498 results on '"Zoran Gatalica"'
Search Results
2. The assessment of tumor-infiltrating lymphocytes in invasive apocrine carcinoma of the breast in relation to the HER2 status
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Zoran Gatalica, Nataliya Kuzmova, Inga Rose, Monika Ulamec, Melita Peric-Balja, Faruk Skenderi, and Semir Vranic
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Breast cancer ,special types ,apocrine carcinoma ,tumor-infiltrating lymphocytes (TILs) ,HER2-low ,Biology (General) ,QH301-705.5 - Abstract
In the current study, we assessed the prevalence and molecular features of HER2-low phenotype in the apocrine carcinomas of the breast (ApoCa) and its relationship with tumor-infiltrating lymphocytes (TILs). A cohort of 64 well-characterized therapy-naïve ApoCa was used. The TIL distribution was assessed using the hematoxylin and eosin whole slide/scanned images following the international TILs working group recommendations. Next-generation sequencing (NGS) was performed in a subset of HER2-low ApoCa. All patients were women, with a mean age of 62 years. Forty-three carcinomas were pure apocrine carcinoma (PAC; ER−/AR+), and the remaining 21 were classified as apocrine-like carcinomas (ALCs; ER+/−, AR+/−). HER2/neu was positive (score 3+ by IHC and/or amplified by FISH) in 20/43 (47%) PAC and 4/21 (19%) ALC. The prevalence of HER2-low expression (scores 1+ or 2+ without HER2 amplification) in ApoCa was 39% without significant differences between PAC and ALC (P = 0.14); however, the HER2-low phenotype was more prevalent in triple-negative PAC than in ALC (P < 0.001). Levels of TILs were low (≤10%) in 74% of ApoCa (median 5%, range 0%–50%). TIL levels were significantly higher in ALC than in PAC (P = 0.02). HER2 status had no impact on TIL distribution (P = 0.45). The genomic profile of HER2-low ApoCa was similar to other subtypes of ApoCa. ApoCa has predominantly low TIL, particularly PAC. The prevalence of the HER2-low phenotype in ApoCa is high, which should have therapeutic and clinical implications given the recently approved therapies with antibody–drug conjugates (ADCs) for HER2-low breast cancers.
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- 2024
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3. Assay‐agnostic spatial profiling detects tumor microenvironment signatures: new diagnostic insights for triple‐negative breast cancer
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Colleen Ziegler, Alain Mir, Sangeetha Anandakrishnan, Patrick Martin, Elma Contreras, Isaiah Slemons, Barbara Witkowski, Chris DeSilva, Andrew Farmer, Semir Vranic, Zoran Gatalica, David Richardson, and Dmitry N. Derkach
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immuno‐oncology ,spatial profiling ,triple‐negative breast cancer ,tumor microenvironment ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The role of the tumor microenvironment (TME) in immuno‐oncology has driven demand for technologies that deliver in situ, or spatial, molecular information. Compartmentalized heterogeneity that traditional methods miss is becoming key to predicting both acquired drug resistance to targeted therapies and patient response to immunotherapy. Here, we describe a novel method for assay‐agnostic spatial profiling and demonstrate its ability to detect immune microenvironment signatures in breast cancer patients that are unresolved by the immunohistochemical (IHC) assessment of programmed cell death ligand‐1 (PD‐L1) on immune cells, which represents the only FDA microenvironment‐based companion diagnostic test that has been approved for triple‐negative breast cancer (TNBC). Two distinct physiological states were found that are uncorrelated to tumor mutational burden (TMB), microsatellite instability (MSI), PD‐L1 expression, and intrinsic cancer subtypes.
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- 2023
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4. The deubiquitinase USP10 protects pancreatic cancer cells from endoplasmic reticulum stress
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Udayan Bhattacharya, Elangovan Thavathiru, Fiifi Neizer-Ashun, Chao Xu, Zoran Gatalica, Shailendra Kumar Dhar Dwivedi, Anindya Dey, Priyabrata Mukherjee, and Resham Bhattacharya
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The ubiquitin-specific peptidase 10 (USP10) plays a context-specific, pro or anti-tumorigenic role in different malignancies. However, the role of USP10 in pancreatic cancer remains unclear. Our protein and RNA level analysis from archived specimens and public databases show that USP10 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and expression correlates with poor overall patient survival. Phenotypically, silencing USP10 decreased viability, clonal growth and invasive properties of pancreatic cancer cells. Mechanistically, silencing USP10 upregulated BiP and induced endoplasmic reticulum (ER) stress that led to an unfolded protein response (UPR) and upregulation of PERK, IRE1α. Decreased cell viability of USP10 silenced cells could be rescued by a chemical chaperone that promotes protein folding. Our studies suggest that USP10 by protecting pancreatic cancer cells from ER stress may support tumor progression.
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- 2022
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5. Acinic cell carcinoma of the breast: A comprehensive review
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Azra Ajkunic, Faruk Skenderi, Nada Shaker, Saghir Akhtar, Janez Lamovec, Zoran Gatalica, and Semir Vranic
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Breast cancer ,Special types ,Salivary gland-type tumors ,Acinic cell carcinoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Acinic cell carcinoma of the breast is a rare special subtype of breast cancer in the category of salivary gland-type tumors. It is morphologically similar to acinic cell carcinomas of salivary glands and pancreas and has a triple-negative phenotype (estrogen receptor-negative, progesterone receptor-negative, and Her-2/neu negative). Its molecular genomic features are more similar to triple-negative breast cancer of no special type than to its salivary gland counterpart. However, the clinical course of the mammary acinic cell carcinoma appears to be less aggressive than the usual triple-negative breast carcinomas. This review comprehensively summarizes the current literature on the clinicopathologic, immunohistochemical, and molecular features of this rare and distinct subtype of breast cancer.
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- 2022
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6. An Updated Review of the Biomarkers of Response to Immune Checkpoint Inhibitors in Merkel Cell Carcinoma: Merkel Cell Carcinoma and Immunotherapy
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Adnan Fojnica, Kenana Ljuca, Saghir Akhtar, Zoran Gatalica, and Semir Vranic
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skin ,Merkel cell carcinoma ,therapy ,immune checkpoint inhibitors ,biomarkers ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Merkel cell carcinoma (MCC) is primarily a disease of the elderly Caucasian, with most cases occurring in individuals over 50. Immune checkpoint inhibitors (ICI) treatment has shown promising results in MCC patients. Although ~34% of MCC patients are expected to exhibit at least one of the predictive biomarkers (PD-L1, high tumor mutational burden/TMB-H/, and microsatellite instability), their clinical significance in MCC is not fully understood. PD-L1 expression has been variably described in MCC, but its predictive value has not been established yet. Our literature survey indicates conflicting results regarding the predictive value of TMB in ICI therapy for MCC. Avelumab therapy has shown promising results in Merkel cell polyomavirus (MCPyV)-negative MCC patients with TMB-H, while pembrolizumab therapy has shown better response in patients with low TMB. A study evaluating neoadjuvant nivolumab therapy found no significant difference in treatment response between the tumor etiologies and TMB levels. In addition to ICI therapy, other treatments that induce apoptosis, such as milademetan, have demonstrated positive responses in MCPyV-positive MCC, with few somatic mutations and wild-type TP53. This review summarizes current knowledge and discusses emerging and potentially predictive biomarkers for MCC therapy with ICI.
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- 2023
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7. Comprehensive genomic profiling of a metastatic small cell lung carcinoma with a complete and long-term response to atezolizumab: A case report
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Kresimir Tomic, Dragana Karan Krizanac, Faruk Skenderi, Kristina Krpina, Andrea Carapina Bilic, Kristina Galic, Zoran Gatalica, and Semir Vranic
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Lung cancer ,Small cell lung cancer ,Immunotherapy ,Atezolizumab ,Genomic profiling ,Diseases of the respiratory system ,RC705-779 - Abstract
Small cell lung cancer (SCLC) is a highly aggressive malignancy with a poor outcome. We present the case of a 57-year-old male patient with extensive-stage (ES-SCLC) treated with chemotherapy and atezolizumab. A complete response was achieved with a long remission of ∼three years. Comprehensive genomic profiling (CGP) of the tumor revealed high tumor mutation burden (13 mutations/Mb) and mutations of TP53, RB1 and ERCC4 genes. This case study confirms that a complete response to chemoimmunotherapy may be achieved in the case of ES-SCLC. It further provides the additional value of CGP and predictive testing in the management of ES-SCLC.
