Nodal Burden and Nodal Recurrence in Patients With Isolated Tumor Cells After Neoadjuvant Chemotherapy Treated With Axillary Dissection or Nodal Radiation: the OPBC-05/EUBREAST-14R/ICARO Study (ICARO)

The purposes of this multicenter retrospective cohort study are to determine the residual nodal burden in patients with isolated tumor cells detected in the SLN or the clipped node after NAC and to determine oncologic outcomes in this group of patients after ALND or nodal RT or observation.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Other: Observational study no intervention

Detailed Description

In the context of upfront surgery, the extent of disease in the sentinel lymph nodes (SLNs) significantly predicts the chances of additional non-SLN metastases during axillary lymph node dissection (ALND). For patients with minimal SLN disease (isolated tumor cells [ITCs] and micrometastases), the probability of further non-SLN metastases is between 10-20%. In contrast, for patients with macrometastases, the risk increases to 27-33%.

In patients undergoing neoadjuvant chemotherapy (NAC), those with positive SLNs exhibit a greater residual nodal burden compared to those treated with upfront surgery. For patients with remaining micro- or macrometastases post-NAC, additional positive lymph nodes are found in over 60% of ALND specimens, regardless of receptor subtype. Consequently, ALND remains the standard care for any residual nodal disease after NAC.

Residual ITCs after NAC are present in about 1.5% of all patients undergoing NAC. There is limited data on the likelihood of discovering additional positive lymph nodes in this group, with fewer than 35 documented cases examining residual nodal burden. Therefore, the benefit of ALND for minimal residual disease is uncertain, and axillary management for patients with nodal ITCs is not standardized. Although omitting ALND reduces arm morbidity, identifying residual nodal disease can influence adjuvant therapy recommendations. Despite the lack of consensus on the oncologic safety of omitting ALND in this group, care patterns indicate a growing adoption of this approach. Given the rarity of this clinical scenario and the absence of forthcoming prospective studies, this study utilized real-world data from a large international cohort to determine the incidence of residual non-SLN involvement in patients with ITCs in the SLNs post-NAC, and to compare clinical outcomes in patients with and without ALND as definitive axillary treatment.

