Neoadjuvant pembrolizumab has been approved in combination with chemotherapy for high-risk, early-stage, triple-negative breast cancer, but not all patients with node-positive disease have been able to receive the regimen, according to data presented during the Society of Surgical Oncology 2022 International Conference on Surgical Care.1
“Pembrolizumab has been truly game-changing for patients with high-risk, early-stage, triple-negative breast cancer.”— Elizabeth A. Mittendorf, MD, PhD
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The retrospective analysis of more than 46,000 patients undergoing upfront surgery for early-stage triple-negative breast cancer found that nearly 14% were pathologically node-positive, including more than 10% of clinical T1c tumors and nearly 20% of clinical T2 tumors. Authors of the study noted that a strategy using axillary ultrasound and biopsy at diagnosis to identify nodal disease, as well as routine use in patients with triple-negative-breast-cancer tumors larger than 1 cm with no palpable adenopathy, appears to be effective in newly diagnosed disease.
“Pembrolizumab has been truly game-changing for patients with high-risk, early-stage, triple-negative breast cancer,” said lead author of the study, Elizabeth A. Mittendorf, MD, PhD, Vice Chair for Research in the Department of Surgery at the Brigham and Women’s Hospital and Director of the Breast Immuno-Oncology Program at the Dana-Farber/Brigham Cancer Center, Boston. “Given the benefits, every effort should be made to identify patients who are candidates to receive preoperative pembrolizumab plus chemotherapy.”
As Dr. Mittendorf reported, the results of the phase III KEYNOTE-522 trial showed improved pathologic complete response and event free-survival in patients with early-stage, triple-negative breast cancer who received preoperative pembrolizumab with chemotherapy.2 After a median follow-up of 39 months, the 3-year event-free survival was 84.5% among patients receiving pembrolizumab vs 76.8% for patients receiving placebo. However, these oncologic benefits come at the cost of some treatment-related adverse events, according to Dr. Mittendorf, who noted that approximately 10% to 15% of immune-related adverse events may be permanent.
“Due to potential toxicities with immunotherapy, clinicians must consider how to incorporate pembrolizumab into multidisciplinary treatment planning,” she explained.
According to Dr. Mittendorf, there is consensus that “the addition of immunotherapy to neoadjuvant chemotherapy should be recommended in most patients with node-positive triple-negative breast cancer” given the higher risk of recurrence. Patients with triple-negative breast cancer who present with clinical T1c N0 disease, however, did not meet eligibility criteria for the -KEYNOTE-522 trial.
“We know from data presented at the San Antonio Breast Cancer Symposium by Dr. Peter Schmid that all patients benefit from pembrolizumab with respect to event-free survival regardless of clinical nodal status,” said Dr. Mittendorf.
For this study, Dr. Mittendorf and colleagues sought to determine nodal positivity rates in patients with triple-negative breast cancer who present with clinical T1–2 N0 disease. The researchers also studied the utility of axillary ultrasound in identifying nodal disease in patients with clinical T1–T2 cancer with a negative clinical axillary exam, which was defined as no palpable adenopathy.
Patients with clinical T1–T2 N0 triple-negative breast cancer who underwent upfront surgery were identified from the National Cancer Database (2010–2017) and the Dana-Farber/Brigham Cancer Center database (2016–2021).
Axillary Ultrasound Effective in Identifying Nodal Disease
In the Dana-Farber cohort, researchers identified 343 patients with clinical T1–T2 N0 triple-negative breast cancer who underwent surgery. Of these patients, 50 (14.6%) had pathologically node-positive disease, including 15% of patients with clinical T1c tumors, who did not meet the eligibility criteria for the KEYNOTE-522 trial, said Dr. Mittendorf.
In the National Cancer Database cohort, researchers identified 46,015 patients with clinical T1 and T2 triple-negative breast cancer undergoing upfront surgery. Of these patients, 6,304 (13.7%) had pathologically node-positive disease, including 4.9% for clinical T1a/b tumors, 11.4% for clinical T1c tumors, and 19.7% for clinical T2 tumors.
“The clinical positivity rate in patients with T2 N0 tumors, combined with the event-free survival benefit shown in the trial, gives further support to administering -pembrolizumab to all [patients with] clinical T2 N0 triple-negative breast cancer,” Dr. Mittendorf commented.
With respect to the utility of axillary ultrasound, researchers analyzed an unselected cohort of 499 patients with triple-negative breast cancer who presented with clinical T1–T2 tumors and no palpable adenopathy at Dana-Farber. Ultrasound was performed in 34.1% of patients.
Among patients with T1c tumors and no palpable adenopathy, 7.5% were found to have node-positive disease with axillary ultrasound, confirmed by fine-needle aspiration or core biopsy. Among those with T2 tumors, 30.0% were found to have node-positive disease.
Finally, researchers analyzed a cohort of patients whose tumors were clinical T1–T2 and who were scheduled to undergo neoadjuvant chemotherapy (n = 48). Among those with T1c tumors (n = 19), 15.8% had abnormal nodes on ultrasound, and 33.3% tested positive with fine-needle aspiration or core biopsy. Therefore, in this group with T1c tumors, 5.3% of patients were found to have node-positive disease. In the T2 group (n = 29), 34.5% of patients had abnormal nodes with ultrasound, and 50.0% of those were positive via fine-needle aspiration or core biopsy.
“Based on these findings, we believe that axillary ultrasound and potential biopsy of any suspicious nodes should be performed at the time of diagnosis, as it may identify patients with nodal disease who should be considered for the use of preoperative pembrolizumab,” said Dr. Mittendorf.
DISCLOSURE: Dr. Mittendorf has reported financial relationships with Exact Sciences/Genomic Health, Genentech/Roche, and Merck.
1. Mittendorf EA, Weiss A, Kantor O, et al. Nodal positivity in early stage TNBC: Implications for preoperative immunotherapy. 2022 Society of Surgical Oncology Annual Meeting. Abstract 13. Presented March 14, 2022.
2. Schmid P, Cortes J, Dent R, et al. VP7-2021: KEYNOTE-522: Phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy as neoadjuvant treatment, followed by pembrolizumab vs placebo as adjuvant treatment for early-stage triple-negative breast cancer. ESMO Congress Virtual Plenary Debate. Presented September 1, 2021.
Julie A. Margenthaler, MD, FACS
Julie A. Margenthaler, MD, FACS, Professor of Surgery at Washington University School of Medicine, St. Louis, told The ASCO Post that routine clinical examination may not be enough to properly identify lymph node involvement in patients with triple-negative...