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- 2023
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8. PD-L1 testing by immunohistochemistry in immuno-oncology
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Semir Vranic and Zoran Gatalica
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Cancer ,immunotherapy ,immune checkpoint inhibitors ,predictive biomarkers ,PD-L1 ,immunohistochemistry ,Biology (General) ,QH301-705.5 - Abstract
Immunotherapy, based on immune checkpoint inhibitors targeting the Programmed cell death ligand 1 (PD-L1) and/or Programmed Death Receptor 1 (PD-1), has substantially improved the outcomes of patients with various cancers. However, only ~30% of patients benefit from immune checkpoint inhibitors. Tumor PD-L1 expression, assessed by immunohistochemistry, is the most widely validated and used predictive biomarker to guide the selection of patients for immune checkpoint inhibitors. PD-L1 assessment may be challenging due to the necessity for different companion diagnostic assays for required specific immune checkpoint inhibitors and a relatively high level of inter-assay variability in terms of performance and cutoff levels. In this review, we discuss the role of PD-L1 immunohistochemistry as a predictive test in immunotherapy (immuno-oncology), highlight the complexity of the PD-L1 testing landscape, discuss various preanalytical, analytical and clinical issues that are associated with PD-L1 assays, and provide some insights into optimization of PD-L1 as a predictive biomarker in immuno-oncology.
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- 2023
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9. NUTM1-Rearranged Neoplasms—A Heterogeneous Group of Primitive Tumors with Expanding Spectrum of Histology and Molecular Alterations—An Updated Review
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Wenyi Luo, Todd M. Stevens, Phillip Stafford, Markku Miettinen, Zoran Gatalica, and Semir Vranic
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NUTM1 gene ,NUT protein ,neoplasms ,pathogenesis ,therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Nuclear protein of testis (NUT), a protein product of the NUTM1 gene (located on the long arm of chromosome 15) with highly restricted physiologic expression in post-meiotic spermatids, is the oncogenic driver of a group of emerging neoplasms when fused with genes involved in transcription regulation. Although initially identified in a group of lethal midline carcinomas in which NUT forms fusion proteins with bromodomain proteins, NUTM1-rearrangement has since been identified in tumors at non-midline locations, with non-bromodomain partners and with varied morphology. The histologic features of these tumors have also expanded to include sarcoma, skin adnexal tumors, and hematologic malignancies that harbor various fusion partners and are associated with markedly different clinical courses varying from benign to malignant. Most of these tumors have nondescript primitive morphology and therefore should be routinely considered in any undifferentiated neoplasm. The diagnosis is facilitated by the immunohistochemical use of the monoclonal C52 antibody, fluorescence in situ hybridization (FISH), and, recently, RNA-sequencing. The pathogenesis is believed to be altered expression of oncogenes or tumor suppressor genes by NUT-mediated genome-wide histone modification. NUTM1-rearranged neoplasms respond poorly to classical chemotherapy and radiation therapy. Targeted therapies such as bromodomain and extraterminal domain inhibitor (BETi) therapy are being developed. This current review provides an update on NUTM1-rearranged neoplasms, focusing on the correlation between basic sciences and clinical aspects.
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- 2021
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10. Gliosarcoma vs. glioblastoma: a retrospective case series using molecular profiling
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Christopher Dardis, David Donner, Nader Sanai, Joanne Xiu, Sandeep Mittal, Sharon K. Michelhaugh, Manjari Pandey, Santosh Kesari, Amy B. Heimberger, Zoran Gatalica, Michael W. Korn, Ashley L. Sumrall, and Surasak Phuphanich
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Gliosarcoma ,Glioblastoma ,Molecular profiling ,Pan-cancer analysis ,Epithelial-to-mesenchymal transition ,Immuno-evasion ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Gliosarcoma (GS) refers to the presence of mesenchymal differentiation (as seen using light microscopy) in the setting of glioblastoma (GB, an astrocytoma, WHO Grade 4). Although the same approach to treatment is typically adopted for GS and GB, there remains some debate as to whether GS should be considered a discrete pathological entity. Differences between these tumors have not been clearly established at the molecular level. Methods Patients with GS (n=48) or GB (n=1229) underwent molecular profiling (MP) with a pan-cancer panel of tests as part of their clinical care. The methods employed included next-generation sequencing (NGS) of DNA and RNA, copy number variation (CNV) of DNA and immunohistochemistry (IHC). The MP comprised 1153 tests in total, although results for each test were not available for every tumor profiled. We analyzed this data retrospectively in order to determine if our results were in keeping with what is known about the pathogenesis of GS by contrast with GB. We also sought novel associations between the MP and GS vs. GB which might improve our understanding of pathogenesis of GS. Results Potentially meaningful associations (p
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- 2021
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11. Calcifying nested stromal-epithelial tumor of the liver with recurrence in a transplanted liver – A clinical report with literature review
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Maria Kamal, Doaa Atwi, Zoran Gatalica, and Wenyi Luo
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Calcifying nested stromal epithelial tumor (CNSET) ,Watered-silk morphology ,CDX2 ,CTNNB1 gene ,PIK3CA gene ,TERT promoter ,Pathology ,RB1-214 - Abstract
Calcifying nested stromal-epithelial tumor (CNSET) is a rare liver neoplasm with unknown histogenesis. The tumor mainly affects children and young adults with a female predominance. Although predominantly indolent, rare tumors with aggressive clinical course have been reported. Here we report a CNSET with unique clinical, microscopic, and molecular features. Clinically, the patient presented with mass-associated liver failure with tumor recurrence 3 years later following liver transplantation. Histologically, the tumor showed a unique watered-silk growth pattern composed of small blue cells and diffuse positivity for CDX2 stain. Genetically, the tumor harbors a novel pathologic mutation in PIK3CA in addition to previously reported CTNNB1 and TERT promoter mutations. The case expands the morphologic and immunohistochemical spectrum of CNSET and suggests potential implication of PIK3CA in targeted therapy.
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- 2022
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12. Transient commensal clonal interactions can drive tumor metastasis
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Suha Naffar-Abu Amara, Hendrik J. Kuiken, Laura M. Selfors, Timothy Butler, Marco L. Leung, Cheuk T. Leung, Elaine P. Kuhn, Teodora Kolarova, Carina Hage, Kripa Ganesh, Richard Panayiotou, Rosemary Foster, Bo R. Rueda, Athena Aktipis, Paul Spellman, Tan A. Ince, Joanne Xiu, Matthew Oberley, Zoran Gatalica, Nicholas Navin, Gordon B. Mills, Rodrick T. Bronson, and Joan S. Brugge
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Science - Abstract
Cooperative interactions among tumor cells may have important implications for metastasis. Here, the authors examined the spatio-temporal nature of interactions among clonal populations of ovarian carcinoma cells and found that transient interactions cells can promote metastases via commensal interactions.
