jones, Minetta C. Liu, Shelly Lo, Janice Lu, Anthony Magliocco, Jeffrey B. Matthews, Michelle E. Melisko, Paulette Mhawech-Fauceglia, Stacy L. Moulder, Rashmi K. Murthy, Rita Nanda, Donald W. Northfelt, Idris T. Ocal, Olufunmilayo Olopade, Stefan Pambuccian, Melissa Paoloni, John W. Park, Barbara A. Parker, Jane Perlmutter, Garry Peterson, Mara Rendi, Hope S. Rugo, Sunati Sahoo, Sharon Sams, Ashish Sanil, Husain Sattar, Richard B. Schwab, Ruby Singhrao, Katherine Steeg, Erica Stringer-Reasor, W. Fraser Symmans, Ossama Tawfik, Debasish Tripathy, Megan L. Troxell, Laura J. van't Veer, Sara J. Venters, Tuyethoa Vinh, Rebecca K. Viscusi, Anne M. Wallace, Shi Wei, Amy Wilson, Douglas Yee, Jay C. Zeck, and Pathology
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Adult ,Neoplasm, Residual ,Adolescent ,Receptor, ErbB-2 ,Oncology and Carcinogenesis ,Breast Neoplasms ,RC0254 ,Young Adult ,ErbB-2 ,Clinical Research ,Breast Cancer ,80 and over ,Humans ,Chemotherapy ,Oncology & Carcinogenesis ,Adjuvant ,Aged ,Cancer ,Aged, 80 and over ,Evaluation of treatments and therapeutic interventions ,Middle Aged ,Neoadjuvant Therapy ,Oncology ,Chemotherapy, Adjuvant ,Residual ,6.1 Pharmaceuticals ,Neoplasm ,Female ,I-SPY 2 Trial Consortium ,Patient Safety ,Receptor - Abstract
Background: Previous studies have independently validated the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. We used results from several independent cohorts in a pooled patient-level analysis to evaluate the relationship of RCB with long-term prognosis across different phenotypic subtypes of breast cancer, to assess generalisability in a broad range of practice settings. Methods: In this pooled analysis, 12 institutes and trials in Europe and the USA were identified by personal communications with site investigators. We obtained participant-level RCB results, and data on clinical and pathological stage, tumour subtype and grade, and treatment and follow-up in November, 2019, from patients (aged ≥18 years) with primary stage I–III breast cancer treated with neoadjuvant chemotherapy followed by surgery. We assessed the association between the continuous RCB score and the primary study outcome, event-free survival, using mixed-effects Cox models with the incorporation of random RCB and cohort effects to account for between-study heterogeneity, and stratification to account for differences in baseline hazard across cancer subtypes defined by hormone receptor status and HER2 status. The association was further evaluated within each breast cancer subtype in multivariable analyses incorporating random RCB and cohort effects and adjustments for age and pretreatment clinical T category, nodal status, and tumour grade. Kaplan-Meier estimates of event-free survival at 3, 5, and 10 years were computed for each RCB class within each subtype. Findings: We analysed participant-level data from 5161 patients treated with neoadjuvant chemotherapy between Sept 12, 1994, and Feb 11, 2019. Median age was 49 years (IQR 20–80). 1164 event-free survival events occurred during follow-up (median follow-up 56 months [IQR 0–186]). RCB score was prognostic within each breast cancer subtype, with higher RCB score significantly associated with worse event-free survival. The univariable hazard ratio (HR) associated with one unit increase in RCB ranged from 1·55 (95% CI 1·41–1·71) for hormone receptor-positive, HER2-negative patients to 2·16 (1·79–2·61) for the hormone receptor-negative, HER2-positive group (with or without HER2-targeted therapy; p
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- 2022
37. Less Common Triple-Negative Breast Cancers
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Poonam Vohra, Yunn-Yi Chen, and Gregor Krings
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- 2022
38. Clinicopathologic Study of Gleason Pattern 5 Prostatic Adenocarcinoma With 'Single-cell' Growth Reveals 2 Distinct Types, One With 'Plasmacytoid' Features
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Jane K. Nguyen, Jesse K. McKenney, Cristina Magi-Galluzzi, and Yunn-Yi Chen
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Male ,Biochemical recurrence ,Delta Catenin ,Pathology ,medicine.medical_specialty ,Lymphovascular invasion ,030232 urology & nephrology ,Adenocarcinoma ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Antigens, CD ,Cytology ,Biomarkers, Tumor ,Carcinoma ,medicine ,Humans ,Prospective Studies ,Aged ,Neoplasm Staging ,Retrospective Studies ,Homeodomain Proteins ,Prostatectomy ,030219 obstetrics & reproductive medicine ,business.industry ,Prostatic Neoplasms ,Bone metastasis ,Catenins ,Middle Aged ,Prostate-Specific Antigen ,Cadherins ,medicine.disease ,Treatment Outcome ,Concomitant ,Cribriform ,Immunohistochemistry ,Kallikreins ,Surgery ,Neoplasm Grading ,Anatomy ,business ,Transcription Factors - Abstract
Each Gleason score category of prostatic adenocarcinoma (or Grade Group) may encompass a diverse group of architectural patterns such as well-formed glands, poorly formed glands, cribriform structures, single cells, and/or solid sheets. We have noted heterogeneity within the single-cell subtype of Gleason pattern 5 prostatic adenocarcinoma that has not been fully addressed. Therefore, we retrospectively reviewed a series of radical prostatectomies with high-grade prostatic adenocarcinoma (Grade Group 4 or 5), identifying tumors with a component of single-cell infiltration. Additional cases identified prospectively were also included. TNM status, association with other histologic patterns, and clinical follow-up status were determined. Immunohistochemistry for NKX3.1, E-cadherin, p120 catenin, and prostate-specific antigen (PSA) were performed in each case. Eighteen cases with a component of well-developed Gleason pattern 5 characterized by single infiltrative cells that