MRD Testing in Solid Tumors

Gregory P. Botta, MD, PhD: Molecular residual disease, or MRD, is being evaluated in solid tumors. In just a couple…evaluated is determined if there’s prognostic information that can be given to the patient. Basically, it’s how well they’ll do after either a surgical resection or neoadjuvant or adjuvant therapy. It gives us an end point of either disease-free survival or recurrence-free survival. Those tend to be the end points of a lot of studies. The prognostic information is a tool that the oncologist uses to help guide their treatment decisions. Just as CEA [carcinoembryonic antigen] is a tool, radiographic evidence of disease is a tool, and pathologic staging is a tool, ctDNA [circulating tumor DNA] is being incorporated as a tool to help make these treatment decisions and evaluate surveillance and if there’s recurrence.

Molecular residual disease is evaluated in both a tumor-informed approach and a tumor-naive approach. In the tumor-informed approach, we’re generally taking the tumor out of the patient and running whole-exome sequencing on it. With whole-exome sequencing, you’re getting a variety of genes, not only actionable mutations but also possibly passenger mutations or housekeeper gene mutations. Then they’re taking the germline from the patient and subtracting that from the whole-exome sequencing of the tumor. You’re left with only the tumor pathologic mutations. Those tumor pathologic mutations provide a gene signature, or a gene thumbprint. That gene thumbprint can be extracted from the bloodstream and used to guide whether there’s still residual tumor or molecular residual tumor MRD.

When we find that there’s a positive ctDNA or positive molecular residual disease, that means that genes from the original tumor are found circulating in the bloodstream. That gives us prognostic information depending on the histology. At the end of the day, ctDNA is basically tumor agnostic. It doesn’t matter what histology the tumor is. Every tumor has DNA, and you’re going to be able to get ctDNA from every tumor type. Ultimately, the question that’s left is what that information means for that histology, what prognostic information, and if there are any additional predictive information that we can get from it that help guide treatment. Those are the ongoing studies that we’ll evaluate prospectively.

Transcript edited for clarity.