Evaluation of immunotherapy (I-O)-associated immune cell (IC) dynamics and PD-L1 expression using multispectral immunohistochemistry (mIHC) and single-cell hierarchical regression modeling in early-stage breast cancer (ESBC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12070-e12070
Author(s):  
Katherine Sanchez ◽  
Maritza Martel ◽  
Shu-Ching Chang ◽  
Yaping Wu ◽  
Zhaoyu Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Nearest Neighbor ◽  
Immune Cell ◽  
Early Stage ◽  
Hierarchical Regression ◽  
Cytokine Therapy ◽  
Gm Csf ◽  
Multiple Regions ◽  
Pre Treatment

e12070 Background: In triple negative breast cancer (TNBC), anti-PD-L1 is associated with gains in overall survival, however only in tumors with > 1% PD-L1+ ICs. Locoregional cytokine therapy is being evaluated as a method of priming and redirecting ICs to tumors, which may increase I-O benefit particularly in PD-L1 negative tumors. We report a sensitive method of quantifying I-O-related changes in PD-L1 and ICs using mIHC and single-cell hierarchical regression, which controls for within-tumor and across-patient PD-L1/IC heterogeneity. Methods: Pre-treatment and resection tissues from a phase Ib trial of locoregional cytokines (IRX-2, n = 16 subjects) in ESBC were analyzed. IRX-2 contains immunostimulatory cytokines (GM-CSF, IL-2, IFN-α, INF-γ, and IL-12) and was injected in peri-areolar tissue, which communicates directly with tumor-draining lymphatics. Specimens were analyzed for 1) H&E stromal TILs score; 2) clinical PD-L1 IC expression (Ventana SP142, 2 blinded pathologists); and 3) mIHC (PerkinElmer Vectra). InForm software was used to obtain geospatial outputs of tumor cells (CK+) and ICs (CD3, CD8, CD163) across multiple regions of interest (mean:18; range: 9-32). Mixed-effects modeling was used to evaluate for changes in PD-L1, ICs, and IC/tumor distance metrics. Results: PD-L1 and IC quantity by mIHC was highly concordant with clinical PD-L1 IC classification (JT test = 211, p < .001) and TIL score (r = 0.77). Cytokine therapy was associated with higher PD-L1 IC classification in 9/13 tumors, and increased PD-L1 ICs by mIHC in 14/15 (+337%, 95% CI: 120,769%). After adjusting for heterogeneity, cytokine therapy increased CD3+CD8+ ICs (+173%, CI: 93,287%) and CD3+CD8- ICs (+120%, CI: 21,301%). Therapy was also associated with increased effector-helper T-cell clustering (nearest-neighbor distance, -40%, CI: -29,-50%) and effector cell tumor localization (stromal-tumor interface CD8+ density +90%, Cl: 74, 305%). Conclusions: Our method is concordant with clinical PD-L1 and sTILs scores, and can additionally quantify IC and IC distances. This assay may allow for comparative I-O assessments with increased resolution, and will be used in a randomized phase II trial of pembrolizumab, chemo +/- IRX-2 in stage II/III TNBC.

EPCO-06. AGE- AND REGION-SPECIFIC MULTI-OMIC CHARACTERIZATION OF H3-K27M MUTANT DIFFUSE MIDLINE GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi2-vi2
Author(s):  
Ilon Liu ◽  
Jiang Li ◽  
Daeun Jeong ◽  
Olivia A Hack ◽  
McKenzie Shaw ◽  
...  
Keyword(s):  
Single Cell ◽  
Immune Cell ◽  
Age Groups ◽  
Mesenchymal Cell ◽  
Cell Compartments ◽  
Histone 3 ◽  
Age At Surgery ◽  
Single Nucleus ◽  
Pre Treatment ◽  
Cell Subpopulations

Abstract Diffuse midline gliomas driven by lysine27-to-methionine mutations in histone 3 (H3-K27M DMGs) are among the most fatal brain tumors. Molecular studies including single cell RNA-sequencing (scRNA-seq) of pediatric and predominantly pontine H3-K27M DMGs have shown that the H3-K27M oncohistone keeps glioma cells locked in a stem-like oligodendrocyte precursor cell (OPC) state that is capable of self-renewal and tumor-initiation. However, a comprehensive dissection of the cellular architecture of H3-K27M DMGs across different midline regions and age groups is required to better understand the cell-intrinsic and contextual regulation of H3-K27M DMG cell identities. In particular, the more recently described group of adult H3-K27M DMGs remains understudied. Here, we have collected and characterized 45 H3-K27M mutant patient tumors, spanning pontine (n=26), thalamic (n=17), and spinal (n=2) locations. Median age at surgery was 12 (2-68) years, encompassing 21 early childhood (0-10 years), 12 adolescent (11-20 years), and 12 adult (≥ 21 years) tumors. The majority of samples were obtained pre-treatment (n=28), as opposed to post-treatment or at autopsy (n=17). We profiled all 45 tumors by single cell/single nucleus RNA-seq and selected tumors were further characterized by the single cell assay for transposase-accessible chromatin (scATAC-seq). Our integrated analyses highlight the predominance of transcriptionally and epigenetically defined OPC-like tumor cells as the main cell population of H3-K27M DMGs across all age groups and locations. We further identify distinct age- and location-specific OPC-like cell subpopulations. Comparison of pediatric and adult tumors further demonstrates a significant increase of mesenchymal cell states in adult H3-K27M DMGs, which we link to differences in glioma-associated immune cell compartments between age groups. Together, this study sheds light on the effects of age- and region-dependent microenvironments in shaping cellular identities in H3-K27M DMGs.