comprised ≥5% of the tumor were identified (15/202 retrospective radical prostatectomies with the high-grade disease [7.5%]). The single-cell pattern ranged from 5% to 50% of the tumor volume, with 5 cases containing ≥40%, and variable secondary architecture included diffuse infiltrating single cells with targetoid growth pattern around benign glands, solid expansive nests of noncohesive cells, and corded/single file growth pattern. Further morphologic analysis demonstrated 2 distinct histologic subtypes: (1) (subtype 1; n=9) monomorphic "plasmacytoid" tumor cells with eccentrically placed nuclei and variable intracytoplasmic vacuoles with bland cytology and discohesion and (2) (subtype 2; n=9) more cohesive tumor cells with greater cytologic atypia characterized by prominent nucleoli, greater variability in nuclear size/shape, occasional mitotic figures, and more irregular infiltration. By immunohistochemistry, NKX3.1 nuclear expression and PSA cytoplasmic expression was retained in all cases. Concomitant membranous E-cadherin loss and strong cytoplasmic p120 catenin expression were present in 5 of the 18 (28%) cases, all in subtype 1 (5/9, 56%). Overall, 56% (10/18) of patients had advanced-stage disease (≥pT3b), and 70% (7/10) of these patients had associated lymphovascular invasion. All patients had concomitant cribriform patterns of carcinoma. The outcome was available for 14 patients: 4 died of unknown cause; 6 had biochemical recurrence with distant bone metastasis in 5 of the 6; and 4 patients with
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- 2020
39. Primary mammary angiosarcomas harbor frequent mutations in KDR and PIK3CA and show evidence of distinct pathogenesis
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Gregor Krings, Gregory R. Bean, Robert B. West, Elizabeth M. Hosfield, Francisco Beca, Kimberly H. Allison, Yunn-Yi Chen, Richard K. Sibley, Megan L. Troxell, and Poonam Vohra
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Somatic hypermutation ,Biology ,medicine.disease ,Pathology and Forensic Medicine ,Metastasis ,Loss of heterozygosity ,Pathogenesis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Breast cancer ,030220 oncology & carcinogenesis ,medicine ,Immunohistochemistry ,Angiosarcoma ,Sarcoma ,neoplasms - Abstract
Angiosarcoma (AS) is the most frequent primary sarcoma of the breast but nevertheless remains uncommon, accounting for
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- 2020
40. Immunohistochemical analysis of IDH2 R172 hotspot mutations in breast papillary neoplasms: applications in the diagnosis of tall cell carcinoma with reverse polarity
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Emad A. Rakha, Elaine Zhong, Dilip Giri, Laura C. Collins, Juan P. Palazzo, John R. Lozada, Jorge S. Reis-Filho, Fresia Pareja, Malcolm Hayes, Hannah Y Wen, Achim A. Jungbluth, Denise Frosina, Melinda E. Sanders, Britta Weigelt, Felipe C Geyer, Timothy M. D'Alfonso, Yunn-Yi Chen, Edi Brogi, Rohit Bhargava, Fatemeh Derakhshan, Thais Basili, Stuart J. Schnitt, Gregor Krings, Arnaud Da Cruz Paula, Edaise M da Silva, and Syed A. Hoda
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0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Pathology ,medicine.medical_specialty ,Breast Neoplasms ,Biology ,Medical and Health Sciences ,IDH2 ,Article ,Pathology and Forensic Medicine ,Thyroid carcinoma ,03 medical and health sciences ,0302 clinical medicine ,Biopsy ,Biomarkers, Tumor ,medicine ,Carcinoma ,Humans ,Aged ,Aged, 80 and over ,medicine.diagnostic_test ,Papillary Neoplasm ,Cell Polarity ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Carcinoma, Papillary ,Isocitrate Dehydrogenase ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Female ,Differential diagnosis ,Breast carcinoma - Abstract
Tall cell carcinoma with reverse polarity is a rare subtype of breast carcinoma with solid and papillary growth and nuclear features reminiscent of those of the tall cell variant of papillary thyroid carcinoma. These tumors harbor recurrent IDH2 R172 hotspot mutations or TET2 mutations, co-occurring with mutations in PI3K pathway genes. Diagnosis of tall cell carcinomas with reverse polarity is challenging in view of their rarity and the range of differential diagnosis. We sought to determine the sensitivity and specificity of IDH2 R172 immunohistochemistry for the detection of IDH2 R172 hotspot mutations in this entity. We evaluated 14 tall cell carcinomas with reverse polarity (ten excision and five core needle biopsy specimens), 13 intraductal papillomas, 16 solid papillary carcinomas, and 5 encapsulated papillary carcinomas by Sanger sequencing of the IDH2 R172 hotspot locus and of exons 9 and 20 of PIK3CA, and by immunohistochemistry using monoclonal antibodies (11C8B1) to the IDH2 R172S mutation. The 14 tall cell carcinomas with reverse polarity studied harbored IDH2 R172 hotspot mutations, which co-occurred with PIK3CA hotspot mutations in 50% of cases. None of the other papillary neoplasms analyzed displayed IDH2 R172 mutations, however PIK3CA hotspot mutations were detected in 54% of intraductal papillomas, 6% of solid papillary carcinomas, and 20% of encapsulated papillary carcinomas tested. Immunohistochemical analysis with anti-IDH2 R172S antibodies (11C8B1) detected IDH2 R172 mutated protein in 93% (14/15) of tall cell carcinomas with reverse polarity samples including excision (n = 9/10) and core needle biopsy specimens (n = 5), whereas the remaining papillary neoplasms (n = 34) were negative. Our findings demonstrate that immunohistochemical analysis of IDH2 R172 is highly sensitive and specific for the detection of IDH2 R172 hotspot mutations, and likely suitable as a diagnostic tool in the evaluation of excision and core needle biopsy material of tall cell carcinomas with reverse polarity.
