scholarly journals Tumour-Infiltrating Immune Cell-Based Subtyping and Signature Gene Analysis in Breast Cancer Based on Gene Expression Profiles

2020 ◽  
Vol 11 (6) ◽  
pp. 1568-1583 ◽  
Author(s):  
Jingxin Jiang ◽  
Weiwei Pan ◽  
Yazhang Xu ◽  
Chao Ni ◽  
Dan Xue ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Immune Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Gene Analysis

scholarly journals 909 Differentiation subgroups within LKB1-deficient lung cancer influence both the immune exclusion phenotype and cellular composition of the immune microenvironment

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A954-A955
Author(s):  
Jacob Kaufman ◽  
Doug Cress ◽  
Theresa Boyle ◽  
David Carbone ◽  
Neal Ready ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Plasma Cells ◽  
Immune Cell ◽  
Expression Profiles ◽  
Neuroendocrine Differentiation ◽  
Gene Expression Profiles ◽  
Immune Microenvironment ◽  
Immune Exclusion

BackgroundLKB1 (STK11) is a commonly disrupted tumor suppressor in NSCLC. Its loss promotes an immune exclusion phenotype with evidence of low expression of interferon stimulated genes (ISG) and decreased microenvironment immune infiltration.1 2 Clinically, LKB1 loss induces primary immunotherapy resistance.3 LKB1 is a master regulator of a complex downstream kinase network and has pleiotropic effects on cell biology. Understanding the heterogeneous phenotypes associated with LKB1 loss and their influence on tumor-immune biology will help define and overcome mechanisms of immunotherapy resistance within this subset of lung cancer.MethodsWe applied multi-omic analyses across multiple lung adenocarcinoma datasets2 4–6 (>1000 tumors) to define transcriptional and genetic features enriched in LKB1-deficient lung cancer. Top scoring phenotypes exhibited heterogeneity across LKB1-loss tumors, and were further interrogated to determine association with increased or decreased markers of immune activity. Further, immune cell-types were estimated by Cibersort to identify effects of LKB1 loss on the immune microenvironment. Key conclusions were confirmed by blinded pathology review.ResultsWe show that LKB1 loss significantly affects differentiation patterns, with enrichment of ASCL1-expressing tumors with putative neuroendocrine differentiation. LKB1-deficient neuroendocrine tumors had lower expression of Interferon Stimulated Genes (ISG), MHC1 and MHC2 components, and immune infiltration compared to LKB1-WT and non-neuroendocrine LKB1-deficient tumors (figure 1).The abundances of 22 immune cell types assessed by Cibersort were compared between LKB1-deficient and LKB1-WT tumors. We observe skewing of immune microenvironmental composition by LKB1 loss, with lower abundance of dendritic cells, monocytes, and macrophages, and increased levels of neutrophils and plasma cells (table 1). These trends were most pronounced among tumors with neuroendocrine differentiation, and were concordant across three independent datasets. In a confirmatory subset of 20 tumors, plasma cell abundance was assessed by a blinded pathologist. Pathologist assessment was 100% concordant with Cibersort prediction, and association with LKB1 loss was confirmed (P=0.001).Abstract 909 Figure 1Immune-associated Gene Expression Profiles Affected by Neuroendocrine Differentiation within LKB1-Deficient Lung Adenocarcinomas. Gene expression profiles corresponding to five immune-associated phenotypes are shown with bars indicating average GEP scores for tumors grouped according to LKB1 and neuroendocrine status as indicated. P-values represent results from Student’s T-test between groups as indicated.Abstract 909 Table 1LKB1 Loss Affects Composition of Immune Microenvironment. Values indicate log10 P-values comparing LKB1-loss to LKB1-WT tumors. Positive (red) indicates increased abundance in LKB1 loss. Negative (blue) indicates decreased abundance.ConclusionsWe conclude that tumor differentiation patterns strongly influence the immune microenvironment and immune exclusion characteristics of LKB1-deficient tumors. Neuroendocrine differentiation is associated with the strongest immune exclusion characteristics and should be evaluated clinically for evidence of immunotherapy resistance. A novel observation of increased plasma cell abundance is observed across multiple datasets and confirmed by pathology. Causal mechanisms linking differentiation status to immune activity is not well understood, and the functional role of plasma cells in the immune biology of LKB1-deficient tumors is undefined. These questions warrant further study to inform precision immuno-oncology treatments for these patients.AcknowledgementsThis work was funded by SITC AZ Immunotherapy in Lung Cancer grant (SPS256666) and DOD Lung Cancer Research Program Concept Award (LC180633).ReferencesSkoulidis F, Byers LA, Diao L, et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov 2015;5:860–77.Schabath MB, Welsh EA, Fulp WJ, et al. Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma. Oncogene 2016;35:3209–16.Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discovery 2018;8:822-835.Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543–50.Chitale D, Gong Y, Taylor BS, et al. An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors. Oncogene 2009;28:2773–83.Shedden K, Taylor JM, Enkemann SA, et al. Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med 2008;14:822–7.

Gene expression profiles in premenopausal women with HR+ HER2− early breast cancer

2020 ◽  
Vol 138 ◽  
pp. S76
Author(s):  
H. Ni ◽  
A. Kurt ◽  
J. Kumbrink ◽  
A. Seiler ◽  
D. Mayr ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Early Breast Cancer ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Premenopausal Women

scholarly journals Impact of 70-Gene Signature Use on Adjuvant Chemotherapy Decisions in Patients With Estrogen Receptor–Positive Early Breast Cancer: Results of a Prospective Cohort Study

2017 ◽  
Vol 35 (24) ◽  
pp. 2814-2819 ◽  
Author(s):  
Anne Kuijer ◽  
Marieke Straver ◽  
Bianca den Dekker ◽  
Annelotte C.M. van Bommel ◽  
Sjoerd G. Elias ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Early Stage ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Gene Signature ◽  
Early Stage Breast Cancer ◽  
Er Positive ◽  
Test Result

Purpose Gene-expression profiles increasingly are used in addition to conventional prognostic factors to guide adjuvant chemotherapy (CT) decisions. The Dutch guideline suggests use of validated gene-expression profiles in patients with estrogen receptor (ER) –positive, early-stage breast cancer without overt lymph node metastases. We aimed to assess the impact of a 70-gene signature (70-GS) test on CT decisions in patients with ER-positive, early-stage breast cancer. Patients and Methods In a prospective, observational, multicenter study in patients younger than 70 years old who had undergone surgery for ER-positive, early-stage breast cancer, physicians were asked whether they intended to administer adjuvant CT before deployment of the 70-GS test and after the test result was available. Results Between October 1, 2013, and December 31, 2015, 660 patients, treated in 33 hospitals, were enrolled. Fifty-one percent of patients had pT1cN0, BRII, HER2-Neu-negative breast cancer. On the basis of conventional clinicopathological characteristics, physicians recommended CT in 270 (41%) of the 660 patients and recommended withholding CT in 107 (16%) of the 660 patients. For the remaining 43% of patients, the physicians were unsure and unable to give advice before 70-GS testing. In patients for whom CT was initially recommended or not recommended, 56% and 59%, respectively, were assigned to a low-risk profile by the 70-GS (κ, 0.02; 95% CI, -0.08 to 0.11). After disclosure of the 70-GS test result, the preliminary advice was changed in 51% of patients who received a recommendation before testing; the definitive CT recommendation of the physician was in line with the 70-GS result in 96% of patients. Conclusion In this prospective, multicenter study in a selection of patients with ER-positive, early-stage breast cancer, 70-GS use changed the physician-intended recommendation to administer CT in half of the patients.

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