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- 2020
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13. Population bias in somatic measurement of microsatellite instability status
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Michelle Saul, Kelsey Poorman, Hongseok Tae, Ari Vanderwalde, Phillip Stafford, David Spetzler, Wolfgang M. Korn, Zoran Gatalica, and Jeff Swensen
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checkpoint inhibitor ,DNA mismatch repair ,immunotherapy ,microsatellite instability ,next‐generation sequencing ,population bias ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Microsatellite instability (MSI) is a key secondary effect of a defective DNA mismatch repair mechanism resulting in incorrectly replicated microsatellites in many malignant tumors. Historically, MSI detection has been performed by fragment analysis (FA) on a panel of representative genomic markers. More recently, using next‐generation sequencing (NGS) to analyze thousands of microsatellites has been shown to improve the robustness and sensitivity of MSI detection. However, NGS‐based MSI tests can be prone to population biases if NGS results are aligned to a reference genome instead of patient‐matched normal tissue. We observed an increased rate of false positives in patients of African ancestry with an NGS‐based diagnostic for MSI status utilizing 7317 microsatellite loci. We then minimized this bias by training a modified calling model that utilized 2011 microsatellite loci. With these adjustments 100% (95% CI: 89.1% to 100%) of African ancestry patients in an independent validation test were called correctly using the updated model. This poses not only a significant technical improvement but also has an important clinical impact on directing immune checkpoint inhibitor therapy.
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- 2020
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14. Comparison of the biomarkers for targeted therapies in primary extra‐mammary and mammary Paget's disease
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Zoran Gatalica, Semir Vranic, Božo Krušlin, Kelsey Poorman, Phillip Stafford, Denisa Kacerovska, Wijendra Senarathne, Elena Florento, Elma Contreras, Alexandra Leary, April Choi, and Gino K. In
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extra‐mammary Paget's disease ,immune therapy ,molecular profiling ,targeted therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Primary Extra‐mammary Paget's disease (EMPD) is a very rare cutaneous adenocarcinoma affecting anogenital or axillary regions. It is characterized by a prolonged course with recurrences and eventually distant metastatic spread for which no specific therapy is known. Methods Eighteen EMPD (13 vulvar and five scrotal) and ten mammary Paget's disease (MPD) cases were comprehensively profiled for gene mutations, fusions and copy number alterations, and for therapy‐relevant protein biomarkers). Results Mutations in TP53 and PIK3CA were the most frequent in both cohorts: 7/15 and 5/15 in EMPD; 1/6 and 4/7 in MPD HER2 gene amplification was detected in 4/18 EMPD (3 vulvar and 1 scrotal case) in contrast to MPD where it was detected in the majority (7/8) of cases. TOP2A gene amplification was seen in 2/12 EMPD and 1/6 MPD, respectively. Similarly, no difference in estrogen receptor expression was seen between the EMPD (4/15) and MPD (3/10). Androgen receptor was also expressed in the majority of both cohorts (12/16 EMPD) and (7/8 MPD).Here ARv7 splice variant was detected in 1/7 EMPD and 1/4 MPD cases, respectively. PD‐L1 expression on immune cells was exclusively observed in three vulvar EMPD. In contrast to MPD, six EMPDs harbored a “high” tumor mutation burden (≥10 mutations/Mb). All tested cases from both cohorts were MSI stable. Conclusions EMPD shares some targetable biomarkers with its mammary counterpart (steroid receptors, PIK3CA signaling pathways, TOP2A amplification). HER2 positivity is notably lower in EMPD while biomarkers to immune checkpoint inhibitors (high TMB and PD‐L1) were observed in some EMPD. Given that no consistent molecular alteration characterizes EMPD, comprehensive theranostic profiling is required to identify individual patients with targetable molecular alterations.
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- 2020
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15. Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling
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Stacey M. Gargano, Wijendra Senarathne, Rebecca Feldman, Elena Florento, Phillip Stafford, Jeffrey Swensen, Semir Vranic, and Zoran Gatalica
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biomarkers ,head and neck cancer ,molecular genetics ,next generation sequencing ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Salivary duct carcinoma (SDC) is a rare, aggressive salivary gland malignancy, which often presents at an advanced stage. A proportion of SDC are characterized by HER2 amplification and/or overexpression of androgen receptor (AR), which could be targeted in a subset of patients, but the presence of AR splice variant‐7 (AR‐V7) in some SDC cases could result in resistance to anti‐androgen therapy. We evaluated a cohort of 28 cases of SDC for potentially targetable biomarkers and pathways using immunohistochemistry (IHC) and next‐generation sequencing (DNA and RNA) assays. Pathogenic genetic aberrations were found in all but 1 case and affected TP53 (n = 19), HRAS (n = 7), PIK3CA, ERBB2 (HER2), and NF1 (n = 5 each); KMT2C (MLL3) and PTEN (n = 3 each); BRAF (p.V600E), KDM5C and NOTCH1 (n = 2 each). Androgen receptor was expressed in all cases and 13 of 27 harbored the AR‐V7 splice variant (including a case without any other detectable genetic alteration). HER2 IHC was expressed in 11 of 28 cases. The majority of SDC cases had no biomarkers predictive of immunotherapy response: 5 cases exhibited low (1%‐8%) programmed death ligand 1 (PD‐L1) expression in tumor cells, 2 cases exhibited elevated TMB, and no samples exhibited microsatellite instability. Notably, the pre‐treatment biopsies from 2 patients with metastatic disease, who demonstrated clinical responses to anti‐androgen therapy, showed AR expression and no AR splice variants. We conclude that comprehensive molecular profiling of SDCs can guide the selection of patients for targeted therapies involving AR, HER2, PD‐L1, mitogen‐activated protein kinase, and PIK3CA pathways.
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- 2019
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16. Targeting HER2 expression in cancer: New drugs and new indications
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Semir Vranić, Semir Bešlija, and Zoran Gatalica
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HER2 ,targeted therapy ,mutations ,amplification ,Biology (General) ,QH301-705.5 - Abstract
Functional activation of human epidermal growth factor receptor 2 (HER2) has been shown to strongly promote carcinogenesis, leading to the investigation of HER2-directed agents in cancers with HER2 genomic alterations. This has been best documented in the context of HER2 gene amplification in breast and gastric/gastroesophageal junction carcinomas for which several HER2-directed agents are available and have become a part of standard treatment regimens. Somatic HER2 gene mutations have been recently described at low frequency in a variety of human cancers and have emerged as a novel predictive biomarker for HER2-directed therapies. Preclinical data also indicate that activating HER2 mutations are potent oncogenic drivers in a manner that is analogous to HER2 amplification. HER2 mutations may clinically confer sensitivity to HER2-directed agents as recently shown in a phase II clinical trial with antibody-drug conjugate against HER2 trastuzumab deruxtecan in patients with non-squamous non-small cell lung carcinoma.
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- 2021
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17. Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer
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Katia Khoury, Antoinette R. Tan, Andrew Elliott, Joanne Xiu, Zoran Gatalica, Arielle L. Heeke, Claudine Isaacs, Paula R. Pohlmann, Lee S. Schwartzberg, Michael Simon, W. Michael Korn, Sandra M. Swain, and Filipa Lynce
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breast cancer ,molecular profiling ,PIK3CA-AKT1-PTEN pathway ,PI3K inhibitor ,PD-L1 ,CDH1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: PI3K/AKT signaling pathway is activated in breast cancer and associated with cell survival. We explored the prevalence of PI3K pathway alterations and co-expression with other markers in breast cancer subtypes.Methods: Samples of non-matched primary and metastatic breast cancer submitted to a CLIA-certified genomics laboratory were molecularly profiled to identify pathogenic or presumed pathogenic mutations in the PIK3CA-AKT1-PTEN pathway using next generation sequencing. Cases with loss of PTEN by IHC were also included. The frequency of co-alterations was examined, including DNA damage response pathways and markers of response to immuno-oncology agents.Results: Of 4,895 tumors profiled, 3,558 (72.7%) had at least one alteration in the PIK3CA-AKT1-PTEN pathway: 1,472 (30.1%) harbored a PIK3CA mutation, 174 (3.6%) an AKT1 mutation, 2,682 (54.8%) had PTEN alterations (PTEN mutation in 7.0% and/or PTEN loss by IHC in 51.4% of cases), 81 (1.7%) harbored a PIK3R1 mutation, and 4 (0.08%) a PIK3R2 mutation. Most of the cohort consisted of metastatic sites (n = 2974, 60.8%), with PIK3CA mutation frequency increased in metastatic (32.1%) compared to primary sites (26.9%), p < 0.001. Other PIK3CA mutations were identified in 388 (7.9%) specimens, classified as “off-label,” as they were not included in the FDA-approved companion test for PIK3CA mutations. Notable co-alterations included increased PD-L1 expression and high tumor mutational burden in PIK3CA-AKT1-PTEN mutated cohorts. Novel concurrent mutations were identified including CDH1 mutations.Conclusions: Findings from this cohort support further exploration of the clinical benefit of PI3K inhibitors for “off-label” PIK3CA mutations and combination strategies with potential clinical benefit for patients with breast cancer.