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- 2020
41. Mitotic score and pleomorphic histology in invasive lobular carcinoma of the breast: impact on disease-free survival
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Matina Elise Mamounas, Kelly Fahrner-Scott, Hope S. Rugo, Jasmine Wong, Gregor Krings, Rita A. Mukhtar, Yunn-Yi Chen, Michael Alvarado, Laura J. Esserman, and Cheryl Ewing
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Adult ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Multivariate analysis ,Receptor, ErbB-2 ,Breast Neoplasms ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Mitotic Index ,medicine ,Humans ,Neoplasm Invasiveness ,Stage (cooking) ,skin and connective tissue diseases ,Aged ,Retrospective Studies ,Aged, 80 and over ,Proportional hazards model ,business.industry ,Histology ,Odds ratio ,Middle Aged ,Prognosis ,medicine.disease ,Survival Rate ,body regions ,Carcinoma, Lobular ,Cross-Sectional Studies ,030104 developmental biology ,Receptors, Estrogen ,030220 oncology & carcinogenesis ,Invasive lobular carcinoma ,Cohort ,Female ,Receptors, Progesterone ,business ,Follow-Up Studies - Abstract
Pleomorphic invasive lobular carcinoma (ILC) has long been thought to have worse outcomes than classic ILC and is therefore often treated with chemotherapy. However, recent data question the utility of the pleomorphic designation, as the poor outcomes seen may be related to other associated high-risk features. Importantly, mitotic count may better define a subset of ILC with high risk of recurrence. We sought to determine the impact of pleomorphic histology versus mitotic count on disease-free survival (DFS) in pure ILC. Additionally, we evaluated whether pleomorphic histology was associated with receipt of chemotherapy when adjusting for other factors. We analyzed a cohort of 475 patients with stage I–III pure ILC. We used Kaplan–Meier estimates, and Cox proportional hazards and logistic regression for multivariate analyses. Pleomorphic histology was confirmed by central pathology review. In a multivariate model, pleomorphic histology was not associated with reduced DFS. Only mitotic score, receptor subtype, and pathologic stage were independently and significantly associated with DFS. Patients with pleomorphic ILC were significantly more likely to receive chemotherapy than patients with classic ILC (adjusted odds ratio 2.96, p = 0.026). The pleomorphic designation in ILC does not have clinical utility and should not be used to determine therapy. Rather, mitotic count identified clear prognostic groups in this cohort of pure ILC.
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- 2020
42. Abstract P3-08-16: The impact of residual ductal carcinoma in situ on breast cancer recurrence in the neoadjuvant I-SPY2 TRIAL
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Cheryl Ewing, Gretchen M. Ahrendt, Anne M. Wallace, Gregor Krings, Helen Krontiras, Christina Yau, Kimberly Cole, Sunati Sahoo, Julie E. Lang, Dina Kokh, Brigid K. Killelea, Akiko Chiba, Tod Tuttle, W. Fraser Symmans, Molly Klein, Arpana Naik, Yunn-Yi Chen, Marie Osdoit, Constantine Godellas, Roshni Rao, Nora Jaskowiak, Laura J. Esserman, Bev Parker, Julia Tchou, Rita A. Mukhtar, Ronald Balassanian, Smita Asare, Jodi M. Carter, M. Catherine Lee, Eleni A. Tousimis, Laila Khazai, Shannon Tierney, Judy C. Boughey, and Rachael Lancaster
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,Proportional hazards model ,medicine.medical_treatment ,Carcinoma in situ ,Hazard ratio ,Cancer ,Ductal carcinoma ,medicine.disease ,Breast cancer ,Median follow-up ,Internal medicine ,Medicine ,skin and connective tissue diseases ,business - Abstract
Background: Patients who achieve a pathological complete response (pCR- defined as no invasive cancer) after neoadjuvant chemotherapy (NAC) for breast cancer (BC) have improved outcomes, but there is still controversy about the significance of residual ductal carcinoma in situ (DCIS) on local recurrence rate (LRR). The I-SPY 2 TRIAL is an adaptive neoadjuvant platform trial evaluating novel experimental regimens in comparison to standard chemotherapy in women with high-risk breast cancer. The purpose of this study is to determine if residual DCIS after NAC in early BC affects LRR in patients with or without residual invasive disease in the I-SPY 2 TRIAL. Methods: 933 I-SPY 2 patients with residual cancer burden (RCB) and follow-up data were included in this analysis. Residual DCIS was defined as any carcinoma in situ > 0% on RCB evaluation. Local recurrence was defined as recurrence in breast, chest wall or locoregional nodes and/or skin and subcutaneous tissue. We stratified our cohort into four groups: those without residual invasive disease (defined as RCB0) ± residual DCIS, and those with residual invasive disease (RCB>0) ± residual DCIS. We estimated LRR within each group using the Kaplan Meier method; and used Cox proportional hazards models to assess LRR differences between groups, with: patients with no residual disease (invasive or in situ) as reference group. Results: Among 933 patients assessed, median follow up time was 3.9 years. RCB 0 status was achieved in 337 patients (36%). Of these, 267 (29%) had no residual DCIS, which represents our reference group, and 70 (7%) had residual DCIS. Among 596 (64%) patients who had RCB>0, 296 (32%) had residual DCIS. For patients with RCB0 without DCIS and RCB0 with DCIS, the LRR at 3 years were similar: 2% vs 3% respectively (Hazard ratio: 1.29 [0.26-6.39]). Results were also similar in the RCB>0 group, with a LRR of 10% at 3 years in those without residual DCIS, and 11% in those with residual DCIS. Both RCB>0 groups had significantly higher LRR when compared to the patients with RCB0 without DCIS (Hazard ratio: 5.25 [2.20-12.5]) and HR 5.85 [2.47-13.9] respectively). Conclusion: There was no association between residual DCIS and LRR after neoadjuvant chemotherapy, regardless of resolution of invasive disease. Further work is needed to determine whether residual DCIS should drive locoregional therapy decisions after neoadjuvant chemotherapy for invasive breast cancer. Citation Format: Marie Osdoit, Christina Yau, W. Fraser Symmans, Judy C. Boughey, Smita M. Asare, Ron Balassanian, Jodi M. Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Gretchen Ahrendt, Akiko Chiba, Cheryl Ewing, Constantine Godellas, Nora Jaskowiak, Brigid Killelea, Helen Krontiras, Rachael Lancaster, Julie Lang, M. Catherine Lee, Arpana Naik, Roshni Rao, Julia Tchou, Shannon Tierney, Eleni Tousimis, Tod Tuttle, Anne Wallace, I-SPY 2 TRIAL Consortium, Bev Parker, Laura J. Esserman, Rita A. Mukhtar. The impact of residual ductal carcinoma in situ on breast cancer recurrence in the neoadjuvant I-SPY2 TRIAL [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-16.
