AACR Outstanding Investigator Award: Precision medicine a work in progress


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Fabrice André, MD, PhD
Fabrice André, MD, PhD

Precision medicine is evolving. The pathway toward targeting treatment to each breast cancer patient’s unique tumor is becoming more evident by the year, thanks in large part to Fabrice André, MD, PhD, Director of Research and consultant medical oncologist in breast cancer at Gustave Roussy Cancer Campus, Villejuif, France, and Professor of Medicine at Université Paris-Saclay.

Dr. André received this year’s AACR Outstanding Investigator Award for Breast Cancer Research, supported by the Breast Cancer Research Foundation, for his work helping to establish the concept of using real-time, high-throughput genomic analysis of cancer biopsies to identify potential therapeutic targets. His pioneering work in translational breast cancer research was part of multiple high impact clinical trials of the PI3K inhibitor alpelisib, including MOSCATO, SAFIR01, SAFIR02, BOLERO, and CANTO.

“If we can identify the mechanisms of cancer progression in each patient and each tumor, we can block them, and it will improve progression free survival and overall survival,” he explained. “To do that, we must counter the genomic drivers in each tumor, target the immune checkpoints that allow tumor escape, and block genomic evolution which leads to treatment resistance.”

Dr. André discussed the progression of precision medicine during his lecture Moving Toward Precision Medicine in Patients with Breast Cancer on Friday. Working from the basic concept of targeted therapy, translational and clinical researchers are using multiple genomic and data technologies not just to characterize the drivers of every tumor but also to design, create, and use personalized therapeutic regimens for every patient.

The first step is to identify the mechanisms of cancer progression at work in each patient, he explained. Molecular profiling has identified about 21 recurrent genomic drivers in patients with metastatic breast cancer.

Targeting those validated drivers improves tumor response and progression-free survival, Dr. André continued, but requires genomic testing to determine which driver(s) are present in order to identify which agent(s) are most likely to be more effective in each patient.

“It is feasible to perform genomic profiling using high-throughput technologies in real time,” Dr. André said. “Comprehensive genomic testing is feasible and increases the likelihood of drug access for patients.”

Targeted therapy, like chemotherapy, typically results in treatment resistance. Molecular modeling of each patient’s own genomics can identify immune checkpoints that are involved in tumor escape as well as genome evolution that is likely to produce treatment resistance. APOBEC, for example, is an important cytidine deaminase that transforms C to T and appears to drive genomic evolution in metastatic breast cancer.

“If we can target the mutational process, we will be better able to block genomic evolution and resistance,” Dr. André said.

One of the key strategies in precision medicine is to decipher all of the biologics of cancer and cancer progression in order to more precisely identify the most appropriate targets in each patient. That means new approaches such as assessing protein activation and the chromatin landscape, epigenetics and RNA expression, and spatial proteomics to predict sensitivity to therapies as well as new approaches to data analysis.

“We can broaden the scope of precision medicine to include early identification of patients likely to have poor outcomes, predict treatment toxicities to select less toxic agents, and improve early detection of cancer,” Dr. André said. “The goal is to construct a drug for each patient even when the drug that patient needs does not yet exist.”