Abstract A008: PDX-based screen to evaluate and compare approved CDK4/6 inhibitors in breast cancer and determine palbociclib efficacy in additional tumor types

2019 ◽  
Author(s):  
Lizette Gamez ◽  
Tomoyuki Mashimo ◽  
Alyssa Moriarty ◽  
Kyriakos Papadopoulos ◽  
Drew Rasco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Types ◽  
Additional Tumor

scholarly journals Performance of a novel protease-activated fluorescent imaging system for intraoperative detection of residual breast cancer during breast conserving surgery

2021 ◽  
Vol 187 (1) ◽  
pp. 145-153
Author(s):  
Conor R. Lanahan ◽  
Bridget N. Kelly ◽  
Michele A. Gadd ◽  
Michelle C. Specht ◽  
Carson L. Brown ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Real Time ◽  
Imaging System ◽  
Ex Vivo ◽  
Menopausal Status ◽  
Fluorescent Imaging ◽  
Cancer Subtypes ◽  
Surgical Workflow ◽  
Tumor Types

Abstract Purpose Safe breast cancer lumpectomies require microscopically clear margins. Real-time margin assessment options are limited, and 20–40% of lumpectomies have positive margins requiring re-excision. The LUM Imaging System previously showed excellent sensitivity and specificity for tumor detection during lumpectomy surgery. We explored its impact on surgical workflow and performance across patient and tumor types. Methods We performed IRB-approved, prospective, non-randomized studies in breast cancer lumpectomy procedures. The LUM Imaging System uses LUM015, a protease-activated fluorescent imaging agent that identifies residual tumor in the surgical cavity walls. Fluorescent cavity images were collected in real-time and analyzed using system software. Results Cavity and specimen images were obtained in 55 patients injected with LUM015 at 0.5 or 1.0 mg/kg and in 5 patients who did not receive LUM015. All tumor types were distinguished from normal tissue, with mean tumor:normal (T:N) signal ratios of 3.81–5.69. T:N ratios were 4.45 in non-dense and 4.00 in dense breasts (p = 0.59) and 3.52 in premenopausal and 4.59 in postmenopausal women (p = 0.19). Histopathology and tumor receptor testing were not affected by LUM015. Falsely positive readings were more likely when tumor was present < 2 mm from the adjacent specimen margin. LUM015 signal was stable in vivo at least 6.5 h post injection, and ex vivo at least 4 h post excision. Conclusions Intraoperative use of the LUM Imaging System detected all breast cancer subtypes with robust performance independent of menopausal status and breast density. There was no significant impact on histopathology or receptor evaluation.

scholarly journals Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
L. E. Anselmino ◽  
M. V. Baglioni ◽  
F. Malizia ◽  
N. Cesatti Laluce ◽  
C. Borini Etichetti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Drug Repositioning ◽  
Combined Treatment ◽  
Alternative Therapy ◽  
Breast Cancers ◽  
Mesenchymal Transition ◽  
Tumor Types

AbstractDrug repositioning refers to new uses for existing drugs outside the scope of the original medical indications. This approach fastens the process of drug development allowing finding effective drugs with reduced side effects and lower costs. Colorectal cancer (CRC) is often diagnosed at advanced stages, when the probability of chemotherapy resistance is higher. Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, highly metastatic and difficult to treat. For both tumor types, available treatments are generally associated to severe side effects. In our work, we explored the effect of combining metformin and propranolol, two repositioned drugs, in both tumor types. We demonstrate that treatment affects viability, epithelial-mesenchymal transition and migratory potential of CRC cells as we described before for TNBC. We show that combined treatment affects different steps leading to metastasis in TNBC. Moreover, combined treatment is also effective preventing the development of 5-FU resistant CRC. Our data suggest that combination of metformin and propranolol could be useful as a putative adjuvant treatment for both TNBC and CRC and an alternative for chemo-resistant CRC, providing a low-cost alternative therapy without associated toxicity.

scholarly journals Evaluation of Platelet Indices and Complete Blood Count in Canine Mammary Tumors

2021 ◽  
Vol 49 ◽  
Author(s):  
Zeynep Günay Uçmak ◽  
Lora Koenhemsi ◽  
Melih Uçmak ◽  
Mehmet Erman Or ◽  
Özge Erdoğan Bamaç ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammary Tumor ◽  
Blood Count ◽  
Complete Blood Count ◽  
Mammary Tumors ◽  
Mean Corpuscular Hemoglobin ◽  
Corpuscular Hemoglobin ◽  
Platelet Indices ◽  
Grade 3 ◽  
Tumor Types