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- 2020
43. Abstract P2-20-02: Site of recurrence after neoadjuvant therapy: Clues to biology and impact on endpoints
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Michelle E. Melisko, Kirsten K. Edmiston, HS Han, W. Fraser Symmans, Gregor Krings, Molly Klein, Rita Nanda, Claudine Isaacs, Rebecca K. Viscusi, Sunati Sahoo, David M. Euhus, Jeffrey B. Matthews, Angela DeMichele, Erica Stringer-Reasor, Qamar J. Khan, Laura J. van't Veer, Tara Sanft, Christina Yau, Donald A. Berry, Richard Schwab, Janice Lu, Jane Perlmutter, A. Jo Chien, Donald W. Northfelt, Anne M. Wallace, Zaha Mitri, Jane L. Meisel, Julie E. Lang, Jodi M. Carter, Lajos Pusztai, Hope S. Rugo, Rachel L. Yung, Erin D. Ellis, Anthony D. Elias, Laila Khazai, Kathy S. Albain, Yunn-Yi Chen, Nola M. Hylton, Amy S. Clark, Laura J. Esserman, Christos Hatzis, Judy C. Boughey, Douglas Yee, Kimberly Cole, and Dina Kokh
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Oncology ,Cancer Research ,medicine.medical_specialty ,Proportional hazards model ,medicine.medical_treatment ,Incidence (epidemiology) ,Hazard ratio ,Cancer ,Biology ,medicine.disease ,Breast cancer ,Internal medicine ,Cohort ,medicine ,Neoadjuvant therapy ,Sanctuary site - Abstract
Background: Achieving a pathologic complete response (pCR) has been shown on the patient level to predict excellent long-term event-free survival outcomes. Residual cancer burden (RCB) quantifies the extent of residual disease for patients who did not achieve pCR. A high proportion of metastatic events to the central nervous system (CNS), a known chemotherapy sanctuary site, was previously observed among the small number of relapses in patients achieving a pCR (Symmans et al 2017), raising the possibility that these CNS events may be independent of response in the breast. I-SPY2 is an adaptively randomized, phase II, platform trial that evaluates new drugs and combinations in the neoadjuvant setting for women with high-risk primary breast cancer. In this study, we evaluated the type and sites of recurrences by RCB classes in the I-SPY 2 TRIAL. Methods: I-SPY 2 patients enrolled prior to 11/2016 across 9 experimental and control arms, with available RCB and event-free survival (EFS) data were included in this analysis. The median follow-up is 3.8 years. We summarized the EFS event type, further sub-dividing the distant recurrence events by their site of relapse (CNS-only, CNS and other sites, Non-CNS). We estimated the overall and site-specific distant recurrence incidence in each RCB class at 3 years using a competing risk (Fine-Gray) model. In addition, we assessed the association between RCB and distant recurrence free survival including all distant recurrences (DRFS), as well as excluding the CNS-only recurrences (non-CNS DRFS) using a Cox model. Our statistics do not adjust for multiplicities beyond variables evaluated in this study. Results: Among 938 subjects, there were 180 EFS events, including 28 (16%) local recurrences (without distant recurrence and/or death) and 152 DRFS events. Among the DRFS events, 25 patients died without a distant recurrence. 127 experienced distant recurrences, including 22 (17.3%) with CNS-only, 16 (12.6%) with CNS and other sites, 87 (68.5%) with non-CNS distant recurrence; 2 (1.6%) patients had missing recurrence site information. Incidence of CNS-only recurrences are low and are similar across RCB classes (pCR/RCB-0 (n=338): 1%, RCB-I (n=129): 3%, RCB-II (n=328): 2%, RCB-III (n=143): 2% at 3 years). In contrast, the incidence of non-CNS recurrences increase with increasing RCB (RCB-0: 2%, RCB-I: 4%, RCB-II: 11%, RCB-III: 19% at 3 years). DRFS of RCB-I patients do not significantly differ from those achieving a pCR/RCB-0 (DRFS at 3 years: 92% vs. 95%, hazard ratio: 1.77 (0.87-3.63)); the small numerical difference is further reduced when the CNS-only recurrences are excluded (non-CNS DRFS at 3 years: 95% vs. 96%, hazard ratio: 1.48 (0.61-3.58)). CNS recurrences among DRFS events are proportionally higher within the pCR (5/16 (31%)) and RCB-I (5/12 (42%)) than in the RCB-II (8/57 (14%)) and RCB-III (4/42 (9%)) groups largely because of the relative low frequency of non-CNS recurrence events. Conclusions: In our high-risk I-SPY 2 cohort, CNS-only recurrences are uncommon but appear similar across RCB groups, independent of response, suggesting that the CNS is a treatment sanctuary site. In contrast, non-CNS recurrence rates increase as RCB increases. These findings, if confirmed, support the use of RCB to identify patients with excellent outcomes beyond those achieving a pCR; and suggest that inclusion of CNS only recurrences as an outcome event may impact the association between neoadjuvant therapy response and long-term outcome. Citation Format: Christina Yau, Angela DeMichele, W. Fraser Symmans, Lajos Pusztai, Douglas Yee, Amy S. Clark, Christos Hatzis, Jeffrey B. Matthews, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Kathy S. Albain, A. Jo Chien, Kirsten K. Edmiston, Anthony D. Elias, Erin D. Ellis, David M. Euhus, Heather S. Han, Claudine Isaacs, Qamar J. Khan, Julie E. Lang, Janice Lu, Jane L. Meisel, Zaha Mitri, Rita Nanda, Donald W. Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K. Viscusi, Anne M. Wallace, Rachel Yung, Nola M. Hylton, Judy C. Boughey, Michelle E. Melisko, Jane Perlmutter, Hope S. Rugo, Richard Schwab, Laura J. van' t Veer, Donald A. Berry, Laura J. Esserman. Site of recurrence after neoadjuvant therapy: Clues to biology and impact on endpoints [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-20-02.
