173P - NRF2 levels in high grade serous ovarian cancer: Characterization and treatment

Background

High grade serous ovarian cancer (HGSOC) is the most aggressive type of ovarian cancer with limited therapeutic options. HGSOC is a histologically diverse disease. Furthermore, the cancer genome atlas (TCGA) and other groups have identified four molecular subtypes including immunoreactive, differentiated, proliferative, and mesenchymal, which complicates efforts to find targeted treatment for this deadly disease. NRF2 is an antioxidant agent whose activation in cancer protects tumor cells from oxidative damage by chemotherapies. This activation induces resistance to chemotherapies, and supports tumor growth and metastasis. As an anti-inflammatory pathway, NRF2 is found to modulate the immune microenvironment (IME) of several types of cancers. Activation of the NRF2 signaling is found in about 50% of HGSOC. This study aimed to understand how NRF2 level contributes to the growth and the treatment of HGSOC.

Methods

We performed data analysis on 365 HGSOC samples from TCGA. We used well-established NRF2 and immune gene signatures to analyze the data. Tumor micro array (TMA) of 220 patients with HGSOC was also stained for immunohistochemistry (IHC) for NRF2 and other biomarkers including immune markers.

Results

RNA-seq data analysis showed that NRF2 is active in >50% of patients with HGSOC without alteration. Tumors were grouped based on their molecular subtypes into immunoreactive, differentiated, proliferative, and mesenchymal. These subtypes showed different levels of NRF2. Although the immunoreactive group had significantly (P<0.001) lower NRF2 levels compared to the mesenchymal subtype, the immune score signature was comparable. Further analysis showed that high-NRF2 tumors were enriched with immune suppressive pathways such as TGF-b, epithelial to mesenchymal transition (EMT), and angiogenesis pathways. Furthermore, IHC staining of the HGSOC TMA showed two distinct groups of patients; a group with high NRF2 and a group with low NRF2. These two groups had distinct immune phenotypes.

Conclusions

Our results suggest that NRF2 modulates the IME in HGSOC and could be used to further characterize these tumors. Given that low vs high NRF2 tumors have distinct immune phenotypes, NRF2 may be used to guide treatment with immunotherapy and chemotherapy.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.