Background: Malignant mammary tumors in humans and bitches cause hematological disorders such as anemia, erythrocytosis, thrombocytosis, hyperproteinemia, and leucopenia. Novel studies have been conducted on the predictive and prognostic values of platelet (PLT) indices in human breast cancer (HBC). However, there is little information about the alterations in hematological parameters in canine mammary tumors (CMTs). The aims of this study were to evaluate the platelet indices and complete blood count (CBC) parameters in bitches with and without mammary tumor and to assess the above mentioned parameters with regard to histological tumor types and grades.Materials, Methods & Results: A total of 71 bitches were enrolled in this study. The bitches in the study group were divided into 2 groups which consisted of malignant epithelial mammary tumors (group EMT; n = 43) and malignant mixed mammary tumors (group MMT; n = 12). Control group (group C) consisted of clinically and gynaecologically healthy 16 bitches. Blood samples were obtained to perform the CBC and PLT indices analysis. Histopathological examinations were carried out under a light microscope. Histological tumor types and malignancy grades were classified. The bitches with mammary tumor showed significantly increased PLT values and decreased hematocrit (HCT), hemoglobin (HGB) and mean corpuscular hemoglobin (MCH) values versus the healthy ones, regardless of the tumor type. However, in comparisons with the group C, mean platelet volume (MPV) and mean corpuscular hemoglobin concentration (MCHC) values were different only in the group MMT, while plateletcrit (PCT) and mean corpuscular volume (MCV) values were different only in the group EMT. Also white blood cell (WBC), PLT and PCT values were higher than the referenced laboratory ranges in grade 3 tumors. In the presented study, MPV was considerably correlated with PLT, platelet distribution width (PDW) and PCT. Also, PCT and PLT had high sensitivity and specificity to distinct EMT and MMT from the healthy bitches.Discussion: Microcytic and hypochromic anemia occurs due to the decrease in the amount of HGB. Levels of MCV, MCH, and MCHC in the HBC group were reported to be significantly lower than in humans without breast cancer. Although anemia did not occur in EMT and MMT groups, obtained significances in the HCT, HGB, MCV, MCH, and MCHC levels between the bitches with and without mammary tumor were in line with the previous reports. In this study, WBC levels in grade 3 tumors were significantly higher than grade1 tumors (P < 0.05). Whereas levels of WBC in grade 1 and grade 2 tumors were in referenced laboratory ranges, it was higher in grade 3. Increased level of WBC in grade 3 was supposed to be due to the rise in malignancy as previously reported. Thrombocytosis was detected in 48.83% and 41.66% of the bitches in EMT and MMT groups, respectively. The higher percentage of CMTs with thrombocytosis in this study might be due to the difference in referenced upper limit of PLT in previous studies. The elapsed time between tumor formation and clinical presentation could be another influencing factor. Although PLT and PCT values were not significant according to the histological grading in this study, both parameters were found to be higher in grade 3 than the normal reference values. Further studies conducted with higher populations may lead the differences in these parameters to significance. With the support of further studies, alterations in the above mentioned parameters in bitches may contribute in the diagnosis process, management of treatment and may constitute an easy way to have an idea about the prognosis of mammary tumors.

Incorporating HER2/HER3 targeted therapies across solid tumors: Assessing the impact of digital education on clinician practice patterns.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11036-11036
Author(s):  
Tariqa Ackbarali ◽  
Wendy Turell ◽  
Elizabeth L. del Nido ◽  
Adam Brufsky ◽  
Stephen V. Liu
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Clinical Practice ◽  
Patient Experience ◽  
Targeted Therapies ◽  
Her2 Breast Cancer ◽  
Treatment Plans ◽  
Tumor Types ◽  
Behavioral Impact