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- 2020
44. Abstract P6-10-02: Assessing biomarkers to inform treatment de-escalation: Mid-treatment biopsy cellularity predicts pCR in the I-SPY 2 Trial
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Jane Wei, Jodi M. Carter, Laila Khazai, Laura J. van't Veer, Molly Klein, Gregor Krings, Dina Kokh, Kimberly Cole, Yunn-Yi Chen, Lamorna Brown-Swigart, Ronald Balassanian, Sara J. Venters, Laura J. Esserman, Bev Parker, Amy L. Delson, Christina Yau, Sunati Sahoo, W. Fraser Symmans, and Denise M. Wolf
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Oncology ,Cancer Research ,medicine.medical_specialty ,Randomization ,Invasive carcinoma ,medicine.diagnostic_test ,business.industry ,Locally advanced ,Cancer ,medicine.disease ,Breast cancer ,Internal medicine ,Biopsy ,Cohort ,medicine ,business ,De-escalation - Abstract
Background: The I-SPY 2 TRIAL enrolls women with locally advanced, molecular high-risk breast cancer. An integrated Residual Cancer Burden (iRCB), based on MRI volume change through treatment, is used to predict pathologic complete response (pCR) in the randomization/evaluation Bayesian engine. With the goal of effective de-escalation of treatment for patients exhibiting an early response, biomarkers are being assessed for their ability to predict pCR, alone or with MR data, during treatment. Here, we present the results of a pilot study to examine if invasive tumor cellularity in mid-treatment tissue core biopsies predicts pCR in a 40-patient cohort of I-SPY 2 patients. Other pathologic variables evaluated include Ki67, tumoral histologic features, and stromal tumor-infiltrating lymphocytes (sTILs). Methods: I-SPY 2 TRIAL pathologists (N=4) were provided images of H&E-stained and Ki67 IHC- labelled (DAKO/Agilent, clone MIB-1) core biopsy sections from 40 patients at the inter-regimen time point, ~12-weeks into treatment. Of the 40 patients, 35 had 4 cores, 3 had 3 cores, and 2 had 2 cores assessed. In total, images from 153 cores were evaluated. For each core, pathologists were asked to score the % area occupied by tumor bed (treatment changes and/or residual cancer), % of viable invasive tumor (0-100%) within tumor bed (with Nottingham grading, % Ki67 labelled, and % sTILs, using standardized guidelines). As decided by the pathologist group, only cores with identified tumor bed were included in the initial analysis. Concordance between pathologists was assessed for all scored criteria, using % agreement for dichotomous variables, and Pearson correlation (r)/standard deviation (sd) for continuous variables. The maximum and average cellularity recorded over all cores/patient, averaged over all pathologists, were analyzed for association with pCR using t- tests (significance threshold: p Results: Pathologist were in general agreement about the presence or absence of tumor bed, with greater than 82% agreement between any two (83-96%), and an overall agreement of 77%. For scoring the % of the tumor bed involved by invasive cancer, correlations between pairs of pathologists ranged from 0.79-0.95 (mean(r)=0.87, sd=5%), and agreement on a binary presence/absence of invasive cancer was 78%. Both the mean (t-test: p=7.59E-05) and maximum (t-test: p=0.0012) %invasive tumor at 12 weeks, scored as an average over all pathologists, were significantly higher in patients who did not achieve pCR than in responders. We also treated %invasive cellularity as a dichotomous variable (present/absent). 90% (9/10) of patients scored by all pathologists as 0% invasive tumor cells (absent) achieved a pCR, vs only 20% (6/30) of patients scored as >0% invasive cellularity by one or more pathologists (present) (OR=32, Fisher p=0.0005); yielding a positive predictive value for pCR of 0.9. Ki67 and sTILS at 12 weeks were fairly concordant across pathologists ((r,sd)=(0.92, 8.45%) and (0.82,5.5%), respectively), but did not associate with response (p>0.05 for pCR, RCB01, or RCB index). Tumor histologic grade at 12 weeks, assessed in 29/30 patients with non-zero cellularity, trended toward association (Fisher p=0.078): 44% (4/9) with Grade 3 went on to have a pCR, vs. 15% (2/13) with Grade 2 and 0 with Grade 1. These data demonstrate the utility of invasive tumor cellularity as a predictor of pCR in a clinical setting. Conclusion: In this pilot study we demonstrate that the absence of invasive cancer cells within identified tumor bed in mid-treatment core biopsy samples is highly predictive of pCR. Citation Format: Sara J Venters, Denise M Wolf, Lamorna Brown-Swigart, Christina Yau, Amy L Delson, Bev Parker, Ron Balassanian, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Jane Wei, I-SPY 2 TRIAL Consortium, Laura J Esserman, Laura J van't Veer, W Fraser Symmans. Assessing biomarkers to inform treatment de-escalation: Mid-treatment biopsy cellularity predicts pCR in the I-SPY 2 Trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-02.
