Elsevier

The Lancet Oncology

Volume 23, Issue 12, December 2022, Pages 1517-1524
The Lancet Oncology

Articles
Eliminating breast surgery for invasive breast cancer in exceptional responders to neoadjuvant systemic therapy: a multicentre, single-arm, phase 2 trial

https://doi.org/10.1016/S1470-2045(22)00613-1Get rights and content

Summary

Background

Neoadjuvant systemic therapy (NST) for triple-negative breast cancer and HER2-positive breast cancer yields a pathological complete response in approximately 60% of patients. A pathological complete response to NST predicts an excellent prognosis and can be accurately determined by percutaneous image-guided vacuum-assisted core biopsy (VACB). We evaluated radiotherapy alone, without breast surgery, in patients with early-stage triple-negative breast cancer or HER2-positive breast cancer treated with NST who had an image-guided VACB-determined pathological complete response.

Methods

This multicentre, single-arm, phase 2 trial was done in seven centres in the USA. Women aged 40 years or older who were not pregnant with unicentric cT1–2N0–1M0 triple-negative breast cancer or HER2-positive breast cancer and a residual breast lesion less than 2 cm on imaging after clinically standard NST were eligible for inclusion. Patients had one biopsy (minimum of 12 cores) obtained by 9G image-guided VACB of the tumour bed. If no invasive or in-situ disease was identified, breast surgery was omitted, and patients underwent standard whole-breast radiotherapy (40 Gy in 15 fractions or 50 Gy in 25 fractions) plus a boost (14 Gy in seven fractions). The primary outcome was the biopsy-confirmed ipsilateral breast tumour recurrence rate determined using the Kaplan-Meier method assessed in the per-protocol population. Safety was assessed in all patients who received VACB. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02945579.

Findings

Between March 6, 2017, and Nov 9, 2021, 58 patients consented to participate; however, four (7%) did not meet final inclusion criteria and four (7%) withdrew consent. 50 patients were enrolled and underwent VACB following NST. The median age of the enrolled patients was 62 years (IQR 55–77); 21 (42%) patients had triple-negative breast cancer and 29 (58%) had HER2-positive breast cancer. VACB identified a pathological complete response in 31 patients (62% [95% CI 47·2–75·4). At a median follow-up of 26·4 months (IQR 15·2–39·6), no ipsilateral breast tumour recurrences occurred in these 31 patients. No serious biopsy-related adverse events or treatment-related deaths occurred.

Interpretation

Eliminating breast surgery in highly selected patients with an image-guided VACB-determined pathological complete response following NST is feasible with promising early results; however, additional prospective clinical trials evaluating this approach are needed.

Funding

US National Cancer Institute (National Institutes of Health).

Introduction

In patients with breast cancer, rates of pathological complete response to neoadjuvant systemic therapy (NST) have increased dramatically over the past 25 years.1, 2, 3 In patients with triple-negative breast cancer and HER2-positive breast cancer, rates of pathological complete response to NST have been reported to be approximately 60–80%. This raises the possibility that some patients who receive NST might not require breast and nodal surgery, particularly if they did not receive adjuvant local therapy with radiotherapy.

In 2018, we published the results of a prospective trial showing that image-guided vacuum-assisted core biopsy (VACB) of the primary breast tumour bed following NST can identify patients who are very likely to have had a pathological complete response.4 The requirement that the residual suspicious disease needed to be less than 2 cm on breast imaging after NST allowed for maximal targeted sampling ability. Several other published studies have since tested the hypothesis that image-guided biopsy can accurately identify patients with a pathological complete response. Published rates of false-negative results on VACB for detection of residual disease following NST range from 5% in a study from our group (in which all patients with false-negative findings had only minimal microscopic disease)4 to 40% or more in other studies.5, 6, 7, 8 The success of image-guided VACB is highly dependent on careful selection of appropriate patients and meticulous standardised techniques.8, 9 False-negative rates have been shown to decrease to 0–5% when the procedure is restricted to patients with unicentric triple-negative breast cancer or those with HER2-positive breast cancer and when it is done with the following technical parameters: representative tissue sampling, use of multimodality breast imaging, removal of at least six core biopsy samples, documented clip removal, standardised histopathological processing and examination, and use of larger-gauge (≥9G) VACB needles.6, 8, 10

