5-Year Phase 2 Data Show 0% Recurrence Rate After Surgery Omission in Select Patients With Invasive Breast Cancer

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The omission of surgery following neoadjuvant systemic therapy proved feasible in patients with invasive HER2-positive breast cancer and invasive triple-negative breast cancer (TNBC), according to findings from a nonrandomized phase 2 trial (NCT02945579), which showed that the 5-year recurrence rate was 0%.

Data published in JAMA Oncology demonstrated that at a median follow-up of 55.4 months (interquartile range, 44.0-63.5), the 5-year ipsilateral breast tumor recurrence (IBTR) rate was 0% among evaluable patients who did not undergo surgery and received whole breast radiation alone (n = 31). The 5-year disease-free survival (DFS) and overall survival (OS) rates in this population were both 100%.

“Radiotherapy alone without breast surgery produced excellent oncologic and patient-reported outcomes in highly selected patients with an image-guided, vacuum-assisted biopsy (VAB)–determined pathological complete response [pCR] after neoadjuvant systemic therapy in this inaugural trial in the field,” lead study author Henry M. Kuerer, MD, PhD, and colleagues wrote in the publication.

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

“These findings are promising, as potential missed disease without surgery in such patients would be expected to generally recur early,” Kuerer and colleagues added.

Study Overview and Rationale

Surgical resection has long been the standard of care for patients with nonmetastatic invasive breast cancer; however, the emergence and efficacy of neoadjuvant systemic therapy have called into question the need for surgery in select patients.

“Approximately 60% of patients with TNBC and HER2-positive breast cancer who are treated with neoadjuvant systemic therapy have a pCR, which indicates an excellent long-term prognosis,” study authors wrote.

The phase 2 trial was launched to assess the feasibility of omitting surgery and using radiotherapy alone in patients who achieved a VAB-determined pCR. Investigators enrolled patients at least 40 years of age with pathologically confirmed, nonrecurrent, unicentric invasive HER2-positive breast cancer or TNBC who received neoadjuvant systemic therapy with a non-immunotherapy regimen.

If patients did not have invasive or in situ disease detected on a VAB following neoadjuvant systemic therapy, they did not proceed to surgery, whereas those with residual disease underwent standard breast and nodal surgery. Notably, patients with nodal disease at baseline who achieved a pCR with neoadjuvant therapy could omit surgery if they underwent targeted axillary dissection and had no residual nodal disease. Axillary surgery was not performed in the remainder of the population.

Standard-of-care whole-breast radiation was administered to all patients at 40.05 Gy in 15 fractions. The inclusion of the lower axilla during radiotherapy was optional.

IBTR served as the trial’s primary end point. Secondary end points included DFS; OS; the presence of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) at baseline pCR, 6 months, and 12 months; the proportion of patients recommended for image-guided biopsy during follow-up; and patient-reported outcomes (PROs).

Investigators screened 58 patients and ultimately enrolled 50 women who received a protocol-directed, image-guided biopsy following neoadjuvant therapy. Of these 50 patients, 19 did not achieve a pCR; these patients underwent standard therapy and were included in the trial’s safety analysis. Thirty-one patients experienced a pCR with neoadjuvant therapy and underwent radiation without surgery.

In the overall population, the median age at baseline was 62 years (range, 55-77). Forty-two percent of patients had TNBC, and 58% had HER2-positive breast cancer. More specifically, 36% of patients had HER2-positive, hormone receptor (HR)–positive disease, and 22% had HER2-positive, HR-negative disease. Tumor stage at baseline comprised T1 (50%), T2 (50%), and N1 (18%).

Following neoadjuvant therapy, the mean final tumor size on imaging was 0.90 cm (standard deviation, 0.81). The complete radiologic response rate was 34% (n = 17; 95% CI, 21.2%-48.8%). Based on VAB results, the pCR rate was 62% (95% CI, 47.2%-75.4%). Eight patients who had nodal disease at baseline and experienced a VAB-determined pCR underwent targeted axillary dissection with no residual nodal disease detected.

ctDNA, PRO, and Safety Data

Thirteen patients who achieved a pCR had a total of 33 blood samples collected at baseline, 6 months, and 12 months. CTCs were detected in 2 patients at baseline, 2 patients at 6 months, and 1 patient at 12 months; however, no patients had CTCs detected at more than 1 time point.

Additionally, ctDNA was evaluated in 30 plasma samples from 12 patients gathered at baseline, 6 months, and 12 months. TP53 ctDNA was identified in 2 patients at baseline; this persisted at 6 and 12 months in 1 of these patients. Notably, no patients had both CTCs and ctDNA detected.

“The detection of CTCs or ctDNA could not be correlated with outcomes, as no patients with a breast pCR had a cancer recurrence,” study authors explained.

Regarding PROs, patients’ comfort with enrolling in the trial and omitting surgery was high at baseline and improved over time. The mean baseline Decisional Regret Scale score was 15.2 (SD, 15.9) on a scale of 100. This score lowered to 2.5 (SD, 3.8) at 5 years.

At baseline, the mean FACT-B+4 composite score was 120.7 (SD, 14.9) on a 148-point scale vs 126.7 (SD, 10.6) at 5 years (P = .04). The baseline mean overall Breast Cancer Treatment Outcome Scale score was 1.1 (SD, 0.1).

Changes in breast perception over time were primarily attributable to cosmesis changes. Subscores at 5 years showed an increase in asymmetry at 1.8 (SD, 0.6) compared with 1.1 (SD, 0.2) at baseline (P < .001). However, no long-term differences were reported in breast function, pain, or edema.

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