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- 2020
45. Association of Residual Ductal Carcinoma In Situ With Breast Cancer Recurrence in the Neoadjuvant I-SPY2 Trial
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Marie Osdoit, Christina Yau, W. Fraser Symmans, Judy C. Boughey, Cheryl A. Ewing, Ron Balassanian, Yunn-Yi Chen, Gregor Krings, Anne M Wallace, Somaye Zare, Oluwole Fadare, Rachael Lancaster, Shi Wei, Constantine V. Godellas, Ping Tang, Todd M Tuttle, Molly Klein, Sunati Sahoo, Tina J. Hieken, Jodi M. Carter, Beiyun Chen, Gretchen Ahrendt, Julia Tchou, Michael Feldman, Eleni Tousimis, Jay Zeck, Nora Jaskowiak, Husain Sattar, Arpana M. Naik, Marie Catherine Lee, Marilin Rosa, Laila Khazai, Mara H. Rendi, Julie E. Lang, Janice Lu, Ossama Tawfik, Smita M. Asare, Laura J. Esserman, and Rita A. Mukhtar
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Adult ,Neoplasm, Residual ,Receptor, ErbB-2 ,Carcinoma, Ductal, Breast ,Breast Neoplasms ,Middle Aged ,Neoadjuvant Therapy ,Young Adult ,Carcinoma, Intraductal, Noninfiltrating ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Female ,Surgery ,Neoplasm Recurrence, Local ,Retrospective Studies ,Aged - Abstract
ImportancePathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer strongly correlates with overall survival and has become the standard end point in neoadjuvant trials. However, there is controversy regarding whether the definition of pCR should exclude or permit the presence of residual ductal carcinoma in situ (DCIS).ObjectiveTo examine the association of residual DCIS in surgical specimens after neoadjuvant chemotherapy for breast cancer with survival end points to inform standards for the assessment of pathologic complete response.Design, Setting, and ParticipantsThe study team analyzed the association of residual DCIS after NAC with 3-year event-free survival (EFS), distant recurrence-free survival (DRFS), and local-regional recurrence (LRR) in the I-SPY2 trial, an adaptive neoadjuvant platform trial for patients with breast cancer at high risk of recurrence. This is a retrospective analysis of clinical specimens and data from the ongoing I-SPY2 adaptive platform trial of novel therapeutics on a background of standard of care for early breast cancer. I-SPY2 participants are adult women diagnosed with stage II/III breast cancer at high risk of recurrence.InterventionsParticipants were randomized to receive taxane and anthracycline-based neoadjuvant therapy with or without 1 of 10 investigational agents, followed by definitive surgery.Main Outcomes and MeasuresThe presence of DCIS and EFS, DRFS, and LRR.ResultsThe study team identified 933 I-SPY2 participants (aged 24 to 77 years) with complete pathology and follow-up data. Median follow-up time was 3.9 years; 337 participants (36%) had no residual invasive disease (residual cancer burden 0, or pCR). Of the 337 participants with pCR, 70 (21%) had residual DCIS, which varied significantly by tumor-receptor subtype; residual DCIS was present in 8.5% of triple negative tumors, 15.6% of hormone-receptor positive tumors, and 36.6% of ERBB2-positive tumors. Among those participants with pCR, there was no significant difference in EFS, DRFS, or LRR based on presence or absence of residual DCIS.Conclusions and RelevanceThe analysis supports the definition of pCR as the absence of invasive disease after NAC regardless of the presence or absence of DCIS.Trial RegistrationClinicalTrials.gov Identifier NCT01042379.