scholarly journals Abstract 351: Alterations in immune cell signatures during breast cancer metastasis at single cell resolution

2020 ◽  
Author(s):  
Juliane Winkler ◽  
Weilun Tan ◽  
Christopher McGinnis ◽  
Zev Gartner ◽  
Spyros Darmanis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Cancer Metastasis ◽  
Immune Cell ◽  
Breast Cancer Metastasis

scholarly journals Single-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Woosung Chung ◽  
Hye Hyeon Eum ◽  
Hae-Ock Lee ◽  
Kyung-Min Lee ◽  
Han-Byoel Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Primary Breast Cancer ◽  
Immune Cell ◽  
Rna Seq

scholarly journals 0827 Prevalence And Factors Associated With Pre-treatment Insomnia Symptoms In Women With Early Stage Breast Cancer

SLEEP ◽  
2019 ◽  
Vol 42 (Supplement_1) ◽  
pp. A332-A332
Author(s):  
Kaitlyn Mahon ◽  
Sheila N Garland ◽  
Joshua Rash ◽  
Kayla Wall ◽  
Renee Lester ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Stage ◽  
Early Stage Breast Cancer ◽  
Factors Associated ◽  
Pre Treatment ◽  
Insomnia Symptoms

Novel association of pre-chemotherapy immune cell profiles with functional decline and resilience in women with breast cancer receiving chemotherapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 549-549
Author(s):  
Nikesha Gilmore ◽  
Supriya Gupta Mohile ◽  
Huiwen Xu ◽  
Kah Poh Loh ◽  
Amber Kleckner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Physical Function ◽  
Immune Cell ◽  
Functional Decline ◽  
Cell Counts ◽  
Increased Risk ◽  
Novel Association ◽  
Pre Treatment ◽  
General Physical ◽  
Relationship Of

549 Background: Chemotherapy adversely affects physical function. While many patients recover after treatment (i.e. are resilient), some are unable to return to their pre-treatment function (i.e. are non-resilient). Since immune dysfunction may play a role in functional decline, we assessed the relationship of pre-chemotherapy immune cell profiles with functional decline and resilience in women with breast cancer receiving chemotherapy. Methods: This study was based on a large nationwide cohort study in women with stage I-III breast cancer. Physical function was measured by the Functional Assessment of Cancer Therapy: General – Physical subscale (FACT-PWB) ≤7 days before chemotherapy (T1), ≤1 month after chemotherapy (T2), and 6 months after T2 (T3). Functional decline at T2 and T3 was defined as > 1 point decrease (clinically meaningful difference) in FACT-PWD score from T1. Patients were considered non-resilient if they had T2 functional decline and did not return to within 1 point of their baseline FACT-PWB score by T3. Immune cell counts, neutrophil:lymphocyte ratio (NLR), and lymphocyte:monocyte ratio (LMR) were obtained at T1. Multivariate logistic regressions were used to determine whether immune cell counts and ratios were associated with functional decline and being non-resilient controlling for baseline FACT-PWD, age, race, education, and marital status. Results: One-third of patients (178/529; mean age 53, range 22-81) had functional decline from T1-T3. Of the 59% (n = 310) of patients with functional decline at T2, 50% (n = 147) did not recover by T3 (i.e. were non-resilient). Patients with a low ( < median) NLR at T1 were twice as likely to have functional decline by T3 than those with a high (≥ median) NLR [Adjusted Odds Ratio (AOR) 1.8, 95% CI: 1.2-2.8, p < 0.01]. Similarly, in patients with functional decline at T2, those with a low NLR at T1 were twice as likely to be non-resilient than those with high NLR (AOR: 1.9, 95% CI: 1.1-3.2, p = 0.01). Conversely, patients with high T1 lymphocytes were twice as likely to be non-resilient than those with low lymphocytes (AOR: 1.8, 95% CI: 1.1-3.1, p = 0.02). Conclusions: One-third of women with breast cancer have clinically meaningful, persistent functional decline six months after completing chemotherapy. Higher pre-chemotherapy lymphocytes and lower NLR may be useful to identify which women are at increased risk of functional decline and reduced ability to regain baseline physical function. These findings can inform interventions to ameliorate this decline.

