Titles and Affiliations
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
Research area
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. Moreover, about 20 percent of patients show early resistance to therapy as their disease evolves after a few months. For these patients, it’s important to propose different therapies as soon as possible, perhaps as early as at diagnosis. This could involve adding other therapies to endocrine therapy or using novel approaches as new therapies are developed. Studies have shown that cancer cells release tumor DNA or circulating tumor DNA (ctDNA) into the blood which can be detected by liquid biopsy. If the level of ctDNA does not decrease after a few weeks of therapy, the patient’s outcome is very poor, and resistance will likely occur. Dr. André is leveraging this technology to predict which patients are most likely to benefit from existing therapies so that treatment decisions can be made more nimbly and accurately. His studies will also seek to determine the efficacy of switching to novel therapies in patients with metastatic hormone receptor (HR)-positive/HER2-negative breast cancer, yielding new insights into the development of metastases and improving outcomes for patients.
Progress Thus Far
The SAFIR clinical trials (NCT03386162) investigated the mechanisms of resistance to P13K inhibitor, alpelisib (PIQRAY®), which blocks a key gene (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 the presence of PIK3CA mutations in the ctDNA of patients with metastatic breast cancer was a predictor of worse outcomes compared to those without PIK3CA mutations. These results suggest a role for this gene in response to targeted therapy. Dr. André is now conducting SAFIR03, a multi-year clinical trial to measure ctDNA in patients receiving endocrine therapy to identify which patients with persistent levels of ctDNA following treatment and are candidates for additional or new drugs.
What’s next
Dr. Andre and his team will expand SAFIR03 to evaluate the relatively new antibody-drug conjugate trastuzumab-deruxtecan (T-DXD, Enhertu®) and other agents as alternatives for patients whose ctDNA levels do not decrease with standard-of-care therapies. Drugs that show efficacy will be tested in large comparative trials in this specific patient population. These studies could represent a paradigm shift from endocrine therapy to new drugs or drug combinations early in the course of treatment for those patients that are likely to develop resistant breast cancer.
Biography
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.