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- 2022
46. Assessment of Residual Cancer Burden and Event-Free Survival in Neoadjuvant Treatment for High-risk Breast Cancer: An Analysis of Data From the I-SPY2 Randomized Clinical Trial
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Shi Wei, Richard Schwab, Gregor Krings, Lajos Pusztai, Rashmi Krishna Murthy, Lauren LeBeau, Megan L. Troxell, Adam Asare, Erin D. Ellis, Sharon Sams, Donald A. Berry, Fang Fan, Anne M. Wallace, Andres Forero-Torres, Christina Yau, Angela DeMichele, Donald W. Northfelt, Mara H. Rendi, Laila Khazai, Husain Sattar, Xiuzhen Duan, Ronald Balassanian, Rebecca K. Viscusi, Hyo S. Han, Barbara A. Parker, A. Jo Chien, Brian Leyland-Jones, Meredith Buxton, Idris Tolgay Ocal, Yunn Yi Chen, Qamar J. Khan, Brian Datnow, Barbara Haley, Tuyethoa Vinh, Kathy S. Albain, Laura van 't Veer, Minetta C. Liu, Michael Feldman, Amy S. Clark, Kirsten H. Edmiston, W. Fraser Symmans, Sonal Shad, Kathleen Kemmer, Judy C. Boughey, Julie E. Lang, Paulette Mhawech-Fauceglia, Teresa Helsten, Douglas Yee, Molly Klein, Rita Nanda, Claudine Isaacs, Anthony D. Elias, Sara J. Venters, Nola M. Hylton, Jay Zeck, Laura J. Esserman, Beiyun Chen, Hope S. Rugo, Smita Asare, Sunati Sahoo, Jeffrey B. Matthews, and Jane Perlmutter
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Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,Cyclophosphamide ,Receptor, ErbB-2 ,medicine.medical_treatment ,Breast Neoplasms ,Disease-Free Survival ,law.invention ,Breast cancer ,Randomized controlled trial ,law ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Stage (cooking) ,Neoadjuvant therapy ,Original Investigation ,Chemotherapy ,business.industry ,Hazard ratio ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,Neoadjuvant Therapy ,Progression-Free Survival ,Chemotherapy, Adjuvant ,Female ,business ,medicine.drug - Abstract
Importance Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. Objective To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. Design, Setting, and Participants The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) andERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. Interventions Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. Main Outcomes and Measures Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). Results A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) andERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. Conclusions and Relevance In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. Trial Registration ClinicalTrials.gov Identifier:NCT01042379
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- 2021
47. Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer
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Valerie M. Weaver, E. Shelley Hwang, Ori Maller, Xinmiao Yu, Jennifer L. Leight, Hui Zhang, Catherine C. Park, Yunn-Yi Chen, Po-Jui Huang, Jason J. Northey, Brenda P. Alston-Mills, Nastaran Zahir, Johnathon N. Lakins, and Allison P. Drain
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0301 basic medicine ,Nude ,Apoptosis ,Triple Negative Breast Neoplasms ,Mice, SCID ,Matrix (biology) ,Medical and Health Sciences ,Extracellular matrix ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Mice, Inbred NOD ,Tumor Microenvironment ,Immunology and Allergy ,skin and connective tissue diseases ,Triple-negative breast cancer ,Cancer ,Tumor ,NF-kappa B ,Chemoradiotherapy ,Neoadjuvant Therapy ,Extracellular Matrix ,Paclitaxel ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,6.1 Pharmaceuticals ,Stromal cell ,Cell Survival ,Immunology ,Mice, Nude ,SCID ,Article ,Cell Line ,03 medical and health sciences ,Breast cancer ,Stroma ,Cell Line, Tumor ,Breast Cancer ,Organoid ,medicine ,Animals ,Humans ,Solid Tumors ,business.industry ,JNK Mitogen-Activated Protein Kinases ,medicine.disease ,Xenograft Model Antitumor Assays ,Enzyme Activation ,030104 developmental biology ,chemistry ,Cancer research ,Inbred NOD ,business - Abstract
Soft extracellular matrix protects breast cancer cells from apoptosis and reduces the efficacy of chemo- and radiation therapies through enhanced NF-κB signaling and diminished proapoptotic JNK activity. Therapeutic targeting of the NF-κB–JNK axis may thwart treatment resistance in breast cancer., Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment resistance. TNBCs are fibrotic, yet little is known regarding how the extracellular matrix (ECM) evolves following therapy and whether it impacts treatment response. Analysis revealed that while primary untreated TNBCs are surrounded by a rigid stromal microenvironment, chemotherapy-resistant residual tumors inhabit a softer niche. TNBC organoid cultures and xenograft studies showed that organoids interacting with soft ECM exhibit striking resistance to chemotherapy, ionizing radiation, and death receptor ligand TRAIL. A stiff ECM enhanced proapoptotic JNK activity to sensitize cells to treatment, whereas a soft ECM promoted treatment resistance by elevating NF-κB activity and compromising JNK activity. Treatment-resistant residual TNBCs residing within soft stroma had elevated activated NF-κB levels, and disengaging NF-κB activity sensitized tumors in a soft matrix to therapy. Thus, the biophysical properties of the ECM modify treatment response, and agents that modulate stiffness-dependent NF-κB or JNK activity could enhance therapeutic efficacy in patients with TNBC.
