DR-218 Large-scale analysis of non-coding alterations in endocrine therapy resistance of breast cancer

Breast cancer is the second leading cause of cancer-related death in women worldwide. Hormone therapy has been proven effective to increase survival after surgical removal in 80% of patients (Estrogen Receptor alpha-, ERa-positive breast cancers). Nevertheless, in many cases the residual tumor evolves, develops resistance and continues to spread. As compared to the initial tumor, we currently know very little about the resistant disease. This is partly due to scarce use of re-biopsy at time of first relapse in the clinical practice. This dramatically curbs our ability to properly treat relapsing patients, as targeted-therapies remain dictated by the information collected at time of diagnosis. Additional factors restrict our understanding on how genetic alterations drive cancer onset and progression. We often limit our search to the protein-coding part of the human genome; on the other hand, resolution at a genomic scale is poor. As cancer cells tend to accumulate a large number of aberrations that carry no functional significance, one critical problem is how to recognize those propelling the disease, particularly among those residing in regions that control the activity of genes rather than in genes themselves. We are currently developing a novel strategy to overcome these limitations and identify genetic and epigenetic alterations driving resistance. We designed an innovative approach to investigate thousands of potentially critical regions at very high resolution. We are currently collecting this information longitudinally, at diagnosis and at first relapse, for hundreds of patients that underwent hormone therapies. We plan to integrate this information into novel analytical tools to pinpoint driver alterations recurring across multiple patients. This is expected to identify new actionable targets in metastatic breast cancer and – by applying these tools to larger cohorts of breast and other cancers – to reveal new critical biological principles driving tumor evolution.

Luca Magnani, Imperial College London, United Kingdom