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Background The PAM50-based (Prosigna) risk of recurrence (ROR) score and intrinsic subtypes are prognostic for women with high-risk breast cancer. We investigate the predictive ability of Prosigna regarding the effectiveness of cyclophosphamide-based adjuvant chemotherapy in premenopausal patients with high-risk breast cancer. Methods Prosigna assays were performed on the NanoString platform in tumors from participants in Danish Breast Cancer Group (DBCG) 77B, a four-arm trial that randomized premenopausal women with high-risk early breast cancer to no systemic treatment, levamisole, oral cyclophosphamide (C) or cyclophosphamide, methotrexate and fluorouracil (CMF). Results In total, this retrospective analysis included 460 women (40% of the 1146 randomized patients). The continuous Prosigna ROR score was prognostic in the no systemic treatment group (unadjusted P  < 0.001 for disease-free survival (DFS), P  = 0.001 for overall survival (OS)). No statistically significant interaction of continuous ROR score and treatment on DFS and OS was found. A highly significant association was observed between intrinsic subtypes and C/CMF treatment for DFS ( P interaction  = 0.003 unadjusted, P  = 0.001 adjusted) and OS ( P interaction  = 0.04). In the adjusted analysis treatment with C/CMF was associated with a reduced risk of DFS events in patients with basal-like (hazard ratio (HR) 0.14; 95% CI 0.06; 0.32) and luminal B (HR 0.48; 95% CI 0.27; 0.84) subtypes but not in patients with Human epidermal growth factor receptor-enriched (HR 1.05; 95% CI 0.56; 1.95) or luminal A (HR 0.61; 95% CI 0.32; 1.16) subtypes. Conclusion The Prosigna ROR score and intrinsic subtypes were prognostic in high-risk premenopausal patients with breast cancer, and intrinsic subtypes identify high-risk patients with or without major benefit from adjuvant C/CMF treatment.

Gene fusions have long been known to drive cancer. Initial discovery of gene fusions was opportunistic, and functional assessment was done individually and experimentally. There is no comprehensive systems biology approach to understanding the impact of gene fusions on the signaling networks within tumor cells. An integrative computational approach was taken to achieve a better understanding of gene fusions and their complex influence on pathways and interaction networks in the context of lung cancer. Using well-studied fusions and publicly available gene expression data, the effect of fusion events on the expression pattern of gene networks revealed unique differences in tumors with gene fusions, tumors without gene fusions, and normal samples. This approach identifies gene expression signatures associated with specific fusions, and provides a model for integrating experimental and pathway data to better understand the biology of a fusion genes and their roles in oncogenesis.

Purpose: Somatic TP53 (p53) mutations and 17p deletions with genomic loss of p53 occur in 37-46% of acute myeloid leukemia (AML) cases with adverse risk cytogenetics and are associated with primary induction failure (PIF), high risk of relapse and dismal prognosis. Herein, we aimed to characterize the immune landscape of p53 mutated AML and to determine whether p53 abnormalities identify a patient subgroup that may benefit from T-cell targeting immunotherapy approaches. Experimental Design: The NanoString Pan-Cancer IO 360 assay was used for the immune transcriptomic analysis of 64 diagnostic bone marrow (BM) samples from adults with p53 mutated AML (n=42) or p53 wild type AML (n=22), and 35 BM samples from heavily pretreated patients with relapsed/refractory (R/R) AML (10 cases with p53 mutations and/or 17p deletion with genomic loss of p53) who received immunotherapy with flotetuzumab, an investigational CD123xCD3 bispecific DART molecule (NCT02152956). In silico data series included The Cancer Genome Atlas (TCGA) cohort (147 adults with non-promyelocytic AML; 13 with p53 mutations) and the HOVON cohort (618 adults with non-promyelocytic AML; 14 with p53 mutations). Results: All TCGA cases with p53 mutations showed high levels of immune infiltration, negative immune checkpoints, inflammatory chemokines, interferon (IFN)-γ-inducible molecules and a higher tumor inflammation signature (TIS) score relative to TCGA cases with other risk-defining molecular lesions. The comparison between p53 mutated and p53 wild type primary BM samples showed higher expression of IFN-γ, FoxP3, negative immune checkpoints and molecules associated with features of exhaustion and senescence in the former cohort and allowed the computation of a 34-gene immune classifier prognostic for overall survival. In vitro modeling experiments with AML cell lines showed an increased expression of IFN-γ and inflammation pathway genes in KG-1 cells with a loss-of-function mutation of p53 compared with Kasumi-1 cells with a gain-of-function mutation of p53. Finally, 5 out of 10 (50%) patients with R/R AML and p53 mutations and/or 17p deletion with genomic loss of p53 showed evidence of anti-leukemic activity of flotetuzumab immunotherapy and had higher TIS, Treg, CD8, inflammatory chemokine and PD1 scores at baseline compared with non-responders. Conclusions: This study provides evidence for a correlation between IFN-γ-dominant immune subtypes and p53 abnormalities. The favorable overall response rate to flotetuzumab encourages the implementation of this immunotherapeutic approach in this patient subgroup.

This study dissected the complexity of the immune architecture of acute myeloid leukemia (AML) at high resolution and assessed its influence on therapeutic response. Using 387 primary bone marrow samples from three discovery cohorts of children and adults with AML, we defined immune-infiltrated and immune-depleted disease subtypes and unraveled critical differences in immune gene expression across age groups and disease stages. Importantly, interferon (IFN)-γ-related mRNA profiles were predictive for both chemotherapy resistance and response of primary refractory/relapsed AML to flotetuzumab immunotherapy. Our compendium of microenvironmental gene and protein profiles sheds novel insights into the immuno-biology of AML and will inform the delivery of personalized immunotherapies to IFN-γ-dominant AML subtypes.