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- 2020
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18. Microsatellite instability status determined by next‐generation sequencing and compared with PD‐L1 and tumor mutational burden in 11,348 patients
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Ari Vanderwalde, David Spetzler, Nianqing Xiao, Zoran Gatalica, and John Marshall
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Antineoplastic agents/therapeutic use ,checkpoint inhibitor ,DNA mismatch repair ,microsatellite instability ,next‐generation sequencing ,precision medicine ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Microsatellite instability (MSI) testing identifies patients who may benefit from immune checkpoint inhibitors. We developed an MSI assay that uses data from a commercially available next‐generation sequencing (NGS) panel to determine MSI status. The assay is applicable across cancer types and does not require matched samples from normal tissue. Here, we describe the MSI‐NGS method and explore the relationship of MSI with tumor mutational burden (TMB) and PD‐L1. MSI examined by PCR fragment analysis and NGS was compared for 2189 matched cases. Mismatch repair status by immunohistochemistry was compared to MSI‐NGS for 1986 matched cases. TMB was examined by NGS, and PD‐L1 was determined by immunohistochemistry. Among 2189 matched cases that spanned 26 cancer types, MSI‐NGS, as compared to MSI by PCR fragment analysis, had sensitivity of 95.8% (95% confidence interval [CI] 92.24, 98.08), specificity of 99.4% (95% CI 98.94, 99.69), positive predictive value of 94.5% (95% CI 90.62, 97.14), and negative predictive value of 99.2% (95% CI, 98.75, 99.57). High MSI (MSI‐H) status was identified in 23 of 26 cancer types. Among 11,348 cases examined (including the 2189 matched cases), the overall rates of MSI‐H, TMB‐high, and PD‐L1 positivity were 3.0%, 7.7%, and 25.4%, respectively. Thirty percent of MSI‐H cases were TMB‐low, and only 26% of MSI‐H cases were PD‐L1 positive. The overlap between TMB, MSI, and PD‐L1 differed among cancer types. Only 0.6% of the cases were positive for all three markers. MSI‐H status can be determined by NGS across cancer types. MSI‐H offers distinct data for treatment decisions regarding immune checkpoint inhibitors, in addition to the data available from TMB and PD‐L1.
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- 2018
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19. Poly-ligand profiling differentiates trastuzumab-treated breast cancer patients according to their outcomes
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Valeriy Domenyuk, Zoran Gatalica, Radhika Santhanam, Xixi Wei, Adam Stark, Patrick Kennedy, Brandon Toussaint, Symon Levenberg, Jie Wang, Nianqing Xiao, Richard Greil, Gabriel Rinnerthaler, Simon P. Gampenrieder, Amy B. Heimberger, Donald A. Berry, Anna Barker, John Quackenbush, John L. Marshall, George Poste, Jeffrey L. Vacirca, Gregory A. Vidal, Lee S. Schwartzberg, David D. Halbert, Andreas Voss, Daniel Magee, Mark R. Miglarese, Michael Famulok, Günter Mayer, and David Spetzler
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Science - Abstract
Patients’ selection is particularly important in cancer treatment. Here the authors present a proof-of-principle methodology that could be potentially important in assisting therapeutic decisions in the treatment of breast cancer patients.
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- 2018
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20. Correction to: Gliosarcoma vs. glioblastoma: a retrospective case series using molecular profiling
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Christopher Dardis, David Donner, Nader Sanai, Joanne Xiu, Sandeep Mittal, Sharon K. Michelhaugh, Manjari Pandey, Santosh Kesari, Amy B. Heimberger, Zoran Gatalica, Michael W. Korn, Ashley L. Sumrall, and Surasak Phuphanich
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Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2021
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21. Association Between Programmed Death-Ligand 1 Expression and the Vascular Endothelial Growth Factor Pathway in Angiosarcoma
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Sanjay P. Bagaria, Zoran Gatalica, Todd Maney, Daniel Serie, Mansi Parasramka, Steven Attia, Murli Krishna, and Richard W. Joseph
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angiosarcoma ,programmed death-ligand 1 ,immune microenvironment ,checkpoint pathway ,vascular endothelial growth factor ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Angiosarcoma is a vascular malignancy associated with a poor prognosis and chemotherapy resistance. The tumor immune microenvironment of angiosarcoma has not been characterized. We investigated the expression of programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) in angiosarcoma and correlated these findings with vascular endothelial growth factor (VEGF)-related gene expression and survival. Using archived formalin-fixed paraffin-embedded tissues of primary and metastatic angiosarcoma specimens, we characterized the immunohistochemical (IHC) expression of PD-L1 and PD-1. In addition, we extracted RNA from each tumor and quantified the expression of VEGF-related genes, and then tested if these genes were associated with PD-L1 and PD-1 expression and clinical outcomes. Retrospective review identified 27 angiosarcoma specimens collected between 1994 and 2012. IHC expression of tumor PD-L1, tumor-infiltrating immune cell PD-L1, and tumor-infiltrating immune cell PD-1 expression was identified in 5 (19%), 9 (33%), and 1 (4%) specimens, respectively. Expression of PD-L1 and PD-1 was not associated with VEGF-related gene expression or survival. PD-L1 tumor and tumor-infiltrating immune cells expression was identified in a large proportion of patients. Though neither was associated with VEGF-related gene expression or prognosis, targeting PD-1/PD-L1 may be of benefit for a significant proportion of angiosarcomas that do not respond to surgery, chemotherapy, or radiation.
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- 2018
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22. Comprehensive molecular profiling of advanced/metastatic olfactory neuroblastomas.
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Jasmina Topcagic, Rebecca Feldman, Anatole Ghazalpour, Jeffrey Swensen, Zoran Gatalica, and Semir Vranic
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Medicine ,Science - Abstract
Olfactory neuroblastoma (ONB) is a rare, locally aggressive, malignant neoplasm originating in the olfactory epithelium in the nasal vault. The recurrence rate of ONB remains high and there are no specific treatment guidelines for recurrent/metastatic ONBs. This study retrospectively evaluated 23 ONB samples profiled at Caris Life Sciences (Phoenix, Arizona) using DNA sequencing (Sanger/NGS [Illumina], n = 15) and gene fusions (Archer FusionPlex, n = 6), whole genome RNA microarray (HumanHT-12 v4 beadChip, Illumina, n = 4), gene copy number assays (chromogenic and fluorescent in situ hybridization), and immunohistochemistry. Mutations were detected in 63% ONBs including TP53, CTNNB1, EGFR, APC, cKIT, cMET, PDGFRA, CDH1, FH, and SMAD4 genes. Twenty-one genes were over-expressed and 19 genes under-expressed by microarray assay. Some of the upregulated genes included CD24, SCG2, and IGFBP-2. None of the cases harbored copy number variations of EGFR, HER2 and cMET genes, and no gene fusions were identified. Multiple protein biomarkers of potential response or resistance to classic chemotherapy drugs were identified, such as low ERCC1 [cisplatin sensitivity in 10/12], high TOPO1 [irinotecan sensitivity in 12/19], high TUBB3 [vincristine resistance in 13/14], and high MRP1 [multidrug resistance in 6/6 cases]. None of the cases (0/10) were positive for PD-L1 in tumor cells. Overexpression of pNTRK was observed in 67% (4/6) of the cases without underlying genetic alterations. Molecular alterations detected in our study (e.g., Wnt and cKIT/PDGFRA pathways) are potentially treatable using novel therapeutic approaches. Identified protein biomarkers of response or resistance to classic chemotherapy could be useful in optimizing existing chemotherapy treatment(s) in ONBs.
