Next Article in Journal
Molecular Insights into Potential Contributions of Natural Polyphenols to Lung Cancer Treatment
Next Article in Special Issue
Hyperprogressive Disease during Anti-PD-1 (PDCD1) / PD-L1 (CD274) Therapy: A Systematic Review and Meta-Analysis
Previous Article in Journal
Genetic and Lineage Classification of Glioma-Initiating Cells Identifies a Clinically Relevant Glioblastoma Model
Previous Article in Special Issue
FAK-Copy-Gain Is a Predictive Marker for Sensitivity to FAK Inhibition in Breast Cancer
 
 
Article

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

1
Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA
2
Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA
3
Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA
4
Department of Medicine, University of Arizona College of Medicien-Tucson, University of Arizona Cancer Center, Tucson, AZ 85719, USA
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(10), 1566; https://doi.org/10.3390/cancers11101566
Received: 11 September 2019 / Revised: 8 October 2019 / Accepted: 9 October 2019 / Published: 15 October 2019
(This article belongs to the Special Issue Cancer Biomarkers)
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. View Full-Text
Keywords: breast cancer; HER2; trastuzumab; gene signature; PD-1; survival outcome; tumor evolution breast cancer; HER2; trastuzumab; gene signature; PD-1; survival outcome; tumor evolution
Show Figures

Figure 1

MDPI and ACS Style

Hendricks, W.P.D.; Briones, N.; Halperin, R.F.; Facista, S.; Heaton, P.R.; Mahadevan, D.; Kim, S. PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer. Cancers 2019, 11, 1566. https://doi.org/10.3390/cancers11101566

AMA Style

Hendricks WPD, Briones N, Halperin RF, Facista S, Heaton PR, Mahadevan D, Kim S. PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer. Cancers. 2019; 11(10):1566. https://doi.org/10.3390/cancers11101566

Chicago/Turabian Style

Hendricks, William P. D., Natalia Briones, Rebecca F. Halperin, Salvatore Facista, Paul R. Heaton, Daruka Mahadevan, and Suwon Kim. 2019. "PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer" Cancers 11, no. 10: 1566. https://doi.org/10.3390/cancers11101566

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop