Advancing Neoadjuvant Therapy for HER2+ Breast Cancer Through ctDNA Monitoring

Adrienne Waks, MD

The DAPHNe trial (NCT03716180) showed that circulating tumor DNA (ctDNA) is a promising biomarker for monitoring treatment response and minimal residual disease (MRD) in early-stage HER2-positive breast cancer, with neoadjuvant paclitaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta) therapy showing high efficacy in clearing ctDNA.¹

Among the 98 patients enrolled in the DAPHNe trial, 50 had at least 1 plasma sample sequenced for ctDNA analysis. The median age of these patients was 50 years, and 92% had clinical stage II disease. A total of 64% of patients had hormone receptor–positive tumors. Residual cancer burden (RCB) scores were classified as RCB 0 in 66% of patients, RCB I in 4%, RCB II in 28%, and RCB III in 2%.

At baseline, 92% of patients had detectable ctDNA, with a median detected level of 210 parts per million. The detection rate varied based on tumor stage: 100% of patients with T3/T4 tumors or positive nodes had detectable ctDNA at baseline, while 91% of patients with T1/T2 or node-negative tumors also had detectable ctDNA.

After 12 weeks of neoadjuvant therapy, most patients had cleared their ctDNA, and 4% had detectable ctDNA at pre-operative and post-operative timepoints. At later follow-up points, more than 90% of patients had sustained clearance of ctDNA.

In an interview with Targeted Oncology^TM, Adrienne Waks, MD, senior physician and the associate director of breast oncology clinical research at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, provided insights into the significance of these findings and their clinical implications for patients with HER2-positive breast cancer.

Breast cancer cells: © LASZLO- stock.adobe.com

Targeted Oncology: What are the unmet needs in this patient population?

Waks: We were looking at patients with early stage, stage II, and stage III HER2-positive breast cancer. And I think in that space, the biggest unmet need at the moment is that we have this expanding set of options for how we treat them. We can give a lot of chemotherapy, we can give a lot of anti-HER2 drugs. We can give a little chemotherapy. We could give no chemotherapy and only anti-HER2 drugs. So, it's a good problem to have. In some ways, we have all these different options, but a big issue at the moment is we don't know how to customize them. We don't know how to figure out which patient needs the most that we can give them, which patient could get away with a lot less and obviously be spared unnecessary toxicity.

What were the overall goals of the DAPHNe trial?

This was a study where we took this patient set of about 100 patients with stage II and III, HER2-positive breast cancer, and we treated them with neoadjuvant chemotherapy, single-agent taxol for 12 weeks, and then 2 anti-HER2 drugs: trastuzumab and pertuzumab. We then brought all those patients to surgery and looked at how good or bad of a response they had to those 12 weeks of therapy. That was the sort of parent trial itself. What we were doing in this poster is diving into the circulating tumor DNA on a subset of those patients. Looking at when they were first diagnosed with breast cancer and enrolled on the trial, could we detect circulating tumor DNA using this novel assay called next personnel? And then as they went through their treatment for their surgery after their surgery, and then a later follow up time point? Could we detect circulating tumor DNA for them?

What were the main findings from the trial?

What we found was that at baseline, the patients who had not yet had surgery for breast cancer still had a breast tumor in place. At baseline, we could detect circulating tumor DNA in 92% of them. We were happy with that number. Ideally, you would want it to be 100%, since they have a tumor in place, so detecting circulating tumor DNA in all of them would be reassuring. But compared with other assays and datasets out there, 92% is a good, high number. At baseline, with the tumor in place, the detectability rate was good, and that was one important finding for us.

Over the 12 weeks of therapy, when we retested their circulating tumor DNA before surgery, we found that almost all of them had cleared their circulating tumor DNA—though not quite all, but almost all. Then, postoperatively, when we looked at their adjuvant therapy about a year later, the large majority—over 90% to 95%—had persistent clearance of circulating tumor DNA at those later time points.

Based on these findings, what are the implications for clinicians?

Circulating tumor DNA is a promising technology, particularly in the neoadjuvant setting, although it can be applied to almost any scenario in breast cancer. Specifically, in the neoadjuvant setting, I think it holds potential for identifying who might need more chemotherapy or additional drugs before surgery and who could safely receive an abbreviated course and proceed to surgery earlier.

I believe our study aligns with that hypothesis, though our cohort is too small to draw definitive conclusions. That said, it does suggest that circulating tumor DNA is a dynamic marker that we can monitor to better understand how well treatments are working—potentially even earlier than traditional methods like taking someone to surgery and analyzing their pathology under a microscope.

Do you find that ctDNA is predictive of long-term outcomes?

If you are wondering if circulating tumor DNA, a positive vs a negative result, has some correlation with whether a patient will recur or not recur in the future? I think the answer to that is yes. It is clear that the positive predictive value—meaning the likelihood that if you have a positive result, you will ultimately experience a recurrence—is much stronger than the negative predictive value. In other words, if you have a negative result and undetectable ctDNA, it is not as reassuring that you won’t experience a recurrence in the future, although it’s still a good sign.

I think we are increasingly aware that we need to improve the sensitivity of these assays to make both the positive and negative predictive values more reliable. Additionally, if we measure circulating tumor DNA at multiple time points—especially if it remains negative over time—that can give higher confidence that the long-term risk of recurrence is lower. So, while I believe these correlations exist, they are far from a one-to-one relationship. At this point, I do not think ctDNA is a tool we can routinely use in clinical practice to guide decisions.

REFERENCE:

1. Waks AG, Tarantino P, Li T, et al. Prevalence and dynamics of circulating tumor DNA (ctDNA) among patients (pts) with HER2+ breast cancer (BC) receiving neoadjuvant paclitaxel/trastuzumab/pertuzumab (THP) in the DAPHNe trial. J Clin Oncol. 2024;42(Suppl 16):558. doi:10.1182/blood-2024-202676