Seeking targets that may quickly identify patients with hard-to-treat breast cancer so that more accurate treatment decisions can be made in real time.

Impact

Targeted therapies, such as CDK4/6 or P13K inhibitors, in combination with endocrine therapy are standard of care for treating metastatic hormone receptor (HR)-positive/HER2-negative breast cancer patients. 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 targeted therapies with particular focus on response to the P13K inhibitor alpelisib ((PIQRAY®). His research may uncover ways to predict which patients are most likely to benefit from alpelisib, other drugs in its class, or other novel therapies so that treatment decisions can be made more nimbly and accurately. His results will also yield new insights into the development of metastases and improve outcomes for these patients. 

Progress Thus Far

Dr. André and his colleagues have characterized biopsy samples from over 2000 metastatic breast tumors by whole exome sequencing. In his work, they uncovered genomic alterations in several important genes including CHD4, which his team found to predict resistance to CDK4/6 inhibitors. In related work, Dr. André launched a clinical trial to discover the mechanisms of resistance to P13K inhibitor, alpelisib (PIQRAY®), which blocks a key protein (PIK3CA) involved in the progression of breast cancers. HR-positive/HER2-negative tumors that have PIK3CA gene mutations benefited from treatment with alpelisib. Using liquid biopsy techniques, his team found that PIK3CA mutations in the blood of patients with metastatic breast cancer was a predictor of worse outcome compared to those without PIK3CA mutations His results suggest a role for this protein in response to targeted therapy.   

What’s next

The team is testing the utility of liquid biopsy to identify non-responding patients early in the course of treatment. They will continue to sequence biopsy samples from patients before treatment and after tumor progression to identify alterations that may be driving therapy resistance. By identifying genomic events that occur before metastasis, treatment decisions could then be adjusted in real time to ultimately prevent disease progression and improve outcomes for patients with hard-to-treat metastatic breast cancer.