MRD Assay Is New Step in Urothelial Cancer Testing

Arjun V. Balar, MD

A post hoc analysis from the IMvigor010 study (NCT02450331) evaluating circulating tumor (ct) DNA in patients receiving adjuvant atezolizumab (Tecentriq) in high-risk muscle-invasive urothelial cancer after surgery was presented at the European Society of Medical Oncology Immuno-Oncology Virtual Congress in 2020.

Although the overall study was negative for the primary end point— disease-free survival (DFS)—the post hoc analysis caught participants’ attention. Natera has developed an assay where customized DNA probes derived from an individual patient’s tumor can be used to detect ctDNA in the blood as means for early detection of tumor recurrence. Patients who had persistent ctDNA after surgery had a higher risk for systemic relapse than those who did not. Furthermore, they derived a DFS benefit from adjuvant atezolizumab.

These data served as the basis for the ongoing IMVigor011 study (NCT04660344), which focuses only on ctDNA-positive patients after surgery to confirm if adjuvant atezolizumab improves DFS. More recently, Natera has developed a commercial rollout of this minimal residual disease (MRD) assay for routine use in clinical practice, and many of my colleagues are using this for their patients who receive standard-of-care.

Although I’m absolutely thrilled that the scientific and biotech communities have been able to successfully develop this assay, I do have concerns about rapid rollout in clinical practice without fully understanding the potential effects on patient care. For instance, in the postsurgical setting for a patient on observation, until we fully understand the clinical meaning of ctDNA positivity in the context of negative CT or MRI imaging, this may create unnecessary stress and anxiety for the patient, more frequent imaging, ctDNA testing, and ultimately unnecessary health care utilization and excess cost, especially if we do not yet have data to demonstrate that early intervention with therapy necessarily improves outcomes.

One scenario where this assay may have immediate use is for a patient who has achieved a durable complete response or deep partial response to immunotherapy and is considering discontinuing therapy. A negative ctDNA level (ideally converted from a positive ctDNA) could provide a bit more comfort and assurance in making that decision, at the same time acknowledging the potential limitations and unknowns of the assay. In times such as these, I remember what one of my favorite medical school professors taught me: Don’t order a test unless you know exactly what you intend to do with the results!