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Fabrice André, MD, PhD
Director of Research, Gustave Roussy Cancer Center
Head, Institut National de la Santé et de la Recherche Médicale Unit U981
Professor, Department of Medical Oncology
Institut Gustave Roussy
Research area: 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 such as alpelisib, other drugs in its 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 CDK4/6 inhibitor, alpelisib (PIQRAY®), 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 alpelisib 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.
Full Research Summary
Research area: Identifying new targets that mediate resistance to combined treatment with endocrine therapy and CDK4/6 inhibitors and that can be used to develop novel treatment strategies to improve outcomes for patients.
Impact: Targeted therapies, such as CDK4/6 inhibitors, are promising treatment options for many breast cancer patients. For patients with metastatic hormone receptor (HR)-positive/HER2-negative breast cancer, CDK4/6 inhibitor combined with endocrine therapy is the standard of care. Although this combination has been transformative, the vast majority of patients will relapse within three years of treatment. Dr. André is identifying mechanisms of resistance which could lead to new targeted treatment combinations to improve outcomes for metastatic breast cancer patients.
Current investigation: Dr. André and his colleagues will focus on the effect of the combination of endocrine therapy and CDK4/6 inhibitors on DNA methylation patterns—chemical modifications that disrupt gene expression—and whether these alterations drive resistance to this therapy.
What he’s learned so far: Dr. André and his colleagues have been focused on the molecular characterization of metastatic breast cancer. Specifically, they have examined biopsy samples from over 2000 metastatic breast cancers by whole exome sequencing and identified genomic alterations that were enriched in patients with metastatic breast cancer. Among these, two genes KMT2C and CHD4 that are involved in the regulation of gene expression, were mutated. His team also found that CHD4 mutations, predict resistance to CDK4/6 inhibitors. These data suggest that KMT2C and CHD2 may be important markers of resistance to endocrine therapy and CDK4/6 inhibitors.
What’s next: Dr. André and his team will analyze the changes in DNA and RNA from 220 breast cancer samples before and after combined treatment with endocrine therapy and CDK4/6 inhibitors. Their analysis will reveal DNA methylation patterns associated with KMT2C and CHD4 mutations that have occurred with treatment and will help them evaluate the role of KMT2C and CHD4 in resistance to combined endocrine and anti-CDK4/6 therapy.
Fabrice André MD, PhD, is an oncologist based at Gustave Roussy Cancer Cancer, Villejuif, France. He is Professor of Medicine at University Paris Saclay. His BCRF research focuses on the characterisation of molecular alterations in metastatic breast cancers. He is leading several prospective trials that aim to show the clinical utility of genomic tests for patients with metastatic breast cancers. He is also leading development of targeted therapies in the same setting. He is the chair of INSERM Unit U981, a research team dedicated to target identification. He is the Editor in Chief of Annals of Oncology.