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- 2018
- Full Text
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23. Immunohistochemical Analysis of the Natural Killer Cell Cytotoxicity Pathway in Human Abdominal Aortic Aneurysms
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Irene Hinterseher, Charles M. Schworer, John H. Lillvis, Elizabeth Stahl, Robert Erdman, Zoran Gatalica, Gerard Tromp, and Helena Kuivaniemi
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human aorta ,immunohistochemistry ,double-staining ,AAA ,aortic aneurysm ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Our previous analysis using genome-wide microarray expression data revealed extreme overrepresentation of immune related genes belonging the Natural Killer (NK) Cell Mediated Cytotoxicity pathway (hsa04650) in human abdominal aortic aneurysm (AAA). We followed up the microarray studies by immunohistochemical analyses using antibodies against nine members of the NK pathway (VAV1, VAV3, PLCG1, PLCG2, HCST, TYROBP, PTK2B, TNFA, and GZMB) and aortic tissue samples from AAA repair operations (n = 6) and control aortae (n = 8) from age-, sex- and ethnicity-matched donors from autopsies. The results confirmed the microarray results. Two different members of the NK pathway, HCST and GRZB, which act at different steps in the NK-pathway, were actively transcribed and translated into proteins in the same cells in the AAA tissue demonstrated by double staining. Furthermore, double staining with antibodies against CD68 or CD8 together with HCST, TYROBP, PTK2B or PLCG2 revealed that CD68 and CD8 positive cells expressed proteins of the NK-pathway but were not the only inflammatory cells involved in the NK-pathway in the AAA tissue. The results provide strong evidence that the NK Cell Mediated Cytotoxicity Pathway is activated in human AAA and valuable insight for future studies to dissect the pathogenesis of human AAA.
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- 2015
- Full Text
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24. Apocrine carcinoma of the breast: A brief update on the molecular features and targetable biomarkers
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Semir Vranic, Rebecca Feldman, and Zoran Gatalica
- Subjects
breast cancer ,special types ,apocrine carcinoma ,androgen receptor ,biomarkers ,targeted therapy ,Biology (General) ,QH301-705.5 - Abstract
Apocrine carcinoma of the breast is a rare, primary breast cancer characterized by the apocrine morphology, estrogen receptor-negative and androgen receptor-positive profile with a frequent overexpression of Her-2/neu protein (~30%). Apart from the Her-2/neu target, advanced and/or metastatic apocrine carcinomas have limited treatment options. In this review, we briefly describe and discuss the molecular features and new theranostic biomarkers for this rare mammary malignancy. The importance of comprehensive profiling is highlighted due to synergistic and potentially antagonistic molecular events in the individual patients.
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- 2017
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25. Metastatic Cancer of Cowper's Gland: A Rare Cancer Managed Successfully by Molecular Profiling
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Charles E. Myers, Zoran Gatalica, Anthony Spinelli, Michael Castro, Erica Linden, Oliver Sartor, and Mathew Sargent
- Subjects
c-kit ,Molecular profiling ,Cowper’s gland ,Adenoid cystic carcinoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Cancer of Cowper's gland is a very rare cancer. This case represents the 9th case in the medical literature. As such, there are no phase II or phase III trials to guide treatment. In this article, we report the successful treatment of a patient over a 7-year period guided solely by molecular profiling. Through multiple cycles to treatment, the cancer was controlled using drugs targeting c-kit, as the cancer steadily increased the expression of c-kit. This report also documents the use of a novel drug combination based on sunitinib that was well tolerated and may warrant testing in other c-kit-dependent cancers.
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- 2014
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26. PD-L1 Status in Refractory Lymphomas.
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Semir Vranic, Nilanjan Ghosh, Jeffery Kimbrough, Nurija Bilalovic, Ryan Bender, David Arguello, Yvonne Veloso, Aida Dizdarevic, and Zoran Gatalica
- Subjects
Medicine ,Science - Abstract
Targeted immunotherapy based on PD-1/PD-L1 suppression has revolutionized the treatment of various solid tumors. A remarkable improvement has also been observed in the treatment of patients with refractory/relapsing classical Hodgkin lymphoma (cHL). We investigated PD-L1 status in a variety of treatment resistant lymphomas. Tumor samples from 78 patients with therapy resistant lymphomas were immunohistochemically (IHC) investigated for the expression of PD-L1 using two antibody clones (SP142 and SP263, Ventana). Thirteen PD-L1+ cases were further analyzed for gene copy number variations (CNV) by NGS and for PD-L1/JAK2/PD-L2 co-amplification using fluorescent in-situ hybridization assay (FISH). PD-L1 positivity (≥5% positive cancer cells, IHC) was present in 32/77 (42%) and 33/71 cases (46%) using SP142 and SP263 antibodies, respectively. Concordance between the two anti-PD-L1 clones was high with only three (4%) discrepant cases. The strongest and consistent (10/11 cases) expression was observed in cHL and primary mediastinal B-cell lymphomas (3/3). Diffuse large B-cell lymphomas (DLBCL) were frequently positive (13/26) irrespective of subtype. Follicular (1/8), peripheral T-cell (3/11) and mantle cell (1/8) lymphomas were rarely positive, while small lymphocytic lymphoma/CLL and marginal zone lymphomas were consistently negative (3/3). Co-amplification/CNVs of PD-L1/JAK2/PD-L2 were observed in 3 cases of DLBCL and cHL, respectively. Of note, all three cHL-amplified cases were positive by FISH, but not by NGS. Since only a fraction of the IHC positive lymphoma cases were positive by FISH and NGS assays, other mechanisms are involved in PD-L1 upregulation, especially in DLBCL. FISH assay may be more suitable than NGS assay for determination of PD-L1 alterations in cHL.
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- 2016
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27. Towards Molecular Profiling in Multiple Myeloma: A Literature Review and Early Indications of Its Efficacy for Informing Treatment Strategies
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Wolfgang Willenbacher, Andreas Seeber, Normann Steiner, Ella Willenbacher, Zoran Gatalica, Jeff Swensen, Jeffery Kimbrough, and Semir Vranic
- Subjects
plasma cell dyscrasias ,multiple myeloma ,molecular profiling ,treatment ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by the clonal expansion of plasma cells. Despite dramatic improvements in patients′ survival over the past decade due to advances in therapy exploiting novel molecular targets (immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies), the treatment of relapsed and refractory disease remains challenging. Recent studies confirmed complex, dynamic, and heterogeneous genomic alterations without unifying gene mutations in MM patients. In the current review, we survey recent therapeutic strategies, as well as molecular profiling data on MM, with emphasis on relapsed and refractory cases. A critical appraisal of novel findings and of their potential therapeutic implications will be discussed in detail, along with the author’s own experiences/views.
