Identifying targets  for development of novel treatment strategies to prevent resistance to combined treatment with endocrine therapy and CDK4/6 inhibitors and improve outcomes for patients.

Impact

Targeted therapies, such as CDK4/6 inhibitors, are standard care with endocrine therapy for patients  with metastatic hormone receptor (HR)-positive/HER2-negative breast cancer. In spite of initial responses, the vast majority of patients will relapse within three years of treatment. Dr. André is identifying genetic markers associated with poor response to this targeted therapy—which could help predict which patients are most likely to benefit from CDK4/6 inhibitors, other drugs in this class, or novel therapies. These studies could yield new insights into the development of metastases.

Progress Thus Far

Dr. André and his colleagues have characterized biopsy samples from over 2000 metastatic breast cancers by whole exome sequencing. They have identified genomic alterations that were enriched in patients with metastatic breast cancer including the mutation of two genes, KMT2C and CHD4, that are involved in the regulation of gene expression. His team also found that CHD4 mutations predict resistance to CDK4/6 inhibitors. In related work, Dr. André launched a clinical trial to discover the mechanisms of resistance to a CDK4/6 inhibitor which blocks a key protein involved in the progression of breast cancers. His results suggest a role for this protein in response to chemotherapy and therefore, targeted therapy with CDK4/6 inhibitors before chemotherapy may benefit some patients.

What’s next

Dr. André and his team are sequencing circulating tumor DNA (ctDNA) from patients before treatment and after tumor progression to identify alterations that may be driving resistance to CDK4/6 directed therapy. Dr. André is also focusing on methods to improve outcomes for patients with hard-to-treat metastatic breast cancer by identifying genomic events that occur before metastasis. His team will perform molecular testing on primary tumors and matched metastases to identify these early events.