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- 2021
48. Pan-TRK Immunohistochemistry
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Sandra E. Barnick, Yunn Yi Chen, Gregor Krings, Anne Vincent-Salomon, Beth T. Harrison, Elizabeth Fowler, Stuart J. Schnitt, Jason L. Hornick, Beiyun Chen, Elizabeth M. Hosfield, Gregory R. Bean, and Laetitia Fuhrmann
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Adult ,Male ,0301 basic medicine ,Paris ,Pathology ,medicine.medical_specialty ,Adolescent ,Breast Neoplasms ,Receptors, Nerve Growth Factor ,In situ hybridization ,Breast Neoplasms, Male ,Pathology and Forensic Medicine ,Fusion gene ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Biomarkers, Tumor ,medicine ,Humans ,In Situ Hybridization, Fluorescence ,Aged ,Aged, 80 and over ,Tissue microarray ,Proto-Oncogene Proteins c-ets ,medicine.diagnostic_test ,business.industry ,Carcinoma ,Middle Aged ,Immunohistochemistry ,United States ,Staining ,Repressor Proteins ,ETV6 ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,Surgery ,Gene Fusion ,Anatomy ,Breast carcinoma ,business ,Fluorescence in situ hybridization - Abstract
Secretory carcinoma is a special-type breast carcinoma underpinned by a recurrent t(12;15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion. Immunohistochemistry (IHC) using a pan-TRK antibody has been recently shown to help identify NTRK rearrangements in other tumor types. The purpose of this study was to assess the diagnostic utility of pan-TRK IHC in secretory carcinoma of the breast. Pan-TRK IHC was performed using a rabbit monoclonal antibody on whole sections of 24 breast secretory carcinomas and tissue microarray sections of other breast carcinoma types (n=203) and histologic mimics (n=15). Cases were assessed for staining intensity and localization. The 24 patients with secretory carcinoma had a median age of 44 years and a median tumor size of 1.0 cm. ETV6 fluorescence in situ hybridization was positive in all cases tested (n=20). Twenty-three cases (95.8%) showed staining with pan-TRK, which was exclusively nuclear in 19, primarily nuclear with weak cytoplasmic staining in 3, and primarily cytoplasmic with focal nuclear staining in 1. The nuclear staining was diffuse in 17 and at least focally strong in 17. The only pan-TRK negative case was a core biopsy with limited tumor. Among the 203 nonsecretory carcinomas, 21 (10.3%) showed focal, weak nuclear staining in
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- 2019
49. Pleomorphic and Florid Lobular Carcinoma In Situ Variants of the Breast
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Joseph T. Rabban, Yunn-Yi Chen, Melike Pekmezci, Gregor Krings, Tianming Chu, and Eliah R. Shamir
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Adult ,0301 basic medicine ,In situ ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Lobular carcinoma ,Breast Neoplasms ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,skin and connective tissue diseases ,Aged ,Aged, 80 and over ,Invasive carcinoma ,business.industry ,Optimal treatment ,Apocrine ,Middle Aged ,medicine.disease ,Radiation therapy ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,Surgery ,Surgical excision ,Breast Carcinoma In Situ ,Anatomy ,business ,Core biopsy - Abstract
The natural history and optimal treatment of pleomorphic (PLCIS) and florid (FLCIS) lobular carcinoma in situ variants remains uncertain. We reviewed the clinicopathologic features and management of LCIS variants at our institution over a 20-year period. Of 85 cases (61 PLCIS, 24 FLCIS), 77% were associated with invasive carcinoma (84% lobular, 13% ductal/lobular, 3% ductal) and only 17% (9 PLCIS, 5 FLCIS) were pure. Most (81%) invasive carcinomas were grade 2, with all grade 3/pleomorphic invasive lobular carcinomas (ILC) associated with PLCIS, and all grade 1 tumors associated with FLCIS. PLCIS-associated invasive carcinomas were more often ER- (21%) or HER2+ (14%) than FLCIS-associated tumors (100% ER+, 6% HER2+). LCIS variants were unifocal and co-localized with invasive carcinoma in 20/20 selected spatially mapped cases, whereas classic LCIS (CLCIS) was multifocal with wider distribution (10/17). Of 21 pure LCIS variants on core biopsy, all represented the radiographic (95%) or palpable (5%) target. The excisional upgrade rate was similar for PLCIS (38%) and FLCIS (33%). Pure LCIS variants on core biopsy were often (20%) HER2+ and had a higher Ki-67-index than synchronous CLCIS (P=0.002). Lower ER expression in LCIS variants versus CLCIS was due to ER- apocrine PLCIS. ER and HER2 were consistently concordant between LCIS variants and upgraded ILC but discordant between synchronous CLCIS and LCIS variants in 5/14 (36%). Pure LCIS variants were excised to negative margins and frequently (58%) treated with endocrine but not radiation therapy without recurrences. In summary, PLCIS and FLCIS demonstrate features of direct precursor lesions warranting surgical excision.
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- 2019
50. Abstract P1-08-01: Withdrawn
- Author
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Katie M. O'Brien, W.-P. Koh, Elisabete Weiderpass, T E Rohan, Kimberly A. Bertrand, Walter C. Willett, J.-M. Yuan, H. O. Adami, Timothy J. Key, Victoria A. Kirsh, M. C. Boutron-Ruault, M. Dorronsoro, Giovanna Masala, RL Milne, Antonia Trichopoulou, Rudolph Kaaks, Dale P. Sandler, Atsuko Sadakane, E. Riboli, Susan E. Hankinson, Minouk J. Schoemaker, Linet, Laure Dossus, Anthony J. Swerdlow, AH Eliassen, Michael Jones, Hazel B. Nichols, Mark N. Brook, Laura Baglietto, Leslie R. Bernstein, Huiyan Ma, Melissa A. Merritt, Malin Sund, Rulla M. Tamimi, Susanna C. Larsson, LB Wright, Cari M. Kitahara, Alicja Wolk, G.G. Giles, Avonne E. Connor, Kotaro Ozasa, Anne Zeleniuch-Jacquotte, Yunn-Yi Chen, C. H. van Gils, Inger T. Gram, Julie R. Palmer, Giske Ursin, Kim Overvad, and K Visvanathan
- Subjects
Cancer Research ,Oncology - Abstract
This abstract was withdrawn by the authors. Citation Format: Schoemaker MJ, Nichols HB, Wright LB, Brook MN, Jones ME, O'Brien KM, Adami H-O, Baglietto L, Bernstein L, Bertrand KA, Boutron-Ruault M-C, Chen Y, Connor AE, Dorronsoro M, Dossus L, Eliassen AH, Giles GG, Gram IT, Hankinson SE, Kaaks R, Key TJ, Kirsh VA, Kitahara CM, Koh W-P, Larsson SC, Linet MS, Ma H, Masala G, Merritt MA, Milne RL, Overvad K, Ozasa K, Palmer JR, Riboli E, Rohan TE, Sadakane A, Sund M, Tamimi RM, Trichopoulou A, Ursin G, Van Gils CH, Visvanathan K, Weiderpass E, Willett WC, Wolk A, Yuan J-M, Zeleniuch-Jacquotte A, Sandler DP, Swerdlow AJ. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-01.
- Published
- 2019
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