Browsing by Author "Thomas, Alexandra"

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    Bulk and Single-Cell Profiling of Breast Tumors Identifies TREM-1 as a Dominant Immune Suppressive Marker Associated With Poor Outcomes
    (Frontiers Media, 2021-12-08) Pullikuth, Ashok K.; Routh, Eric D.; Zimmerman, Kip D.; Chifman, Julia; Chou, Jeff W.; Soike, Michael H.; Jin, Guangxu; Su, Jing; Song, Qianqian; Black, Michael A.; Print, Cristin; Bedognetti, Davide; Howard-McNatt, Marissa; O’Neill, Stacey S.; Thomas, Alexandra; Langefeld, Carl D.; Sigalov, Alexander B.; Lu, Yong; Miller, Lance D.; Biostatistics and Health Data Science, School of Medicine
    Background: Triggering receptor expressed on myeloid cells (TREM)-1 is a key mediator of innate immunity previously associated with the severity of inflammatory disorders, and more recently, the inferior survival of lung and liver cancer patients. Here, we investigated the prognostic impact and immunological correlates of TREM1 expression in breast tumors. Methods: Breast tumor microarray and RNAseq expression profiles (n=4,364 tumors) were analyzed for associations between gene expression, tumor immune subtypes, distant metastasis-free survival (DMFS) and clinical response to neoadjuvant chemotherapy (NAC). Single-cell (sc)RNAseq was performed using the 10X Genomics platform. Statistical associations were assessed by logistic regression, Cox regression, Kaplan-Meier analysis, Spearman correlation, Student's t-test and Chi-square test. Results: In pre-treatment biopsies, TREM1 and known TREM-1 inducible cytokines (IL1B, IL8) were discovered by a statistical ranking procedure as top genes for which high expression was associated with reduced response to NAC, but only in the context of immunologically "hot" tumors otherwise associated with a high NAC response rate. In surgical specimens, TREM1 expression varied among tumor molecular subtypes, with highest expression in the more aggressive subtypes (Basal-like, HER2-E). High TREM1 significantly and reproducibly associated with inferior distant metastasis-free survival (DMFS), independent of conventional prognostic markers. Notably, the association between high TREM1 and inferior DMFS was most prominent in the subset of immunogenic tumors that exhibited the immunologically hot phenotype and otherwise associated with superior DMFS. Further observations from bulk and single-cell RNAseq analyses indicated that TREM1 expression was significantly enriched in polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and M2-like macrophages, and correlated with downstream transcriptional targets of TREM-1 (IL8, IL-1B, IL6, MCP-1, SPP1, IL1RN, INHBA) which have been previously associated with pro-tumorigenic and immunosuppressive functions. Conclusions: Together, these findings indicate that increased TREM1 expression is prognostic of inferior breast cancer outcomes and may contribute to myeloid-mediated breast cancer progression and immune suppression.
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    E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group
    (American Society of Clinical Oncology, 2021) Connolly, Roisin M.; Zhao, Fengmin; Miller, Kathy D.; Lee, Min-Jung; Piekarz, Richard L.; Smith, Karen L.; Brown-Glaberman, Ursa A.; Winn, Jennifer S.; Faller, Bryan A.; Onitilo, Adedayo A.; Burkard, Mark E.; Budd, George T.; Levine, Ellis G.; Royce, Melanie E.; Kaufman, Peter A.; Thomas, Alexandra; Trepel, Jane B.; Wolff, Antonio C.; Sparano, Joseph A.; Medicine, School of Medicine
    Purpose: Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Patients and methods: E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15. Results: Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; P = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; P = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. Conclusion: The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.