Applications of ctDNA Assessment in Metastatic Breast Cancer and Relapse

Transcript:

Aditya Bardia, MD, MPH: Circulating tumor DNA [ctDNA] essentially refers to the tumor DNA that can be detected by molecular tests. It is being utilized in metastatic breast cancer for therapy selection, and potentially monitoring as well. For example, if a patient has hormone receptor-positive breast cancer that is metastatic, if after first-line therapies, endocrine plus CDK4/6, the patient has disease progression, it‘s reasonable to consider a ctDNA-based test to detect the presence of a PIK3CA mutation. If a patient has a PIK3CA mutation, you could consider a PI3K inhibitor, alpelisib, which is FDA approved. There are other alterations that can also be detected based on ctDNA, and that can be used for therapy selection in genotype-driven clinical trials. The other application is response to treatment, more like a tumor marker. There is some evidence, including from our group, that if a patient has an increase in circulating tumor DNA, that is a harbinger for subsequent radiological progression.

At the 2021 San Antonio Breast Cancer Symposium, we saw the results of a clinical trial called PADA. In that trial, patients were monitored by ctDNA in the first-line setting. And if a patient had a rise in ctDNA, they were randomized to continue the same treatment vs switch the endocrine backbone to fulvestrant. And it showed that if you switch based on ctDNA, that’s associated with improvement in progression-free survival. Thus, the evidence is building for the use of ctDNA for monitoring as well. The final thing in terms of where ctDNA could be helpful in the metastatic setting is to identify the mechanism of resistance, examples being mutations in the estrogen receptor, mutations in the HER2 [human epidermal growth factor receptor 2]. Those are acquired alterations that can be detected with ctDNA testing and could be helpful in subsequent therapy selection.

Monitoring for ctDNA in the adjuvant setting potentially could help detect disease before you can see it on restaging scans. That’s the promise with these ctDNA-based assays. There are ongoing studies that are looking at this question, a couple of studies that have completed small data sets but provide proof of principle. For example, there was a publication a couple of years ago in Clinical Cancer Research by [Raoul Charles] Coombes, [MD,] et al, where they looked at patients with breast cancer in the adjuvant setting who had blood drawn every 6 months for 4 years. They found that patients usually had detectable ctDNA before having radiological relapse, with a median of about 8.9 months in terms of the time lag. Thus, it provides proof of principle that you can detect ctDNA before a patient would have radiological progression. The next step is whether that actually makes a difference in terms of outcomes. There are ongoing studies looking at intervening at the time you detect ctDNA to see if you can clear the ctDNA with an investigational or novel therapy.

Transcript edited for clarity.