Skipping Surgery in Early HER2+ Breast Cancer or TNBC? Phase 2 Trial Data Highlight Feasibility of Selective Omission

Henry M. Kuerer, MD, PhD

Selective elimination of breast surgery in patients with early-stage HER2-positive breast cancer or triple-negative breast cancer (TNBC) who achieve a pathologic complete response (pCR) following neoadjuvant systemic therapy may offer a safe and effective treatment de-escalation strategy, according to Henry M. Kuerer, MD, PhD.

Findings from a 5-year follow-up analysis of a phase 2 trial (NCT02945579) demonstrated that at a median follow-up of 55.4 months (interquartile range, 44.0-63.5), evaluable patients who skipped surgery (n = 31) experienced a 5-year ipsilateral breast tumor recurrence rate of 0%. The 5-year disease-free survival (DFS) and overall survival (OS) rates were both 100%.

“In testing this new paradigm, we were fortunate that there were no recurrences,” Kreuer said. “This is likely attributable to the efficacy of systemic therapy and radiotherapy for these patients. This is something we cannot ignore—it warrants further investigation.”

In the interview with OncLive®, Kuerer discussed the rationale for omitting breast surgery in certain patients with early-stage breast cancer and the criteria used for selection; detailed the 5-year findings from the study; and highlighted the next steps to determine if the omission of surgery for select patients with breast cancer could have a role in clinical practice.

Kuerer is a professor and executive director of the Breast Programs in the Department of Breast Surgical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: What is the clinical rationale for evaluating the elimination of breast surgery in select patients with early-stage breast cancer?

Kuerer: We've known for a long time that certain patients have an exceptional response to neoadjuvant systemic therapy. For [early stage] TNBC and HER2-positive breast cancer, the complete pathologic response [rate] now—even without immunotherapy—is approximately 60%; therefore, we needed to figure out a way to identify those patients safely so we could avoid that surgery. People may say a lumpectomy is not a big deal. Why even do this [evaluation of the omission of surgery]? It is because I don't really believe that those patients without any residual disease will benefit from surgery.

We had to figure out a way to identify [patients who could forgo surgery]. The problem was that our best imaging, including mammogram, ultrasound, and breast MRI, can overestimate and underestimate disease. We designed an inaugural method to select patients with highly strict eligibility, as well as technical standards, and after the chemo, we biopsied [the tumor] under direct imaging with what's called the vacuum-assisted core biopsy. We previously demonstrated that we could do that with an accuracy of 98%. I will tell you up-front that a lot of studies have been done that show a much higher false negative rate. The problem with those studies is their inadequate sampling and selection criteria. We use a vacuum-assisted core biopsy. Many people, including medical oncologists, even some surgeons and radiation oncologists, may not know that you can, under image guidance, use this one stick to [access] the area of the tumor bed, and the radiologist can carefully move around the tumor bed and sample tiny portions of tissue.

We found in our initial foundation study that we needed to remove approximately 12 portions of that tissue to get an accurate assessment of residual disease. Another issue is that there is concern about the false-negative rate because, we have these great systemic therapies that can be given to patients after surgery if they have residual disease to increase disease free survival. We believe that sampling of this methodology that is under direct imaging with a very strict histological assessment of all the tissue that's removed is probably more accurate than standard surgery. [With] standard surgery and the margin assessment, we may think that the false-negative rate is 0. However, whenever we do very classic studies and we take more margins or go back and take more tissue, approximately 8% to 19% of the time, there is more disease found. We believe that this methodology for detection of residual disease is probably more accurate,

What was the trial design, methodology, and patient eligibility criteria used in this study?

We were testing the hypothesis that if there is no residual disease detected [after neoadjuvant therapy], we could just move on to standard radiotherapy without the surgery, because it would be redundant. Why remove breast tissue and sometimes even breast if there's no disease? We only involved patients with tumors that were less than 5 cm, HER2- positive breast cancer or TNBC, but they had to shrink down on breast imaging.

We only used mammogram and ultrasound in this trial, and the tumor had to shrink down to less than 2 cm, and we had to assess the tumor bed with at least 12 portions of tissue using a vacuum-assisted core biopsy. As I mentioned, other prior studies did not utilize that technique, which resulted in high false-negative rates.

For this trial, those patients who didn't have any residual disease on the vacuum-assisted core biopsy did not have surgery. We followed them every 6 months with imaging and physical exams. The primary outcome being [measured] was in-breast local recurrence or ipsilateral breast tumor recurrence. If there was residual disease, patients had their standard surgery.