11036 Background: Improved understanding of the interactions between HER2 and HER3, the heterogeneity of HER-expressing disease, and mechanisms of resistance to anti-HER2 therapy has led to increasing number of treatment options to address clinical needs. Tumor types of interest, impacted by HER2/HER3 expression and pathophysiology were breast cancer, non-small cell lung cancer (NSCLC), gastric cancer, and colorectal cancer (CRC). Increasing competency in these areas is deemed critical to clinician’s ability to individualize treatment plans and improve patient outcomes. Methods: A 2-hour CME activity was broadcast live-online in September 2020 and remains on-demand through September 2021 at OMedLive.com. The educational initiative was divided into one hour addressing HER2 and HER3, testing guidelines, resistance mechanisms and emerging data elucidating recent and ongoing clinical trials across NSCLC, gastric cancer, and CRC. The second hour focused on individualizing metastatic HER2+ breast cancer, HER2-low breast cancer as an emerging subtype, and management of side effects. Knowledge and competence questions were administered pre-, immediate post-, and 2 mos. post-activity. Behavioral impact questions were also asked at follow-up. Data from these questions were analyzed to determine engagement and clinical impact. Results: To date, 448 clinicians participated in the activity. Across the seven CME test questions, improvements in knowledge and competence were observed in the clinical applications of HER2-directed agents and HER3 antibody drug conjugates (ADCs), first-line standard of care for HER2+ breast cancer, and adverse event management for HER2 ADCs. At 2-mos. follow-up, 67% reported improved behavioral impact on both clinical practice and patient experience and outcomes. Clinicians provided specific write-in examples of these changes, noting improved patient-reported outcomes, improved treatment adherence, improved competence developing treatment plans, and increased understanding of HER2/HER3 pathophysiology. Updated and expanded results will be shared. Conclusions: The activity was successful in improving clinician understanding of the relationship between HER2/HER3, pathophysiology across tumor types, and applications of emerging targeted therapies. Open-ended responses to behavioral impact questions illustrated clear improvements in clinician-reported patient experience and outcomes, clinical practice management, and knowledge of emerging HER2/HER3 therapies and their uses across multiple solid tumors.

scholarly journals Breaking the scale: how disrupting the karyoplasmic ratio gives cancer cells an advantage for metastatic invasion

2017 ◽  
Vol 45 (6) ◽  
pp. 1333-1344
Author(s):  
Andrea Rizzotto ◽  
Eric C. Schirmer
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Cancer Cells ◽  
Nuclear Size ◽  
Nuclear Morphology ◽  
Metastatic Tumors ◽  
Size Regulation ◽  
Diagnosis And Prognosis ◽  
Ploidy Changes ◽  
Tumor Types

Nuclear size normally scales with the size of the cell, but in cancer this ‘karyoplasmic ratio’ is disrupted. This is particularly so in more metastatic tumors where changes in the karyoplasmic ratio are used in both diagnosis and prognosis for several tumor types. However, the direction of nuclear size changes differs for particular tumor types: for example in breast cancer, larger nuclear size correlates with increased metastasis, while for lung cancer smaller nuclear size correlates with increased metastasis. Thus, there must be tissue-specific drivers of the nuclear size changes, but proteins thus far linked to nuclear size regulation are widely expressed. Notably, for these tumor types, ploidy changes have been excluded as the basis for nuclear size changes, and so, the increased metastasis is more likely to have a basis in the nuclear morphology change itself. We review what is known about nuclear size regulation and postulate how such nuclear size changes can increase metastasis and why the directionality can differ for particular tumor types.

scholarly journals Tumor Cell Associated Hyaluronan-CD44 Signaling Promotes Pro-Tumor Inflammation in Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1325 ◽  
Author(s):  
Patrice M. Witschen ◽  
Thomas S. Chaffee ◽  
Nicholas J. Brady ◽  
Danielle N. Huggins ◽  
Todd P. Knutson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Chronic Wound ◽  
Gene Signature ◽  
Tumor Formation ◽  
Human Breast ◽  
Inflammatory Microenvironment ◽  
Tumor Types

Cancer has been conceptualized as a chronic wound with a predominance of tumor promoting inflammation. Given the accumulating evidence that the microenvironment supports tumor growth, we investigated hyaluronan (HA)-CD44 interactions within breast cancer cells, to determine whether this axis directly impacts the formation of an inflammatory microenvironment. Our results demonstrate that breast cancer cells synthesize and fragment HA and express CD44 on the cell surface. Using RNA sequencing approaches, we found that loss of CD44 in breast cancer cells altered the expression of cytokine-related genes. Specifically, we found that production of the chemokine CCL2 by breast cancer cells was significantly decreased after depletion of either CD44 or HA. In vivo, we found that CD44 deletion in breast cancer cells resulted in a delay in tumor formation and localized progression. This finding was accompanied by a decrease in infiltrating CD206+ macrophages, which are typically associated with tumor promoting functions. Importantly, our laboratory results were supported by human breast cancer patient data, where increased HAS2 expression was significantly associated with a tumor promoting inflammatory gene signature. Because high levels of HA deposition within many tumor types yields a poorer prognosis, our results emphasize that HA-CD44 interactions potentially have broad implications across multiple cancers.

