A prospective, randomized trial of sentinel lymph node biopsy versus no additional staging in patients with T1-T2 invasive breast cancer and negative axillary ultrasound

Amy E. Cyr,  M.D.

Project Overview
Sentinel lymph node biopsy (SLNB) is currently the standard of care for staging the axilla in breast cancer. However, SLNB is an invasive surgical procedure and lacks accuracy, failing to detect metastatic spread to the axilla in approximately 10-15% of cases. In addition, it is now known that microscopic spread of breast cancer to the axilla is clinically insignificant, and the current goal of axillary staging has now evolved to detect patients with significant spread of disease. Therefore, SLNB is an imperfect strategy for staging the axilla, and we are convinced that alternative, noninvasive strategies should be considered. In this application we evaluate the potential role of axillary ultrasound (AUS) as a strategy for staging the axilla in breast cancer. Our hypothesis is that AUS represents a viable screening study for the detection of clinically significant disease in the axilla; if the AUS is negative, SLNB can be safely omitted. To test this hypothesis we propose a prospective randomized non-inferiority trial comparing no further axillary staging versus SLNB in women with clinical T1-T2, N0 M0 breast cancer and negative AUS. Support from the Longer Life Foundation will allow us to complete the pilot phase of the trial, and demonstrate feasibility. Unlike most randomized prospective trials in surgery which face difficulty in accrual, we believe that the majority of eligible patients will choose to participate in this trial. After demonstrating feasibility, we will be ideally positioned to compete for peerreviewed research funding. Of note, our study has the potential to dramatically impact current paradigms for axillary staging in breast cancer, and we conservatively estimate that successful validation of AUS as a screening study may obviate the need for SLNB in over 100,000 women per year.

Progress Report:
Specific Aim 1: Evaluate the performance characteristics of AUS in a retrospective study. We identified 654 clinically node-negative breast cancer patients who underwent AUS at WUSM at the time of initial diagnosis. Of these patients, 269 had an abnormal AUS, and of those, 155 (58%) had axillary.

Patients with cT1-2N0 invasive breast cancer undergo AUS. 
Patients with negative AUS are eligible for enrollment and randomization. 
Randomized to no SLNB (Arm 1) Breast surgery followed by indicated adjuvant therapy Standard follow-up with clinical examination and imaging. 
Randomized to SLNB (Arm 2) Breast surgery followed by indicated adjuvant therapy. 
Standard follow-up with clinical examination and imaging disease identified by SLNB.

Three hundred eighty-five patients had a normal AUS. Of those, 61 (16%) were found to have axillary disease on surgical pathology. This data was presented at the 2014 American Society of Breast Surgeons meeting.

We then performed a blinded review of patients as described above. Sixty patients with false-negative AUS were matched with 60 patients with true-negative AUS. Two medical oncologists were blinded to actual treatment completed and made systemic therapy recommendations based on tumor characteristics, treating all patients as lymph node negative. In preliminary statistical analyses, the concordance between actual treatment and blinded review recommendations was similar in both groups.

We are currently in the process of performing subset analyses by intrinsic subtype. However, the preliminary results provide strong evidence that disease in the axilla that cannot be detected by AUS does not appear to have a significant impact upon medical decision-making.

This data also strongly supports our overall hypothesis that AUS is able to detect clinically significant axillary disease.

Specific Aim 2: Complete the pilot phase of a prospective randomized non-inferiority clinical trial comparing no further axillary staging versus SLNB in women with clinical T1-T2 N0 M0 breast cancer and negative AUS. This report is as of seven months into our first year of funding from The Longer Life Foundation. To date we have randomized 28 patients, 14 to each treatment arm. There have been three adverse events, all in the standard of care arm, (Arm 2). These were all known surgical complications, and included wound infection and seroma. There have been no recurrences in either arm. Although the median time to axillary recurrence is only 14.8 months, we do not yet have that length of follow-up. As a surrogate marker of axillary recurrence, we are prospectively monitoring the false negative rate of AUS in Arm 2. Patients in Arm 2 undergo AUS followed by SLNB, and therefore the two procedures can be compared. Of the 14 patients in Arm 2, three had false negative AUS; two patients had clinically insignificant disease (< 2.0 mm). The third patient had a 7 mm focus of disease. Given these small numbers, we have not identified prospectively any predictors of false-negative AUS.