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- 2018
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28. An Update on the Molecular and Clinical Characteristics of Apocrine Carcinoma of the Breast
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Semir Vranic and Zoran Gatalica
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therapy ,Cancer Research ,Carcinoma ,Breast Neoplasms ,Triple Negative Breast Neoplasms ,apocrine carcinoma ,Immunohistochemistry ,MicroRNAs ,Sweat Gland Neoplasms ,Apocrine Glands ,Oncology ,Receptors, Androgen ,androgen receptor ,Biomarkers, Tumor ,Humans ,Female ,Breast ,Mitogen-Activated Protein Kinases ,molecular features - Abstract
Apocrine carcinoma of the breast is a rare malignancy. According to 2019 WHO classification, apocrine cellular features and a characteristic steroid receptor profile (Estrogen receptor (ER)-negative and androgen receptor (AR)-positive) define apocrine carcinoma. Her-2/neu protein expression is reported in ∼30-50% of apocrine carcinomas, while NGS analysis showed frequent PIK3CA/PTEN/AKT and TP53 mutations Followed by deregulation in the mitogen-activated protein kinase pathway components (mutations of KRAS, NRAS, BRAF). A recent miRNA study indicates various miRNAs (downregulated hsa-miR-145-5p and upregulated 14 miRNAs such as hsa-miR-182-5p, hsa-miR-3135b, and hsa-miR-4417) may target the commonly altered pathways in apocrine carcinomas such as ERBB2/HER2 and mitogen-activated protein kinase signaling pathway. Although AR expression is a hallmark of apocrine carcinoma, little is known regarding the efficacy/resistance to antiandrogens. Success of bicalutamide, a non-steroidal anti-androgen, was reported in a case of Her2-negative apocrine carcinoma. Two recent studies, however, described presence of anti-androgen resistance biomarkers (a splice variant ARv7 and AR/NCOA2 co-amplification) in a subset of AR+ apocrine carcinomas, cautioning the use of anti-androgens in AR+ triple-negative breast carcinomas. Apocrine carcinomas rarely show biomarkers predictive of response to immune checkpoint inhibitors (PD-L1 expression, MSI-H status, and TMB-high). Therefore, a comprehensive cancer profiling of apocrine carcinomas is necessary to identify potential therapeutic targets for a truly individualized treatment approach.
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- 2022
29. Supplementary Figure 4 from Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC
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Aiwu Ruth He, Michael Atkins, Louis Weiner, John Marshall, Christopher Loffredo, Petra Prins, Anteneh Tesfaye, Tiger Zhang, Perry Feng, Jaydeep Kachhela, Reena Jha, Filip Banovac, Rohit Satoskar, Eddie Island, Lynt Johnson, Thomas Fishbein, David Kleiner, Sandeep Reddy, Zoran Gatalica, Bhaskar Kallakury, Jiji Jiang, Hongkun Wang, Yunan Wu, and Andrew Gabrielson
- Abstract
Graphical distributions of CD3+ and CD8+ T lymphocyte densities in the TI and IM.
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- 2023
30. Supplementary Figure 3 from Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC
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Aiwu Ruth He, Michael Atkins, Louis Weiner, John Marshall, Christopher Loffredo, Petra Prins, Anteneh Tesfaye, Tiger Zhang, Perry Feng, Jaydeep Kachhela, Reena Jha, Filip Banovac, Rohit Satoskar, Eddie Island, Lynt Johnson, Thomas Fishbein, David Kleiner, Sandeep Reddy, Zoran Gatalica, Bhaskar Kallakury, Jiji Jiang, Hongkun Wang, Yunan Wu, and Andrew Gabrielson
- Abstract
ImageJ plug-in code for image analysis.
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- 2023
31. Figure S3 from An Emerging Landscape for Canonical and Actionable Molecular Alterations in Primary and Metastatic Prostate Cancer
- Author
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Elisabeth I. Heath, W. Michael Korn, Zoran Gatalica, Michelle Saul, Rebecca A. Feldman, Timothy Lindsay, Matthew Zibelman, and Nancy A. Dawson
- Abstract
differential rates of mutations in primary and metastatic prostate cancers
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- 2023
32. Supplementary Figure 5 from Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC
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Aiwu Ruth He, Michael Atkins, Louis Weiner, John Marshall, Christopher Loffredo, Petra Prins, Anteneh Tesfaye, Tiger Zhang, Perry Feng, Jaydeep Kachhela, Reena Jha, Filip Banovac, Rohit Satoskar, Eddie Island, Lynt Johnson, Thomas Fishbein, David Kleiner, Sandeep Reddy, Zoran Gatalica, Bhaskar Kallakury, Jiji Jiang, Hongkun Wang, Yunan Wu, and Andrew Gabrielson
- Abstract
Bivariate analysis of TIL pattern and tumor stage, cellular differentiation, and vascular invasion.
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- 2023
33. Data from Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC
- Author
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Aiwu Ruth He, Michael Atkins, Louis Weiner, John Marshall, Christopher Loffredo, Petra Prins, Anteneh Tesfaye, Tiger Zhang, Perry Feng, Jaydeep Kachhela, Reena Jha, Filip Banovac, Rohit Satoskar, Eddie Island, Lynt Johnson, Thomas Fishbein, David Kleiner, Sandeep Reddy, Zoran Gatalica, Bhaskar Kallakury, Jiji Jiang, Hongkun Wang, Yunan Wu, and Andrew Gabrielson
- Abstract
Immune cells that infiltrate a tumor may be a prognostic factor for patients who have had surgically resected hepatocellular carcinoma (HCC). The density of intratumoral total (CD3+) and cytotoxic (CD8+) T lymphocytes was measured in the tumor interior and in the invasive margin of 65 stage I to IV HCC tissue specimens from a single cohort. Immune cell density in the interior and margin was converted to a binary score (0, low; 1, high), which was correlated with tumor recurrence and relapse-free survival (RFS). In addition, the expression of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) was correlated with the density of CD3+ and CD8+ cells and clinical outcome. High densities of both CD3+ and CD8+ T cells in both the interior and margin, along with corresponding Immunoscores, were significantly associated with a low rate of recurrence (P = 0.007) and a prolonged RFS (P = 0.002). In multivariate logistic regression models adjusted for vascular invasion and cellular differentiation, both CD3+ and CD8+ cell densities predicted recurrence, with odds ratios of 5.8 [95% confidence interval (CI), 1.6–21.8] for CD3+ and 3.9 (95% CI, 1.1–14.1) for CD8+. Positive PD-L1 staining was correlated with high CD3 and CD8 density (P = 0.024 and 0.005, respectively) and predicted a lower rate of recurrence (P = 0.034), as well as prolonged RFS (P = 0.029). Immunoscore and PD-L1 expression, therefore, are useful prognostic markers in patients with HCC who have undergone primary tumor resection. Cancer Immunol Res; 4(5); 419–30. ©2016 AACR.
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- 2023
34. Supplementary Data Figure S2 from An Emerging Landscape for Canonical and Actionable Molecular Alterations in Primary and Metastatic Prostate Cancer
- Author
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Elisabeth I. Heath, W. Michael Korn, Zoran Gatalica, Michelle Saul, Rebecca A. Feldman, Timothy Lindsay, Matthew Zibelman, and Nancy A. Dawson
- Abstract
JAK1 mutation frequency across tumors
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- 2023
35. Supplementary Data Table S1 from An Emerging Landscape for Canonical and Actionable Molecular Alterations in Primary and Metastatic Prostate Cancer
- Author
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Elisabeth I. Heath, W. Michael Korn, Zoran Gatalica, Michelle Saul, Rebecca A. Feldman, Timothy Lindsay, Matthew Zibelman, and Nancy A. Dawson
- Abstract
patient and tumor characteristics
- Published
- 2023
36. Supplementary Figure 6 from Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC
- Author
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Aiwu Ruth He, Michael Atkins, Louis Weiner, John Marshall, Christopher Loffredo, Petra Prins, Anteneh Tesfaye, Tiger Zhang, Perry Feng, Jaydeep Kachhela, Reena Jha, Filip Banovac, Rohit Satoskar, Eddie Island, Lynt Johnson, Thomas Fishbein, David Kleiner, Sandeep Reddy, Zoran Gatalica, Bhaskar Kallakury, Jiji Jiang, Hongkun Wang, Yunan Wu, and Andrew Gabrielson
- Abstract
Kaplan-Meier analysis of RFS stratified by pattern of CD3+ and CD8+ T lymphocytes.