scholarly journals Single-Cell Transcriptomic Analysis of Tumor-Derived Fibroblasts and Normal Tissue-Resident Fibroblasts Reveals Fibroblast Heterogeneity in Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1307 ◽  
Author(s):  
Aimy Sebastian ◽  
Nicholas R. Hum ◽  
Kelly A. Martin ◽  
Sean F. Gilmore ◽  
Ivana Peran ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Mhc Class Ii ◽  
Smooth Muscle Actin ◽  
Class Ii ◽  
Normal Breast ◽  
Syngeneic Mouse Model ◽  
Elevated Expression ◽  
Tumor Types ◽  
Antigen Presenting

Cancer-associated fibroblasts (CAFs) are a prominent stromal cell type in solid tumors and molecules secreted by CAFs play an important role in tumor progression and metastasis. CAFs coexist as heterogeneous populations with potentially different biological functions. Although CAFs are a major component of the breast cancer stroma, molecular and phenotypic heterogeneity of CAFs in breast cancer is poorly understood. In this study, we investigated CAF heterogeneity in triple-negative breast cancer (TNBC) using a syngeneic mouse model, BALB/c-derived 4T1 mammary tumors. Using single-cell RNA sequencing (scRNA-seq), we identified six CAF subpopulations in 4T1 tumors including: 1) myofibroblastic CAFs, enriched for α-smooth muscle actin and several other contractile proteins; 2) ‘inflammatory’ CAFs with elevated expression of inflammatory cytokines; and 3) a CAF subpopulation expressing major histocompatibility complex (MHC) class II proteins that are generally expressed in antigen-presenting cells. Comparison of 4T1-derived CAFs to CAFs from pancreatic cancer revealed that these three CAF subpopulations exist in both tumor types. Interestingly, cells with inflammatory and MHC class II-expressing CAF profiles were also detected in normal breast/pancreas tissue, suggesting that these phenotypes are not tumor microenvironment-induced. This work enhances our understanding of CAF heterogeneity, and specifically targeting these CAF subpopulations could be an effective therapeutic approach for treating highly aggressive TNBCs.

scholarly journals On-target restoration of a split T cell-engaging antibody for precision immunotherapy

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Agnes Banaszek ◽  
Thomas G. P. Bumm ◽  
Boris Nowotny ◽  
Maria Geis ◽  
Kim Jacob ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Single Chain Variable Fragment ◽  
Single Chain ◽  
Preclinical Models ◽  
Variable Heavy ◽  
Suitable Target ◽  
Single Positive ◽  
Variable Light ◽  
Tumor Types

AbstractT cell-engaging immunotherapies are changing the landscape of current cancer care. However, suitable target antigens are scarce, restricting these strategies to very few tumor types. Here, we report on a T cell-engaging antibody derivative that comes in two complementary halves and addresses antigen combinations instead of single molecules. Each half, now coined hemibody, contains an antigen-specific single-chain variable fragment (scFv) fused to either the variable light (VL) or variable heavy (VH) chain domain of an anti-CD3 antibody. When the two hemibodies simultaneously bind their respective antigens on a single cell, they align and reconstitute the original CD3-binding site to engage T cells. Employing preclinical models for aggressive leukemia and breast cancer, we show that by the combinatorial nature of this approach, T lymphocytes exclusively eliminate dual antigen-positive cells while sparing single positive bystanders. This allows for precision targeting of cancers not amenable to current immunotherapies.

Immune Checkpoint Inhibition for Triple-negative Breast Cancer

2016 ◽  
Vol 12 (01) ◽  
pp. 31 ◽  
Author(s):  
Poornima Saha ◽  
Rita Nanda ◽  
◽  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Multiple Tumor ◽  
Clinical Challenge ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Tumor Types

Triple-negative breast cancer remains an important clinical challenge with no targeted therapy available for treatment. Recently, drugs targeting the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) axis have been investigated, with promising responses across multiple tumor types. Two drugs—pembrolizumab and atezolizumab—have recently been explored in advanced triple-negative breast cancer and have demonstrated promising responses.

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