Research Seeks to Establish the Efficacy of Minimally Invasive Breast Cancer Procedures and Tests

Yuan Yuan, MD, PhD

The treatment of patients with node-positive breast cancer post–neoadjuvant chemotherapy may shift away from the use of lymph node dissection as ongoing studies delineate the potential role of less invasive, systemic treatment methods, according to Yuan Yuan, MD, PhD.

For instance, the ongoing phase 3 A011202 trial (NCT01901094) is evaluating whether radiation therapy to the undissected axilla and regional lymph nodes is noninferior to axillary lymph node dissection with radiation therapy to the regional lymph nodes in terms of invasive breast cancer recurrence–free survival. The study is enrolling patients with node-positive breast cancer who have received neoadjuvant chemotherapy followed by surgery in which 1 to 8 lymph nodes were removed.1

Furthermore, Yuan added that in addition to research in the surgical sector of care, the role of circulating tumor DNA (ctDNA) testing is another area that requires further elucidation. The rising use of ctDNA analyses across clinical trials could further establish the role of minimally invasive biomarker collection methods in the breast cancer treatment field, she noted.

The ongoing phase 3 SERENA-6 trial (NCT04964934) is one example of a ctDNA-guided breast cancer study. SERENA-6 is investigating a CDK4/6 inhibitor plus either camizestrant (AZD9833) or an aromatase inhibitor in patients with hormone receptor–positive, HER2-negative metastatic breast cancer who have detectable ESR1 mutations per ctDNA testing before disease progression.2

“We have a lot to subject to interpretation, and sometimes, we also don’t have enough drugs in our hands to help these patients,” Yuan said in an interview with OncLive® following a State of the Science Summit™ on breast cancer, which she chaired.

In the interview, Yuan discussed how targeted lymph node dissection may change treatment approaches for patients with node-positive breast cancer, questions regarding the utility of ctDNA testing for disease monitoring, and the need for increased research and guidance surrounding treatment plans for patients with positive ctDNA results. 

Yuan is a professor of medicine, the director of Breast Oncology, and the medical director of the Breast Oncology Disease Research Group at Cedars-Sinai Medical Center in Los Angeles, California. She is also a health sciences clinical professor at the University of California, Los Angeles.

OncLive: How do you determine the optimal extent of axillary surgery in patients with lymph node involvement in the neoadjuvant setting?

Yuan: Over the past 5 to 10 years, [a treatment trend has been] to try to minimize surgery as much as possible and as safely as possible. A bunch of clinical trials led to our old approach of lymph node dissection down to the sentinel lymph nodes. Now, the standard practice for patients who are clinically lymph node negative is sentinel lymph node [dissection] once they complete neoadjuvant chemotherapy and are planned for surgery. If a patient has clinical N1 disease, meaning less than 3 positive nodes, [we] try to see if systemic therapy can downstage the nodes successfully [so we can] minimize the surgery. [That is known as] targeted lymph node dissection or targeted lymph node removal [and] will give patients minimum toxicity. That’s evolving right now.

However, we’re waiting for data for patients who had a complete response [(CR) with neoadjuvant therapy]. [For example, in patients where an] MRI initially showed 3 or 4 [positive] lymph nodes [in whom], at time of repeat MRI after chemotherapy or after immunotherapy, the MRI shows a complete resolution of the lymph nodes, what do we do? The standard practice will remain lymph node sampling and dissection. [However], can we minimize the total intervention? We’re eagerly waiting for large datasets [to answer that question].

What research is needed to solidify the role of ctDNA results in treatment decision-making for patients with breast cancer in the metastatic and neoadjuvant settings?

ctDNA is such an interesting topic. It’s been around for a bit, and I personally have not been a big adapter of it until recently. More questions than answers remain, definitely in the neoadjuvant setting. For example, the I-SPY group had published solid data with the use of ctDNA in the neoadjuvant setting. A quick drop in ctDNA [levels] predicts higher pathologic CR rates and higher event-free survival rates. That’s interesting.

In the metastatic setting, [we are using ctDNA] for disease monitoring. Every day, we’re being challenged by patients [to explain how we know they are] cancer free. Currently, patients are not satisfied with the answer. We usually quote our guidelines. We do not have strong evidence to support frequent usage of tumor markers, such as CEA and CA 27.29, or frequent scans, but perhaps one day for high-risk patients—[those with] stage II and III node-positive, high-risk disease—we may be able to use ctDNA as a way to monitor [disease]. That remains to be seen.

What questions remain regarding the optimal treatment of patients who have disease recurrence per ctDNA?

[Another] dilemma is when we see the ctDNA is coming up and growing over time, but we don’t see anything on the scan, so we can’t confirm [the disease] histology [via] estrogen receptor/HER2 stain. It’s a puzzling, confusing stage to treat these patients [who you may have thought would] recur a few months later, but now are confused on what to do for them. Even if we [decide to] give chemotherapy [to those patients at that point], are we changing their trajectory of disease or are we barely moving that lead time arrow? It is difficult.

Additionally, I’m seeing [varying] second opinions coming from my colleagues [regarding] ctDNA. Sometimes [ctDNA levels] go up, go down, go up, go down, and show wobbly numbers. Patients are extremely nervous, sitting in their chairs and wondering when the disease is going to come back. [There are] a lot of psychological factors [involved] that we don’t know how to handle.

I hope one day we will have clear, delineated pathways [to guide us] when [patients] have their first abnormal ctDNA [levels]. [Should] oncologists sit tight and wait for another 3 months or repeat [the ctDNA biopsy, and] if it confirms [the initial findings], then [start an] action plan? We’re missing an algorithm. Do we give chemotherapy to a patient without visible disease who just has positive ctDNA [levels] or can we do something smarter, maybe administer a targeted therapy? This is a blank space that needs to be filled with knowledge and answers we don’t have right now.

References

1. Comparison of axillary lymph node dissection with axillary radiation for patients with node-positive breast cancer treated with chemotherapy. ClinicalTrials.gov. Updated February 2, 2024. Accessed October 4, 2024. https://clinicaltrials.gov/study/NCT01901094
2. Phase III study to assess AZD9833+ CDK4/6 inhibitor in HR+/HER2-MBC with detectable ESR1m before progression (SERENA-6) (SERENA-6). ClinicalTrials.gov. Updated September 27, 2024. Accessed October 4, 2024. https://clinicaltrials.gov/study/NCT04964934