Search

PurposeThe recent increase in the incidence of ductal carcinoma in situ (DCIS) has sparked debate over the classification and treatment of this disease. Although DCIS is considered a precursor lesion to invasive breast cancer, some DCIS may have more or less risk than is realized. In this study, we characterized the immune microenvironment in DCIS to determine if immune infiltrates are predictive of recurrence.MethodsFifty-two cases of high-grade DCIS (HG-DCIS), enriched for large lesions and a history of recurrence, were age matched with 65 cases of non-high-grade DCIS (nHG-DCIS). Immune infiltrates were characterized by single- or dual-color staining of FFPE sections for the following antigens: CD4, CD8, CD20, FoxP3, CD68, CD115, Mac387, MRC1, HLA-DR, and PCNA. Nuance multispectral imaging software was used for image acquisition. Protocols for automated image analysis were developed using CellProfiler. Immune cell populations associated with risk of recurrence were identified using classification and regression tree analysis.ResultsHG-DCIS had significantly higher percentages of FoxP3+ cells, CD68+ and CD68+PCNA+ macrophages, HLA-DR+ cells, CD4+ T cells, CD20+ B cells, and total tumor infiltrating lymphocytes compared to nHG-DCIS. A classification tree, generated from 16 immune cell populations and 8 clinical parameters, identified three immune cell populations associated with risk of recurrence: CD8+HLADR+ T cells, CD8+HLADR- T cells, and CD115+ cells.ConclusionThese findings suggest that the tumor immune microenvironment is an important factor in identifying DCIS cases with the highest risk for recurrence and that manipulating the immune microenvironment may be an efficacious strategy to alter or prevent disease progression.

PURPOSE: A subset of estrogen receptor–positive (ER-positive) breast cancer (BC) contains high levels of tumor-infiltrating lymphocytes (TILs), similar to triple-negative BC (TNBC). The majority of immuno-oncology trials target TNBCs because of the greater proportion of TIL-rich TNBCs. The extent to which the immune microenvironments of immune-rich ER-positive BC and TNBC differ is unknown. PATIENTS AND METHODS: RNA sequencing data from The Cancer Genome Atlas (TCGA; n = 697 ER-positive BCs; n = 191 TNBCs) were used for discovery; microarray expression data from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n = 1,186 ER-positive BCs; n = 297 TNBCs) was used for validation. Patients in the top 25th percentile of a previously published total TIL metagene score distribution were considered immune rich. We compared expression of immune cell markers, immune function metagenes, and immuno-oncology therapeutic targets among immune-rich subtypes. RESULTS: Relative fractions of resting mast cells (TCGA P adj =.009; METABRIC P adj = 4.09E-15), CD8+ T cells (TCGA P adj =.015; METABRIC P adj = 0.390), and M2-like macrophages (TCGA P adj= 4.68E-05; METABRIC P adj =.435) were higher in immune-rich ER-positive BCs, but M0-like macrophages (TCGA P adj = 0.015; METABRIC P adj =.004) and M1-like macrophages (TCGA P adj = 9.39E-08; METABRIC P adj = 6.24E-11) were higher in immune-rich TNBCs. Ninety-one immune-related genes (eg, CXCL14 , CSF3R , TGF-B3 , LRRC32/GARP , TGFB-R2) and a transforming growth factor β (TGF-β) response metagene were significantly overexpressed in immune-rich ER-positive BCs, whereas 41 immune-related genes (eg, IFNG , PD-L1 , CTLA4 , MAGEA4) were overexpressed in immune-rich TNBCs in both discovery and validation data sets. TGF-β pathway member genes correlated negatively with expression of immune activation markers (IFNG , granzyme-B, perforin) and positively with M2-like macrophages (IL4 , IL10 , and MMP9) and regulatory T-cell (FOXP3) markers in both subtypes. CONCLUSION: Different immunotherapy strategies may be optimal in immune-rich ER-positive BC and TNBC. Drugs targeting the TGF-β pathway and M2-like macrophages are promising strategies in immune-rich ER-positive BCs to augment antitumor immunity. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the utilization of local anesthesia or peripheral nerve block with monitored anesthesia care (LPMAC) and its impact on the perioperative outcomes of hybrid lower extremity revascularization (LER) compared with general anesthesia (GA). Materials and Methods: A search of the ACS-NSQIP database between 2005 and 2017 identified 9430 patients who underwent hybrid LER for peripheral artery disease. Excluding 449 ineligible cases left 8981 hybrid LER patients for analysis. The patients were dichotomized based on the anesthetic technique: 8631 (96.1%) GA and 350 (3.9%) LPMAC. The GA patients were matched 3:1 based on propensity scores to patients in the LPMAC group based on gender, age, race, functional status, transfer status, chronic obstructive pulmonary disease (COPD), dialysis status, American Society of Anesthesiologists (ASA) class, emergent surgery, preoperative sepsis, indication, and type of open and endovascular procedure. Outcomes including complications, mortality, procedure time, and hospital length of stay were compared between the matched groups (801 GA vs 267 LPMAC). Results: Comparing the unmatched groups, those treated under LPMAC were older (72.7±9 vs 68±8.4 years, p<0.001) and had higher rates of COPD (24.3% vs 17%, p=0.001), dialysis dependence (8.1% vs 4.2%, p=0.002), preoperative sepsis (6.6% vs 4.2%, p=0.029), and ASA class ≥IV (29.1% vs 24.1%, p=0.036) than in the unmatched GA cohort. In the matched comparison, LPMAC was associated with lower overall morbidity (25.5% vs 32.3%, p=0.042) and shorter operating time (202.7±98 vs 217.7±102 minutes, p=0.034) compared with GA. The rate of myocardial infarction was lower (1.1% vs 2.4%) and ventilator use for >48 hours was less frequent (0.4% vs 2.6%) for LPMAC patients, though statistical significance was not reached. There was no difference in mortality or hospital length of stay. Conclusion: LPMAC is an infrequent anesthetic technique for hybrid LER and is primarily used for patients with a high burden of comorbidities. LPMAC is associated with reduced overall morbidity and operating time. Further studies are needed to identify which patients undergoing hybrid LER benefit most from LPMAC. [ABSTRACT FROM AUTHOR]