scholarly journals Pre-treatment Haemoglobin Concentration is a Prognostic Factor in Patients with Early-stage Breast Cancer

2005 ◽  
Vol 33 (3) ◽  
pp. 319-328 ◽  
Author(s):  
EG Kandemir ◽  
A Mayadagli ◽  
O Turken ◽  
M Yaylaci ◽  
A Ozturk
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Prognostic Factor ◽  
Early Stage ◽  
Haemoglobin Concentration ◽  
Disease Free Survival ◽  
Early Stage Breast Cancer ◽  
Free Survival ◽  
Pre Treatment ◽  
Disease Free

We investigated the prevalence of anaemia (haemoglobin concentration < 12 g/dl) in 336 women with early-stage breast cancer and its association with other known prognostic factors. The median follow-up period was 60.5 months (range 9-123 months). Seventy-nine women (23.5%) had a low pre-treatment haemoglobin concentration, but anaemia was not correlated with age, tumour size, nodal status, histological grade or hormone receptor status. Univariate analysis revealed that disease-free survival and overall survival were shorter in patients with anaemia at the time of diagnosis than in patients with normal haemoglobin concentrations. Anaemia remained a significant prognostic factor for disease-free survival and overall survival in the multivariate analysis (relative risk, 1.884 and 1.785, respectively). These results suggest that pre-treatment haemoglobin concentration is an independent prognostic factor in patients with early-stage breast cancer.

scholarly journals Prospective Monitoring of Circulating Epithelial Tumor Cells (CETC) Reveals Changes in Gene Expression during Adjuvant Radiotherapy of Breast Cancer Patients

2021 ◽  
Vol 28 (5) ◽  
pp. 3507-3524
Author(s):  
Matthias Mäurer ◽  
Katharina Pachmann ◽  
Thomas Wendt ◽  
Dorothea Schott ◽  
Andrea Wittig
Keyword(s):  
Breast Cancer ◽  
Single Cell ◽  
Tumor Cells ◽  
Early Stage ◽  
Breast Cancer Patients ◽  
Ki 67 ◽  
Epithelial Tumor ◽  
Before And After ◽  
Epithelial Tumor Cells ◽  
Cell Expression

Circulating epithelial tumor cells (CETC) are considered to be responsible for the formation of metastases. Therefore, their importance as prognostic and/or predictive markers in breast cancer is being intensively investigated. Here, the reliability of single cell expression analyses in isolated and collected CETC from whole blood samples of patients with early-stage breast cancer before and after radiotherapy (RT) using the maintrac® method was investigated. Single-cell expression analyses were performed with qRT-PCR on a panel of selected genes: GAPDH, EpCAM, NANOG, Bcl-2, TLR 4, COX-2, PIK3CA, Her-2/neu, Vimentin, c-Met, Ki-67. In all patients, viable CETC were detected prior to and at the end of radiotherapy. In 7 of the 9 (77.8%) subjects examined, the CETC number at the end of the radiotherapy series was higher than before. The majority of genes analyzed showed increased expression after completion of radiotherapy compared to baseline. Procedures and methods used in this pilot study proved to be feasible. The method is suitable for further investigation of the underlying molecular biological mechanisms occurring in cells surviving radiotherapy and possibly the development of radiation resistance.

scholarly journals DCIS genomic signatures define biology and correlate with clinical outcome: a Human Tumor Atlas Network (HTAN) analysis of TBCRC 038 and RAHBT cohorts

2021 ◽  
Author(s):  
Siri H Strand ◽  
Belen Rivero-Gutierrez ◽  
Kathleen E Houlahan ◽  
Jose A Seoane ◽  
Lorraine King ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Immune Cell ◽  
De Novo ◽  
Ductal Carcinoma ◽  
Early Stage ◽  
Expression Patterns ◽  
Human Tumor ◽  
Multiscale Approach

Ductal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We have performed the first multiscale, integrated profiling of DCIS with clinical outcomes by analyzing 677 DCIS samples from 481 patients with 7.1 years median follow-up from the Translational Breast Cancer Research Consortium (TBCRC) 038 study and the Resource of Archival Breast Tissue (RAHBT) cohorts. We made observations on DNA, RNA, and protein expression, and generated a de novo clustering scheme for DCIS that represents a fundamental transcriptomic organization at this early stage of breast neoplasia. Distinct stromal expression patterns and immune cell compositions were identified. We found RNA expression patterns that correlate with later events. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.

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