What did the 5-year efficacy data reveal about the feasibility of selectively omitting breast surgery in patients who achieved an exceptional response to neoadjuvant systemic therapy?

[In] our 5-year analysis, the clinical trial demonstrated that [this] new paradigm for the management of highly selected patients with HER2-positive breast cancer and TNBC is both safe and effective, [as] there were no local recurrences. [Patients achieved a] 100% ipsilateral breast tumor recurrence-free survival, as well as 100% DFS and OS.

What should be known regarding safety outcomes?

Patients on this study were followed very carefully for safety and efficacy. The only [notable procedural difference in this trial] was adding the biopsy following neoadjuvant systemic therapy.] You might expect that if you're going to be performing these core biopsies, you would have at least one hematoma out of 50 patients—but we didn’t have that.

There were 2 grade 1 toxicities: one patient experienced some nausea without vomiting during the [biopsy], and one patient had an issue with the vacuum-assisted device, requiring two biopsy passes instead of the single pass used in the other 50 patients.

Patients in this trial received whole-breast, hypofractionated radiotherapy with a boost to the tumor bed. Patients with clinically node-negative disease—the majority of participants—did not receive direct treatment of the lymph nodes. [Among these patients], 75% were clinically N0 and received only tangential irradiation of the axillary region, [meaning] 75% of patients had neither breast surgery nor axillary surgery.

[There is controversy] when we challenge the standard of care that has dominated breast cancer management for 125 years—namely, the primacy of surgery. In randomized trials, we typically value equipoise, meaning that investigators genuinely do not know which approach is better. However, with this novel approach [of omitting surgery], there is clearly not equipoise.

I do believe this model is feasible in nearly every type of breast practice across the United States. As I mentioned, we didn’t require MRI. We’re not opposed to MRI—it just wasn’t mandated for eligibility or to standardize the eligibility or biopsy procedure. The majority [of biopsies were performed using] image-guided stereotactic techniques.

What unanswered questions remain following these findings, and are there any planned or ongoing trials aimed at further evaluating the omission of breast surgery in this setting?

One of the key interests for patients [is whether they] are going to be worried that they didn't have the surgery. A big component of this clinical trial was the patient-reported outcomes. There was a very high level of comfort, which increased over the five years, for patients participating.

Patients didn’t notice any significant differences between the breast that had the cancer and the one that did not, except that [the one treated] with radiotherapy was rated slightly differently. There was a high quality of life at baseline, and this increased over the 5-year period.

There’s been a lot of interest in whether we can identify patients at higher risk if we measure circulating tumor DNA [ctDNA]. One of our end points was to measure—or compare—the outcomes of patients based on these biomarkers. In the trial, 5 patients had circulating tumor cells. Two patients, at various measured time points, had detectable TP53 mutations; one of them later cleared. However, we didn’t have any recurrences, either local or distant, so we cannot draw any conclusions about the prognostic value of these markers. We have now consented for patients to be followed for 10 years.

Regarding next steps, the gold standard is always a randomized clinical trial. The issue with randomization in this [context], especially when we’ve already shown such high efficacy and excellent oncologic outcomes [by omitting surgery], is that it would be hard for a patient to accept [being randomly assigned to the surgical arm].

One approach is being pursued in South Korea where they perform a biopsy and follow the patient in a single-arm design. There has also been interest from cooperative groups to potentially conduct this type of study at a national level [in the United States].

What are some of the potential limitations of omitting surgery in clinical practice?

When you have such a success in a small phase 2 trial, the next question, I believe, is to test it in a lot more patients and not necessarily go on to a randomized trial. If we had a lot of patients and a very, very low recurrence for locoregional control in this scenario, that would be enough to change clinical practice, because we [would] know how these patients do when there's no residual disease left.

We need to test this concept using identical techniques with the same eligibility [criteria], and this highly technical, standardized technique must be done that way. We can’t suddenly let's have tumors that are [over] 5 cm, and we will randomly collect 4 or 6 biopsy samples of that area. No, we had success because we had to have the patient's tumor by all imaging abnormalities get down to less than 2 centimeters, and we sampled 12 portions of the tissue. It was accurate, and there were no recurrences.

The next stage is to have several larger phase 2 studies showing that this indeed is safe and effective, which I believe can be done anywhere in the United States, because anywhere where they're doing breast cancer surgery, you need mammograms and ultrasound.

Reference

Kuerer HM, Valero V, Smith BD, et al. Selective elimination of breast surgery for invasive breast cancer: a nonrandomized clinical trial. JAMA Oncol. Published online March 28, 2025. doi:10.1001/jamaoncol.2025.0207