- Published
- 2023
37. Data from PD-1 and PD-L1 Expression in Renal Cell Carcinoma with Sarcomatoid Differentiation
- Author
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Thai H. Ho, Erik P. Castle, Melissa L. Stanton, Nicholas J. Vogelzang, Alan H. Bryce, Sandeep Reddy, Zoran Gatalica, David Bryant, Estrella M. Carballido, Sherri Z. Millis, and Richard W. Joseph
- Abstract
Monoclonal antibodies that target the programmed death-1 (PD-1)–programmed death ligand-1 (PD-L1) axis have antitumor activity against multiple cancers. The presence of sarcomatoid differentiation in renal cell carcinoma (RCC) is associated with resistance to targeted therapy and poor responses to IL2 immunotherapy. Given the aggressive nature of RCC with sarcomatoid differentiation and the exclusion of sarcomatoid histology from metastatic RCC clinical trials, less is understood regarding selection of therapies. Here, we characterized the PD-1/PD-L1 axis in RCC with sarcomatoid differentiation. We directly compared two PD-L1 antibodies and found concordance of PD-L1 positivity in 89% of tested RCCs with sarcomatoid differentiation. Coexpression of PD-L1 on neoplastic cells and the presence of PD-1–positive tumor-infiltrating lymphocytes were identified in 50% (13 of 26) of RCCs with sarcomatoid differentiation. In contrast, only 1 of 29 clear cell RCCs (3%) had concurrent expression of PD-L1 and PD-1 (P = 0.002). Our study suggests that RCC with sarcomatoid differentiation may express PD-1/PD-L1 at a higher percentage than RCC without sarcomatoid differentiation, and patients with these tumors may be good candidates for treatment with anti–PD-1/PD-L1 therapies. Cancer Immunol Res; 3(12); 1303–7. ©2015 AACR.
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- 2023
38. Supplementary Figure 2 from Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC
- Author
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Aiwu Ruth He, Michael Atkins, Louis Weiner, John Marshall, Christopher Loffredo, Petra Prins, Anteneh Tesfaye, Tiger Zhang, Perry Feng, Jaydeep Kachhela, Reena Jha, Filip Banovac, Rohit Satoskar, Eddie Island, Lynt Johnson, Thomas Fishbein, David Kleiner, Sandeep Reddy, Zoran Gatalica, Bhaskar Kallakury, Jiji Jiang, Hongkun Wang, Yunan Wu, and Andrew Gabrielson
- Abstract
Example of computer-assisted evaluation of infiltrate densities.
- Published
- 2023
39. Table S3 from An Emerging Landscape for Canonical and Actionable Molecular Alterations in Primary and Metastatic Prostate Cancer
- Author
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Elisabeth I. Heath, W. Michael Korn, Zoran Gatalica, Michelle Saul, Rebecca A. Feldman, Timothy Lindsay, Matthew Zibelman, and Nancy A. Dawson
- Abstract
characterization of frequently mutated genes in MSI-H
- Published
- 2023
40. Supplemental Table from PD-1 and PD-L1 Expression in Renal Cell Carcinoma with Sarcomatoid Differentiation
- Author
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Thai H. Ho, Erik P. Castle, Melissa L. Stanton, Nicholas J. Vogelzang, Alan H. Bryce, Sandeep Reddy, Zoran Gatalica, David Bryant, Estrella M. Carballido, Sherri Z. Millis, and Richard W. Joseph
- Abstract
Supplemental Table. Concordance of Immunohistochemical Staining of PD-L1 Expression (130021 vs SP142 antibody) in 19 Renal Cell Carcinomas With Sarcomatoid Differentiation
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- 2023
41. Supplementary Figure 7 from Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC
- Author
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Aiwu Ruth He, Michael Atkins, Louis Weiner, John Marshall, Christopher Loffredo, Petra Prins, Anteneh Tesfaye, Tiger Zhang, Perry Feng, Jaydeep Kachhela, Reena Jha, Filip Banovac, Rohit Satoskar, Eddie Island, Lynt Johnson, Thomas Fishbein, David Kleiner, Sandeep Reddy, Zoran Gatalica, Bhaskar Kallakury, Jiji Jiang, Hongkun Wang, Yunan Wu, and Andrew Gabrielson
- Abstract
Bivariate analysis of CD3+ and CD8+ cell density and beta-catenin expression.
- Published
- 2023
42. Supplementary Figure 1 from Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC
- Author
-
Aiwu Ruth He, Michael Atkins, Louis Weiner, John Marshall, Christopher Loffredo, Petra Prins, Anteneh Tesfaye, Tiger Zhang, Perry Feng, Jaydeep Kachhela, Reena Jha, Filip Banovac, Rohit Satoskar, Eddie Island, Lynt Johnson, Thomas Fishbein, David Kleiner, Sandeep Reddy, Zoran Gatalica, Bhaskar Kallakury, Jiji Jiang, Hongkun Wang, Yunan Wu, and Andrew Gabrielson
- Abstract
Flowchart of image analysis process.
- Published
- 2023
43. Supplementary Figure 8 from Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC
- Author
-
Aiwu Ruth He, Michael Atkins, Louis Weiner, John Marshall, Christopher Loffredo, Petra Prins, Anteneh Tesfaye, Tiger Zhang, Perry Feng, Jaydeep Kachhela, Reena Jha, Filip Banovac, Rohit Satoskar, Eddie Island, Lynt Johnson, Thomas Fishbein, David Kleiner, Sandeep Reddy, Zoran Gatalica, Bhaskar Kallakury, Jiji Jiang, Hongkun Wang, Yunan Wu, and Andrew Gabrielson
- Abstract
Bivariate analysis of tumor stage with vascular invasion and cellular differentiation.
- Published
- 2023
44. Data from A Phase II Basket Trial of Dual Anti–CTLA-4 and Anti–PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors
- Author
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Razelle Kurzrock, Charles D. Blanke, Melissa Plets, Christopher W. Ryan, Edward Mayerson, Elad Sharon, Helen X. Chen, Christine McLeod, Jourdain Hayward, W. Michael Korn, Zoran Gatalica, Marc Matrana, Tareq Al Baghdadi, Anup Kasi, Manisha H. Shah, Annette Fontaine, Preet Paul Singh, Donna E. Hansel, Francis J. Giles, Young Kwang Chae, Megan Othus, and Sandip P. Patel
- Abstract
Purpose:Immune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (nonpancreatic) neuroendocrine neoplasm cohort of SWOG S1609 dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART).Patients and Methods:We performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the (nonpancreatic) neuroendocrine cohort reported here. Response assessment by grade was not prespecified. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity.Results:Thirty-two eligible patients received therapy; 18 (56%) had high-grade disease. Most common primary sites were gastrointestinal (47%; N = 15) and lung (19%; N = 6). The overall ORR was 25% [95% confidence interval (CI) 13–64%; CR, 3%, N = 1; PR, 22%, N = 7]. Patients with high-grade neuroendocrine carcinoma had an ORR of 44% (8/18 patients) versus 0% in low/intermediate grade tumors (0/14 patients; P = 0.004). The 6-month PFS was 31% (95% CI, 19%–52%); median OS was 11 months (95% CI, 6–∞). The most common toxicities were hypothyroidism (31%), fatigue (28%), and nausea (28%), with alanine aminotransferase elevation (9%) as the most common grade 3/4 immune-related adverse event, and no grade 5 events.Conclusions:Ipilimumab plus nivolumab demonstrated a 44% ORR in patients with nonpancreatic high-grade neuroendocrine carcinoma, with 0% ORR in low/intermediate grade disease.
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- 2023
45. Figure S1 from Detection of NRG1 Gene Fusions in Solid Tumors
- Author
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Stephen V. Liu, Edward S. Kim, Antoinette J. Wozniak, Ari M. Vanderwalde, Alexander I. Spira, Jorge J. Nieva, Patrick C. Ma, Hossein Borghaei, Wolfgang M. Korn, Zoran Gatalica, Jeffrey Swensen, Rebecca A. Feldman, and Sushma Jonna
- Abstract
Figure S1 from Detection of NRG1 Gene Fusions in Solid Tumors
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- 2023
46. Table from Detection of NRG1 Gene Fusions in Solid Tumors
- Author
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Stephen V. Liu, Edward S. Kim, Antoinette J. Wozniak, Ari M. Vanderwalde, Alexander I. Spira, Jorge J. Nieva, Patrick C. Ma, Hossein Borghaei, Wolfgang M. Korn, Zoran Gatalica, Jeffrey Swensen, Rebecca A. Feldman, and Sushma Jonna
- Abstract
Table S1. Descriptions of NRG1 Fusions Identified. *Novel fusion. Abbreviations: NSCLC, non-small cell lung cancer; PDAC, pancreatic ductal adenocarcinoma; GBC, gallbladder cancer (cholangiocarcinoma); CRC, colorectal cancer. RCC, renal cell carcinoma; NET, neuroendocrine tumor.
