Role of ctDNA in the Neoadjuvant Setting of Breast Cancer

Expert perspectives on the value of circulating tumor DNA in the neoadjuvant setting of breast cancer management.


Barry Rosen, MD: What I’ve seen over the past decade among breast surgery is that many of my colleagues have adopted neoadjuvant chemotherapy as a regular tool to treat patients with more advanced breast cancers. I think a nice measuring stick for that is, if we know before surgery that our patient will definitely require chemotherapy, and if our medical oncology colleagues know based upon preoperative testing what their recommendation will be, there can be distinct advantages to giving the systemic treatment prior to local treatment, otherwise known as neoadjuvant chemotherapy. First and foremost, as a surgeon, that really expands the options that I can offer to my patients. If I have a patient who has a large tumor relative to the size of their breast and would otherwise require a mastectomy, if that tumor could be shrunk by their chemotherapy, I will have an option of being able to offer them breast conservation. In a similar manner, we may take a patient who otherwise would require more extensive axillary surgery, and by giving the chemotherapy before the surgery, we might be able to reduce the extent of axillary surgery that’s necessary.

Another distinct advantage of neoadjuvant chemotherapy is that it provides us more meaningful prognostic information than traditional staging. Thus, when we do neoadjuvant chemotherapy, we’re all looking for that same goal of a pathologic complete response [pCR], so that when we do the surgery, eventually a subset of patients will be fortunate enough to find no residual pathologic disease, either in the breast or the axilla. Well, pCR is an all or nothing phenomenon, and we know that there has to be some gradation for some patients who have a very good response without a pCR. I think that what we’re seeing from the preliminary evidence from circulating tumor DNA [ctDNA] testing is that there is a subset of patients who don’t have a pathologic complete response who have an excellent prognosis when doing ctDNA measurements. Specifically, there are those patients who are found to have a level before treatment, and then quickly go down to zero after initiating their chemotherapy. Even if those patients don’t have a pCR, we know that those patients have an excellent prognosis.

Another advantage that resonates with my patients when I talk to them about the option of neoadjuvant chemotherapy is I say to them, if we start with systemic treatment after surgery, we’ve already removed the tumor. How do we know if that chemotherapy is affecting their cancer? Really, all we have to go by are statistics. But if the tumor is left in place, and we watch that tumor shrink, that gives us very compelling evidence that the recipe that our medical oncologists have selected for that patient is effective for that cancer, and I think that’s very meaningful for our patients to see. That gives us dynamic results, and I think of the ctDNA testing in the same manner. This isn’t a static test, like a molecular profile test, which obviously plays a very important role in selecting the ideal therapy for our patients. We all like to speak about personalized medicine or precision medicine, but how often are we really doing precision medicine when it comes to systemic treatment of our patients with breast cancer? We have a regimen, and we usually follow that. But if we have a dynamic measurement of the patient’s response to treatment, through serial measurements of ctDNA levels, perhaps that’ll give us the dynamic information to have more precise treatment, and that if a patient is not responding to treatment, consider altering the regimen.

Aditya Bardia, MD, MPH: There was an interesting study that was presented by the Belgian group, Michail Ignatiadis, [MD, PhD,’s] group [Jules Bordet Institute in Brussels, Belgium], with the lead author being Elisa Agostinetto, [MD]. They looked at their experience in the institution, 52 patients who had received neoadjuvant therapy at their institution. Patients had blood drawn during neoadjuvant therapy, and then after the completion of neoadjuvant therapy and then surgery. They found that the majority of patients had enough tumor cellularity to have the personalized ctDNA assay, the Signatera assay design. A majority of patients had enough blood to have the ctDNA analysis done. In terms of what was seen, they found that all the patients who had a pCR did not have ctDNA. Hence, if the therapy was successful, they had complete pathologic response, those patients also did not have any tumor DNA that was detected, before surgery.

Then, in terms of follow-up, with the median follow-up of about 3 years, they noted that there were 8 patients who had relapsed, and in a majority of them, you could detect ctDNA. Thus, in the multivariate analysis adjusting for pCR, they found that patients who had ctDNA detection had shorter event-free survival compared to patients who did not have ctDNA detected. It provides proof of a principle that detection of ctDNA after neoadjuvant therapy is completed could potentially suggest that this is a patient who’s at high risk of relapse. And maybe in the future, we need intervention studies to address that.

Transcript edited for clarity.

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