Purpose: African-American (AA) patients with triple-negative breast cancer (TNBC) are less likely to achieve pathologic complete response from neoadjuvant chemotherapy and have poorer prognosis than Caucasian patients with TNBC, suggesting potential biological differences by race. Immune infiltration is the most consistent predictive marker for chemotherapy response and improved prognosis in TNBC. In this study, we test the hypothesis that the immune microenvironment differs between AA and Caucasian patients. Methods: RNA-seq expression data were obtained from The Cancer Genome Atlas (TCGA) database for 162 AA and 697 Caucasian breast cancers. Estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-positive, and TNBC subtypes were included in the analyses. Tumor infiltrating lymphocyte (TIL) counts, immunomodulatory scores, and molecular subtypes were obtained from prior publications for a subset of the TNBC cases. Differences in immune cell distributions and immune functions, measured through gene expression and TIL counts, as well as neoantigen, somatic mutation, amplification, and deletion loads, were compared by race and tumor subtype. Results: Immune metagene analysis demonstrated marginal immune attenuation in AA TNBC relative to Caucasian TNBC that did not reach statistical significance. The distributions of immune cell populations, lymphocyte infiltration, molecular subtypes, and genomic aberrations between AA and Caucasian subtypes were also not significantly different. The MHC1 metagene demonstrated increased expression in AA ER-positive cancers relative to Caucasian ER-positive cancers. Conclusions: This study suggests that the immunological differences between AA and Caucasian breast cancers represented by TCGA data are subtle, if they exist at all. We observed no consistent racial differences in immune gene expression or TIL counts in TNBC by race. However, this study cannot rule out small differences in immune cell subtype distribution and activity status that may not be apparent in bulk RNA analysis. [ABSTRACT FROM AUTHOR]

Tumor mutational burden (TMB) is a promising tool to help define patients with triple-negative breast cancer (TNBC) most likely to benefit from immune checkpoint blockade (ICB) therapies. Roughly reflecting the degree of neo-antigens that tumors present to immune cells, TMB associates with multiple measures of tumoral immunogenicity and has proven clinically useful in cancers with relatively high mutation burden. TNBC carries higher TMB than other breast cancer subtypes, and recent data suggest that high-TMB TNBC cases may derive particular benefit from ICB in combination with chemotherapy (GeparNuevo, IMpassion130) or even ICB alone (KEYNOTE-119, TAPUR). Given the recent approval of pembrolizumab and atezolizumab in combination with chemotherapy for PD-L1-positive, metastatic TNBC, standardizing TMB calculation methods and cut-off values is of critical importance to deploy this clinical biomarker., Competing Interests: CONFLICTS OF INTEREST SMT reports institutional research funding from AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Exelixis, Bristol-Myers Squibb, Eisai, Nanostring, Cyclacel, Odonate, Seattle Genetics; and advisor/consultant role for AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Gilead, Immunomedics, Bristol-Myers Squibb, Eisai, Nanostring, Puma, Sanofi, Celldex, Paxman, Odonate, Seattle Genetics, Silverback Therapeutics, G1 Therapeutics, AbbVie, Anthenex, OncoPep, Outcomes4Me, Kyowa Kirin Pharmaceuticals, Daiichi-Sankyo, Samsung Bioepsis Inc., (Copyright: © 2021 O’Meara and Tolaney.)