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- 2023
47. Supplementary Data from A Phase II Basket Trial of Dual Anti–CTLA-4 and Anti–PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors
- Author
-
Razelle Kurzrock, Charles D. Blanke, Melissa Plets, Christopher W. Ryan, Edward Mayerson, Elad Sharon, Helen X. Chen, Christine McLeod, Jourdain Hayward, W. Michael Korn, Zoran Gatalica, Marc Matrana, Tareq Al Baghdadi, Anup Kasi, Manisha H. Shah, Annette Fontaine, Preet Paul Singh, Donna E. Hansel, Francis J. Giles, Young Kwang Chae, Megan Othus, and Sandip P. Patel
- Abstract
Appendix
- Published
- 2023
48. Data from Detection of NRG1 Gene Fusions in Solid Tumors
- Author
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Stephen V. Liu, Edward S. Kim, Antoinette J. Wozniak, Ari M. Vanderwalde, Alexander I. Spira, Jorge J. Nieva, Patrick C. Ma, Hossein Borghaei, Wolfgang M. Korn, Zoran Gatalica, Jeffrey Swensen, Rebecca A. Feldman, and Sushma Jonna
- Abstract
Purpose:NRG1 gene fusions are rare but potentially actionable oncogenic drivers that are present in some solid tumors. Details regarding the incidence of these gene rearrangements are lacking. Here, we assessed the incidence of NRG1 fusions across multiple tumor types and described fusion partners.Experimental Design:Tumor specimens submitted for molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)–certified genomics laboratory and that underwent fusion testing by anchored multiplex PCR for targeted RNA sequencing were retrospectively identified. The overall and tumor-specific incidence was noted, as was the specific fusion partner.Results:Out of 21,858 tumor specimens profiled from September 2015 to December 2018, 41 cases (0.2%) harbored an NRG1 fusion. Multiple fusion partners were identified. Fusion events were seen across tumor types. The greatest incidence was in non–small cell lung cancer (NSCLC, 25), though this represented only 0.3% of NSCLC cases tested. Other tumor types harboring an NRG1 fusion included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer.Conclusions:NRG1 fusions can be detected at a low incidence across multiple tumor types with significant heterogeneity in fusion partner.See related commentary by Dimou and Camidge, p. 4865
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- 2023
49. HER2-positive apocrine carcinoma of the breast: a population-based analysis of treatment and outcome
- Author
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Faruk Skenderi, Mohamad Alhoda Mohamad Alahmad, Emin Tahirovic, Yaman M. Alahmad, Zoran Gatalica, and Semir Vranic
- Subjects
Cancer Research ,Receptor, ErbB-2 ,Carcinoma ,Oncology and carcinogenesis ,Breast Neoplasms ,Prognosis ,Treatment Outcome ,Receptors, Estrogen ,Oncology ,Biomarkers, Tumor ,Humans ,Female ,Receptors, Progesterone ,skin and connective tissue diseases ,neoplasms - Abstract
Purpose Apocrine carcinoma of the breast (APO) expresses HER2 in 30–50% of cases. This study explored the clinicopathological features and outcome of HER2+/APO and matched HER2+/NST cohort. Methods We used the SEER database to explore the cohorts. Univariate and multivariate analyses were used to assess the survival. Based on ER and PR [steroid receptors/SR/] and HER2 status, we divided the cohorts to match the intrinsic molecular subtypes for comparisons. Results We retrieved 259 cases of HER2+/APO. Most HER2+/APO were SR negative (65%). HER2+/APO were more prevalent in the 80+ age group (24.7% vs. 15.7%, p p p = 0.019). This was particularly evident between SR− subgroups (10.4% in HER2+/SR−/NST vs. 4.2% in HER2+/SR−/APO, p = 0.008) and was reaffirmed in breast cancer-specific survival in univariate analysis (p = 0.03). Other than race and SR status, HER2+/APO subgroups did not differ in clinicopathological parameters. Conclusions Our study confirms the rarity of the APO and reveals that SR status in APO does not affect these patients' prognosis. HER2+/APO tumors tend to have a less aggressive phenotype and a more favorable outcome despite a markedly lower ER/PR positivity.
- Published
- 2022
50. Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases
- Author
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Mihaela Farcaş, Zoran Gatalica, Kiril Trpkov, Jeffrey Swensen, Ming Zhou, Reza Alaghehbandan, Sean R. Williamson, Cristina Magi-Galluzzi, Anthony J. Gill, Maria Tretiakova, Jose I. Lopez, Delia Perez Montiel, Maris Sperga, Eva Comperat, Fadi Brimo, Asli Yilmaz, Farshid Siadat, Ankur Sangoi, Yuan Gao, Nikola Ptákova, Levente Kuthi, Kristyna Pivovarcikova, Joanna Rogala, Abbas Agaimy, Arndt Hartmann, Cristoph Fraune, Boris Rychly, Pavel Hurnik, Dušan Durcansky, Michael Bonert, Georgios Gakis, Michal Michal, Milan Hora, and Ondrej Hes
- Subjects
Adult ,Male ,Adolescent ,DNA Copy Number Variations ,TOR Serine-Threonine Kinases ,High-Throughput Nucleotide Sequencing ,Middle Aged ,Kidney ,Carotenoids ,Kidney Neoplasms ,Pathology and Forensic Medicine ,Young Adult ,Mutation ,Biomarkers, Tumor ,Humans ,Female ,Neoplasm Recurrence, Local ,Vitamin A ,Carcinoma, Renal Cell ,Aged - Abstract
A distinct renal tumor has recently been described as "high-grade oncocytic renal tumor" and "sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm". The Genitourinary Pathology Society (GUPS) consensus proposed a unifying name "eosinophilic vacuolated tumor" (EVT) for this emerging entity. In this multi-institutional study, we evaluated 19 EVTs, particularly their molecular features and mutation profile, using next-generation sequencing. All cases were sporadic and none of the patients had a tuberous sclerosis complex. There were 8 men and 11 women, with a mean age of 47 years (median 50; range 15-72 years). Average tumor size was 4.3 cm (median 3.8 cm; range 1.5-11.5 cm). All patients with available follow-up data (18/19) were alive and without evidence of disease recurrence or progression during the follow-up, ranging from 12 to 198 months (mean 56.3, median 41.5 months). The tumors were well circumscribed, but lacked a well-formed capsule, had nested to solid growth, focal tubular architecture, and showed ubiquitous, large intracytoplasmic vacuoles, round to oval nuclei, and prominent nucleoli. Immunohistochemically, cathepsin K, CD117, CD10, and antimitochondrial antigen were expressed in all cases. Other positive stains included: PAX8, AE1/AE3 and CK18. CK7 was typically restricted only to rare scattered cells. Vimentin, HMB45, melan-A, and TFE3 were negative in all cases. All tumors showed retained SDHB. All cases (19/19) showed non-overlapping mutations of the mTOR pathway genes: TSC1 (4), TSC2 (7), and MTOR (8); one case with MTOR mutation showed a coexistent RICTOR missense mutation. Low mutational rates were found in all samples (ranged from 0 to 6 mutations/Mbp). Microsatellite instability and copy number variations were not found in any of the 17 analyzable cases. EVT represents an emerging renal entity that shows a characteristic and readily identifiable morphology, consistent immunohistochemical profile, indolent behavior, and mutations in either TSC1, TSC2, or MTOR genes.
- Published
- 2022
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