Tumor-Informed vs Tumor-Agnostic ctDNA: A Deep Dive Into MRD Assay Selection

Minimal residual disease (MRD) assays based on circulating tumor DNA (ctDNA) fall into 2 main categories: tumor informed and tumor agnostic.

Tumor-informed assays are patient-specific; they require analysis of the primary tumor to identify unique mutations, which are then used to design a customized, highly sensitive test to track these specific mutations in the patient's blood. Data suggest these assays are generally more sensitive than their counterparts, making them preferable in the early-stage setting where the amount of MRD is expected to be very low. Within this group, new-generation assays are ultrasensitive, tracking thousands of alterations and achieving very low limits of detection, whereas first-generation assays track only a few mutations.

Tumor-agnostic assays are computational; they do not require primary tumor tissue. Instead, they use algorithms to estimate the proportion of ctDNA within the total cell-free DNA. These assays are "universal" for all patients but are currently considered less sensitive.

The clinical question should dictate the choice of assay. For trials investigating therapy de-escalation, ultrasensitive, new-generation tumor-informed assays are recommended to confidently detect low levels of MRD. For studies focused on treatment escalation, a less-sensitive assay might suffice.

Crucially, there is currently no proven clinical utility for any MRD assay in early-stage breast cancer, and they should not be used routinely in standard clinical practice. Their main role is currently within clinical trials designed to establish this utility.

In an interview with Targeted Oncology®, Stefania Morganti, MD, PhD, a research fellow at the Dana-Farber Cancer Institute, explained the difference between MRD assays and how this information is used to guide treatment.