AS678 - NSAID use and tumor inflammatory biomarkers in relation to ovarian cancer risk and survival

 

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Investigator Names and Contact Information

Britton Trabert (britton.trabert@hci.utah.edu)

Melissa Merritt (melissa.merritt@sydney.edu.au)

Holly Harris (hharris@fredhutch.org)

Garnet Anderson (garnet@whi.org)

Shelley Tworoger (Shelley.Tworoger@moffitt.org)

Introduction/Intent

Survival rates for ovarian cancer are poor and have remained largely unchanged over time; yet there is new evidence suggesting that use of aspirin may lower risk of developing ovarian cancer. Furthermore, among women with ovarian cancer, aspirin and and non-aspirin nonsteroidal anti-inflammatory drug (hereafter referred to as NSAID) use after diagnosis may vastly improve survival. Using data from the WHI LILAC study, this research will evaluate potential mechanisms of action underlying the aspirin/NSAID-ovarian cancer risk association. Furthermore, we will also identify tumor inflammatory markers for molecular prognostic stratification to inform the optimal placement of aspirin/NSAID use in the treatment paradigm for ovarian cancer.

The major aims of the proposed investigation are to: (i) explore mechanisms by which aspirin/NSAID use reduces ovarian cancer risk; and (ii) define tumor molecular profiles that may explain the prognostic benefit of post-diagnosis aspirin/NSAID use by utilizing ovarian tumor tissues. To achieve these aims, we will apply state-of-the-art multiplex immunofluorescence (IF) technologies to conduct tumor immune expression profiling in ovarian cancer tissue microarrays (TMAs) within the WHI study. Our recent research demonstrates that daily aspirin use versus never use reduced ovarian cancer risk by 10-20%. Additionally, among ovarian cancer patients, we observed a ~30% improvement in ovarian cancer-specific survival in cases who reported recent post-diagnosis use of aspirin or NSAIDs versus never users.

In the current research proposal, we will focus on the biologic mechanisms underlying how aspirin/NSAID use may lower ovarian cancer risk and improve the prognosis of ovarian cancer patients. To meet these objectives we are requesting formalin-fixed paraffin-embedded (FFPE) ovarian tumor blocks to construct TMAs, and using the TMA slides we propose to carry out multiplex IF immune profiling assays. This innovative application will advance our understanding of the mechanisms underlying the observed protective association for aspirin/NSAID use with ovarian cancer risk, and the prognostic benefit of post-diagnosis aspirin/NSAID use, to improve our abilities to prevent and identify improved treatment strategies for this aggressive disease.

Specific Aims and Hypotheses:

1)    Explore potential mechanisms by which aspirin/NSAID use lowers ovarian cancer risk

1. We hypothesize that daily aspirin use will preferentially reduce risk for ovarian cancers that depend on
   
   COX-1 and/or COX-2 function for tumor growth.
2. We hypothesize that the association between daily aspirin use and reduced ovarian cancer risk will be stronger for tumors with an inflammatory response or greater immune suppression as reflected by:
1. High expression of nuclear factor kappa B (NF-κB)
2. High levels of regulatory T cells or tumor-associated macrophages [TAMs], or
3. Low levels of cytotoxic T cells (e.g., measured via CD3+ T cells and CD8+ T cells)

2)    Define tumor molecular profiles that explain how post-diagnosis aspirin/NSAID use versus pre-diagnosis use improves ovarian cancer survival

1. We hypothesize that cases with tumors that express prostaglandin synthesis markers will be more sensitive to the survival benefits of post-diagnosis aspirin/NSAID use.
2. We hypothesize that cases who have an immunosuppressive tumor immune microenvironment (e.g., immune suppressing tumor associated macrophages and T-regulatory cells versus immune activating cytotoxic and activated T-cells) will benefit most from post-diagnosis aspirin/NSAID use.

The aims of this study leverage the compelling epidemiological and experimental data which suggest that inflammation plays an important role in ovarian cancer development and progression. Our goal is to generate key data that are needed to identify tumor inflammatory markers that may underlie the aspirin/NSAID-ovarian cancer risk association, and to to inform the development of efficient clinical trials to test the use of aspirin/NSAIDs together with standard treatment to improve patient survival.

In addition to allowing an investigation of the aims of this project, this research will establish a critically needed infrastructure of tumor tissues/TMAs in the WHI which will be available to support future research focusing on understanding molecular pathways that are important for ovarian cancer development and progression.