PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer
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 t...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/10/1566 |
| _version_ | 1797715407077900288 |
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| author | William P. D. Hendricks Natalia Briones Rebecca F. Halperin Salvatore Facista Paul R. Heaton Daruka Mahadevan Suwon Kim |
| author_facet | William P. D. Hendricks Natalia Briones Rebecca F. Halperin Salvatore Facista Paul R. Heaton Daruka Mahadevan Suwon Kim |
| author_sort | William P. D. Hendricks |
| collection | DOAJ |
| description | 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; <i>p</i> = 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. |
| first_indexed | 2024-03-12T08:06:19Z |
| format | Article |
| id | doaj.art-e3261a1773234c0b9e19ecbeede83c3d |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T08:06:19Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-e3261a1773234c0b9e19ecbeede83c3d2023-09-02T19:32:39ZengMDPI AGCancers2072-66942019-10-011110156610.3390/cancers11101566cancers11101566PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast CancerWilliam P. D. Hendricks0Natalia Briones1Rebecca F. Halperin2Salvatore Facista3Paul R. Heaton4Daruka Mahadevan5Suwon Kim6Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USAIntegrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USAIntegrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USAIntegrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USACancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USADepartment of Medicine, University of Arizona College of Medicien-Tucson, University of Arizona Cancer Center, Tucson, AZ 85719, USACancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USAThe 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; <i>p</i> = 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.https://www.mdpi.com/2072-6694/11/10/1566breast cancerher2trastuzumabgene signaturepd-1survival outcometumor evolution |
| spellingShingle | William P. D. Hendricks Natalia Briones Rebecca F. Halperin Salvatore Facista Paul R. Heaton Daruka Mahadevan Suwon Kim PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer Cancers breast cancer her2 trastuzumab gene signature pd-1 survival outcome tumor evolution |
| title | PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer |
| title_full | PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer |
| title_fullStr | PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer |
| title_full_unstemmed | PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer |
| title_short | PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer |
| title_sort | pd 1 associated gene expression signature of neoadjuvant trastuzumab treated tumors correlates with patient survival in her2 positive breast cancer |
| topic | breast cancer her2 trastuzumab gene signature pd-1 survival outcome tumor evolution |
| url | https://www.mdpi.com/2072-6694/11/10/1566 |
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