Understanding how Estrogen Receptor Positive (ER+) breast cancers evade the immune system

Project description

Estrogen Receptor Positive (ER+) breast cancer is the most prevalent subtype, representing approximately 70% of all breast cancer cases. Endocrine (hormone) therapy is the standard treatment to prevent recurrence, significantly reducing mortality in people with early-stage disease. However, some people still experience relapse, which can occur late – from five to over 10 years after their initial diagnosis. These late recurrent cancers are challenging to predict and resistant to existing therapies. Immunotherapies that activate the person’s own immune system to kill cancer cells have revolutionised the treatment of other cancers. However, ER+ breast cancers can hide from the immune system through unknown means and immunotherapies are currently ineffective. Improving understanding of how ER+ breast cancers escape from being detected by the immune system is essential for the design of new treatments.

PIK3CA is the most frequently mutated cancer-causing gene in ER+ breast cancer, which drives cancer growth and resistance to treatment. Previous research by Professor Christina Mitchell from Monash University and the team have discovered high levels of a phosphoinositide (PI)-phosphatase (type of enzyme) in almost 50% of ER+ breast cancers that is linked to poor prognosis. The team also showed that the mutant PIK3CA gene and the PI-phosphatase work together to create a ‘cloak of invisibility’. This helps ER+ breast cancer cells hide from the immune system for years, leading to late recurrence.

In this NBCF-funded study, the team aims to understand how the mutant PIK3CA gene and the PI-phosphatase help ER+ breast cancer cells escape immune detection.

They will use high-resolution spatial transcriptomics, a cutting-edge gene mapping technology, to understand why ER+ breast cancer may recur and how the immune system can be reactivated to attack the cancer again. This may also lead to the discovery of potential biomarkers that can predict who will experience late recurrence, enabling early intervention to eliminate remaining cancer cells after initial treatment.

Why is this work needed

While most people with ER+ breast cancer respond well to endocrine (hormone) therapy, there remains an ongoing risk of the cancer returning – sometimes many years after initial treatment. This late recurrence can lead to metastatic disease, which is the main cause of death from breast cancer. Immunotherapy has shown encouraging results in treating certain cancers, including some Triple Negative Breast Cancers (TNBC). However, ER+ breast cancers manage to hide from the immune system through mechanisms that remain unclear, making current immunotherapies largely ineffective. Gaining a deeper understanding of how ER+ breast cancers escape immune detection is crucial for the development of new ways to treat ER+ breast cancer effectively.

Expected outcomes

Successful outcomes of this study will uncover the role of the mutant PIK3CA gene and PI-phosphatase in enabling ER+ breast cancer cells to escape immune detection and reveal improved treatments to reactivate the immune system to improve outcomes for people facing late recurrence.