Research in context

Evidence before this study

We searched PubMed for studies published in English from database inception to Aug 1, 2022, on omission of breast cancer surgery following neoadjuvant systemic therapy (NST). Searches were intentionally broad and included the terms “breast cancer” AND “radiation” AND “neoadjuvant chemotherapy” AND (“surgery” OR “biopsy” OR “complete response” OR “pathologic complete response”). We identified several retrospective and a few prospective single-institution and multi-institutional studies evaluating radiotherapy as the definitive local modality after NST. These studies collectively showed unacceptably high locoregional failure rates. These poor outcomes were due to restricted or no use of rudimentary breast imaging techniques, the inability of breast imaging to accurately identify patients who would have a pathological complete response, and poor of knowledge of the molecular subtypes most likely to be associated with an exceptional response. We have recently shown that image-guided vacuum-assisted core biopsy (VACB) can accurately identify patients likely to have a pathological complete response after NST. Other studies using different eligibility and biopsy techniques have shown less robust performance. One previous retrospective study used core biopsy to select patients who might have a pathological complete response after NST. In that study, which showed a high local failure rate in patients who underwent radiotherapy but not surgery after NST, core needle biopsies were done randomly by non-image-guided biopsy of the breast at the time of axillary surgery following NST. Thus, the overall quality of the previous evidence was moderately low (level 3–4). No data from long-term, prospective studies or modern, randomised trials were found.

Added value of this study

To our knowledge, this study is the first modern, prospective trial of omission of surgery in patients with early-stage breast cancer (triple-negative breast cancer and HER2-positive breast cancer) who are exceptional responders to NST as indicated by state-of-the art breast imaging-guided VACB. Compared with previous trials, this modern trial had improved systemic therapy and selective image-guided VACB with stringent histological processing. The protocol-specified early results of this trial suggest that this new potential treatment approach appears promising.

Implications of all the available evidence

Long-term data to corroborate the early results of this trial, taken together with previous historical results and other results from prospective, single-centre, multi-institutional, and cooperative group trials, are necessary before this novel de-escalated treatment approach can become standard of care in this patient population.

Here, we present results of the first planned prospective outcome analysis of a multicentre, single-arm, phase 2 trial of the elimination of breast surgery in patients with localised HER2-positive breast cancer and triple-negative breast cancer who were presumed to have a pathological complete response on the basis of no evidence of residual tumour following percutaneous image-guided VACB after completion of NST.

Section snippets

Study design and participants

This prospective, multicentre, single-arm, phase 2 trial was done in seven centres in the USA (appendix p 2) and had two phases: a feasibility phase (to assess the study procedures in the first six enrolled patients in the first 6 months of follow-up) and an expansion cohort phase. Women aged 40 years or older who were not pregnant with pathologically confirmed, non-recurrent, unicentric, invasive breast cancer who desired breast-conserving therapy who had received initially planned clinically

Results

Between March 6, 2017, and Nov 9, 2021, 58 patients consented to participate (figure). Four (7%) patients did not meet the eligibility criteria (their final tumours were too large on imaging), and four (7%) patients withdrew consent. Fifty (86%) patients (all women; median age 62 years (IQR 55–77) were enrolled and had protocol-directed image-guided VACB following NST. Breast biopsy was done under stereotactic guidance in 43 (86%) patients and under ultrasound guidance in seven (14%) patients.

Discussion

In this multicentre trial investigating the elimination of the need for breast surgery in patients with a pathological complete response on image-guided VACB of the tumour bed after NST, there were no local-regional or distant recurrences at the first reported planned 2-year analysis, with a median follow-up of 26·4 months. Although early, these results are important because recurrences in patients with triple-negative breast cancer or HER2-positive breast cancer with residual disease after NST

Data sharing

Data collected for this study, including deidentified individual participant data and a data dictionary defining each field in the set, will be made available to others on acceptance of an official request to MD Anderson Cancer Center, Houston, TX, USA, after Institutional Review Board approval for release. The study protocol is available in the appendix of this Article, and other related documents can also be made available to others on request to MD Anderson Cancer Center. The data shall be

Declaration of interests

HMK reports consulting fees from Merck; honorarium from Physicians Education Resources; payment as an Editor from the New England Journal of Medicine Group; royalties from McGraw-Hill Professional and Elsevier Publishing; and leadership role in National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group oncology Clinical Trials Cooperative Group, Breast Cancer Committee, local-regional member. BDS reports salary support from

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  • Cited by (0)

    Members are listed in appendix (p 1)

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