Abstract 2837: A surrogate gene expression signature of tumor infiltrating lymphocytes (TILs) predicts degree of benefit from trastuzumab added to standard adjuvant chemotherapy in NSABP (NRG) trial B-31 for HER2+ breast cancer

2015 ◽  
Author(s):  
Seong-Rim Kim ◽  
Patrick G. Gavin ◽  
Katherine L. Pogue-Geile ◽  
Nan Song ◽  
Melanie Finnigan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Adjuvant Chemotherapy ◽  
Gene Expression Signature ◽  
Tumor Infiltrating Lymphocytes ◽  
Expression Signature ◽  
Her2 Breast Cancer ◽  
Infiltrating Lymphocytes ◽  
B 31

scholarly journals PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1566 ◽  
Author(s):  
William P. D. Hendricks ◽  
Natalia Briones ◽  
Rebecca F. Halperin ◽  
Salvatore Facista ◽  
Paul R. Heaton ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Patients ◽  
Gene Expression Signature ◽  
Predictive Biomarkers ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Expression Signature ◽  
Her2 Breast Cancer ◽  
Group 2

The therapeutic HER2-targeting antibody trastuzumab has been shown to elicit tumor immune response in a subset of HER2-positive (HER2+) breast cancer. We performed genomic and immunohistochemical profiling of tumors from eight patients who have completed multiple rounds of neoadjuvant trastuzumabb to identify predictive biomarkers for trastuzumab-elicited tumor immune responses. Immunohistochemistry showed that all tumors had an activated tumor immune microenvironment positive for nuclear NF-κB/p65RelA, CD4, and CD8 T cell markers, but only four out of eight tumors were positive for the PD-1 immune checkpoint molecule, which is indicative of an exhausted immune environment. Exome sequencing showed no specific driver mutations correlating with PD-1 positivity. Hierarchical clustering of the RNA sequencing data revealed two distinct groups, of which Group 2 represented the PD-1 positive tumors. A gene expression signature that was derived from this clustering composed of 89 genes stratified HER2+ breast cancer patients in the TCGA dataset and it was named PD-1-Associated Gene Expression Signature in HER2+ Breast Cancer (PAGES-HBC). Patients with the Group 2 PAGES-HBC composition had significantly more favorable survival outcomes with mortality reduced by 83% (hazard ratio 0.17; 95% CI, 0.05 to 0.60; p = 0.011). Analysis of three longitudinal samples from a single patient showed that PAGES-HBC might be transiently induced by trastuzumab, independent of clonal tumor expansion over time. We conclude that PAGES-HBC could be further developed as a prognostic predictor of trastuzumab response in HER2+ breast cancer patients and be potentially used as an alternative biomarker for anti-PD-1 therapy trials.

scholarly journals Topsentinol L Trisulfate, a Marine Natural Product That Targets Basal-like and Claudin-Low Breast Cancers

Marine Drugs ◽  
2021 ◽  
Vol 19 (1) ◽  
pp. 41
Author(s):  
Nader N. El-Chaar ◽  
Thomas E. Smith ◽  
Gajendra Shrestha ◽  
Stephen R. Piccolo ◽  
Mary Kay Harper ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Lines ◽  
Gene Expression Signature ◽  
Marine Natural Product ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Expression Signature ◽  
Her2 Breast Cancer ◽  
Cancer Types

Patients diagnosed with basal-like breast cancer suffer from poor prognosis and limited treatment options. There is an urgent need to identify new targets that can benefit patients with basal-like and claudin-low (BL-CL) breast cancers. We screened fractions from our Marine Invertebrate Compound Library (MICL) to identify compounds that specifically target BL-CL breast cancers. We identified a previously unreported trisulfated sterol, i.e., topsentinol L trisulfate (TLT), which exhibited increased efficacy against BL-CL breast cancers relative to luminal/HER2+ breast cancer. Biochemical investigation of the effects of TLT on BL-CL cell lines revealed its ability to inhibit activation of AMP-activated protein kinase (AMPK) and checkpoint kinase 1 (CHK1) and to promote activation of p38. The importance of targeting AMPK and CHK1 in BL-CL cell lines was validated by treating a panel of breast cancer cell lines with known small molecule inhibitors of AMPK (dorsomorphin) and CHK1 (Ly2603618) and recording the increased effectiveness against BL-CL breast cancers as compared with luminal/HER2+ breast cancer. Finally, we generated a drug response gene-expression signature and projected it against a human tumor panel of 12 different cancer types to identify other cancer types sensitive to the compound. The TLT sensitivity gene-expression signature identified breast and bladder cancer as the most sensitive to TLT, while glioblastoma multiforme was the least sensitive.

A prognostic eight‐gene expression signature for patients with breast cancer receiving adjuvant chemotherapy

2019 ◽  
Vol 121 (8-9) ◽  
pp. 3923-3934 ◽  
Author(s):  
Qiuxia Cui ◽  
Jianing Tang ◽  
Dan Zhang ◽  
Deguang Kong ◽  
Xing Liao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Adjuvant Chemotherapy ◽  
Gene Expression Signature ◽  
Expression Signature

scholarly journals Topsentinol L Trisulfate, a new Marine Natural Product, that Targets Basal-like and Claudin-low Breast Cancers

2020 ◽  
Author(s):  
Nader N. El-Chaar ◽  
Thomas E. Smith ◽  
Gajendra Shrestha ◽  
Stephen R. Piccolo ◽  
Mary Kay Harper ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Marine Invertebrate ◽  
Human Tumor ◽  
Gene Expression Signature ◽  
Marine Natural Product ◽  
Breast Cancer Cell Lines ◽  
Expression Signature ◽  
Her2 Breast Cancer ◽  
Cancer Types

ABSTRACTBackgroundBreast cancer is a heterogeneous disease. Genomic studies have revealed five different intrinsic subtypes - Luminal A, Luminal B, HER2-enriched, Claudin-low, and Basal-like. Patients diagnosed with Basal-like or Claudin-low breast cancer (BL-CL) suffer from poor prognosis and limited treatment options. Hence, there is an urgent need to identify a new therapeutic lead that can benefit patients with BL-CL breast cancer.MethodsWe used a step-wise screening approach to screen 2778 HP20 fractions from our Marine Invertebrate Compound Library (MICL) to identify compounds that specifically target BL-CL breast cancer. We also performed biochemical investigations to study the effect of the compound in the signaling pathway. Finally, we generated a drug response gene-expression signature and projected it against a human tumor panel of 12 different cancer types to identify other cancer types sensitive to the compound.ResultsWe identified a previously unreported trisulfated sterol, topsentinol L trisulfate (TLT) that exhibits increased efficacy against BL-CL relative to Luminal/HER2+ breast cancer. Biochemical investigation of the effects of TLT on BL-CL revealed its ability to inhibit activation of AMPK and CHK1 and promote activation of p38. The importance of targeting AMPK and CHK1 in BL-CL was validated by treating a panel of breast cancer cell lines with known small molecule inhibitors of AMPK (Dorsomorphin) and CHK1 (Ly2603618) and recording the increased effectiveness against BL-CL compared to Luminal/HER2+ breast cancer. The TLT sensitivity gene-expression signature identified breast and bladder cancer as the most sensitive to TLT while glioblastoma multiforme as least sensitive.ConclusionsOur study identified TLT, a previously uncharacterized trisulfated sterol, as a potential therapeutic selective against BL-CL. Our results also showed that inhibition of AMPK and/or CHK1 might be an effective therapy in BL-CL.

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