271P - Overall expression of human endogenous retroviruses in early breast cancer and their correlation with immunogenicity

Background

Human endogenous retroviruses (HERVs) are carcinogenic due to genomic instability and epigenetic induced transcription. In reaction, the host activates an interferon (IFN)-based innate response. In breast cancer (BC), HERVs are associated with poor prognosis. A high level of HERV expression also activates an antitumour immune response. Using data from The Cancer Genome Atlas, we searched for HERVs expressed in early BC that were related to both anticancer immunity and good prognosis.

Methods

Patients were classified into BC subtypes by immunohistochemistry (IHC), based on hormone receptor (HR) and human epidermal growth factor 2 (HER2) status, i.e. HR+/HER2-, HR-/HER2+, triple-negative (TN). HERV sequences were detected using Telescope software on RNA sequencing data. Only HERVs overexpressed in tumor tissue were kept for further analysis. We computed an overall HERV expression per case by summing HERV counts. Expression was compared across BC subtypes with the Wilcoxon test. HERVs were further selected based on their correlation with enrichment scores of three IFN I pathways. Average expression generates a signature that was assessed for its impact on 5-year Disease-Free Interval (DFI) by Cox regression. Correlations with tumour-infiltrating lymphocytes (TILs), programmed death ligand 1 (PDL1) and estrogen receptor 1 (ESR 1) were evaluated with Pearson’s correlation coefficient.

Results

We analyzed 824 BC tissue samples; 608 (73.8%) HR+/HER2-, 46 (5.6%) HR-/HER2+, 170 (20.6%) TN. HERV expression did not differ across IHC subtypes. In total, 23 HERVs were significantly correlated with the IFN I pathway and selected for further analysis. Average expression differed across IHC subtypes (highest in TN, lowest in HR+/HER2-). HERV signature was significantly correlated with TIL and PD-L1 scores (respectively, Pearson r=0.66 and r=0.53, p <0.001 each) and negatively correlated with ESR1 (r=-0.36, p<0.001). HERV signature was significantly associated with longer DFI in HR+/HER2- cases only (hazard ratio 0.54 [0.33-0.88]; p=0.01).

Conclusions

We identified 23 HERVs with anti-tumor potential, whose signature was associated with better survival in HR+/HER2 BC.

Clinical trial identification

Editorial acknowledgement

We would like to thank Ms Fiona Ecarnot, PhD, University Hospital Besancon France for providing the medical writing and editorial assistance.

Legal entity responsible for the study

Georges Francois Leclerc Cancer Center, Dijon, France.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.