• Study Type: Observational
• Enrollment (Actual): 583

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria
    • Medical University of Vienna
• Belgium
  • Ghent, Belgium
    • University Hospital Ghent
• Brazil
  • Brasília, Brazil
    • Sirio-Libanes Hospital, Department of Oncology
  • Curitiba, Brazil
    • Nossa Senhora das Gracias Hospital
  • Goiânia, Brazil
    • Instituto de Mastologia e Oncologia
  • São Paulo, Brazil
    • Santa Paula Hospital
  • São Paulo, Brazil
    • Sirio-Libanes Hospital, Department of Oncology
• Canada
  • Montréal, Canada
    • Mc Gill University
• Germany
  • Augsburg, Germany
    • Universitätsklinikum Augsburg
  • Düsseldorf, Germany
    • University Hospital Düsseldorf
  • Essen, Germany
    • KEM Evang. Kliniken Essen-Mitte
  • Heidelberg, Germany
    • University Hospital Heidelberg
  • Lübeck, Germany
    • University Hospital Schleswig-Holstein Campus Lübeck
  • Neu Isenburg, Germany
    • German Breast Group
• Greece
  • Athens, Greece
    • Athens Medical Center
  • Heraklion, Greece
    • Heraklion University Hospital
• Israel
  • Tel HaShomer, Israel
    • Sheba Medical Center
• Italy
  • Naples, Italy
    • Instituto Nazionale Tumori (IRCCS)
  • Naples, Italy
    • University of Naples Federico
  • Padua, Italy
    • Veneto Institute of Oncology IRCCS
  • Pavia, Italy
    • Istituti Clinici Scientifici Maugeri IRCCS,
  • Rozzano, Italy
    • Irccs Humanitas Research Hospital
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Asan Medical Center
  • Seoul, Korea, Republic of
    • Samsung Medical Center
  • Seoul, Korea, Republic of
    • Gangnam Severance Hospital
• Netherlands
  • Amsterdam, Netherlands
    • Antoni van Leeuwenhoek
• Poland
  • Zielona Góra, Poland
    • University Hospital of Zielona Góra
• Slovenia
  • Ljubljana, Slovenia
    • Institute of Oncology Ljubljana
• Spain
  • Barcelona, Spain
    • Hospital del Mar
• Sweden
  • Gothenburg, Sweden
    • Sahlgrenska University Hospital Gothenburg
• Switzerland
  • Baden, Switzerland
    • Kantonsspital Baden
  • Zürich, Switzerland
    • University Hospital Zurich
  • Zürich, Switzerland
    • Breastcenter Zürich
  • Basel-Stadt
    • Basel, Basel-Stadt, Switzerland, 4031
      • University Hospital Basel
• Turkey
  • Ankara, Turkey
    • Gülhane Research and Training Hospital
  • Istanbul, Turkey
    • Marmara University, School of Medicine
  • Istanbul, Turkey
    • Istanbul University, Faculty of Medicine
  • Istanbul, Turkey
    • Acıbadem Research Instıtute of Senology
  • Istanbul, Turkey
    • Istanbul University Institute of Oncology
  • Zonguldak, Turkey
    • Zonguldak Bülent Ecevit University
• United Kingdom
  • Cambridge, United Kingdom
    • Cambridge University Hospital
  • London, United Kingdom
    • The Royal Marsden Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85008
      • Valleywise Health Medical Center
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center, Samuel Oschin Cancer Institute
  • Florida
    • Miami, Florida, United States, 33136
      • Miami University
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10016
      • NYU Langone Health
    • New York, New York, United States, 10065
      • Weill Cornell Medical Center
    • New York, New York, United States, 10461
      • Montefiore Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
    • Sayre, Pennsylvania, United States, 18840
      • Guthrie Clinic
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas, MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98133
      • University of Washington
    • Seattle, Washington, United States, 98029
      • Swedish Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Consecutive patients will be included. There is no formal sample size calculation

Description

Inclusion Criteria:

• Consecutive patients affected with T1-4 N0-3 breast cancer
• For cN+: Biopsy proven confirmation is required
• For cN0: any axillary staging technique including palpation is allowed
• Residual ITCs in the SLN or clipped node
• At least 1-year follow-up (12/2021 or later depending on the time of data collection)
• For cN0: SLNB with single or dual tracer mapping
• For cN+: SLNB with dual mapping or targeted axillary dissection (TAD: imaging-guided localization of sampled node in combination with SLN procedure with or without dual mapping)
• Underwent TAD/SLNB +/- ALND +/- axillary RT

Exclusion Criteria:

• Male patients
• Patients with nodal pCR
• Patients with residual nodal micro- or macrometastases
• Stage IV disease at presentation
• Inflammatory breast cancer (T4d) at presentation

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Patients with clinical T1-4 N0-3 breast cancer at diagnosis treated with NAC; This cohort study retrospectively analyzed data from 62 centers in 18 countries, mostly members of the Oncoplastic Breast Consortium (OPBC) network. Patients with clinical T1-4 N0-3 breast cancer at diagnosis treated with neoadjuvant chemotherapy between March 2008 and May 2022 were included if they had isolated tumor cells only. ITCs were defined as clusters of tumor cells ≤0.2 mm or clusters of <200 cells in a single cross-sectional image, determined by sentinel lymph node biopsy, targeted axillary dissection, or the MARI procedure (marking axillary lymph nodes with radioactive iodine seeds). Excluded: patients with inflammatory breast cancer, stage IV disease at presentation, axillary lymph node dissection as a primary procedure, and neoadjuvant endocrine therapy. Also excluded cases with micrometastases or macrometastases in any sentinel lymph nodes at frozen section or final pathology, and those where ITCs were detected by One Step Nucleic Acid Amplification.

Other: Observational study no intervention; Observational study no intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Sentinel Lymph Node Biopsy (SLNB)	Evaluation of the number of SLNB performed	one time assessment before surgery
Number Axillary Radiotherapy	Evaluation of the number of axillary radiotherapy performed	Up to 2 years
Axillary recurrence	Evaluation of the number of axillary recurrence	Up to 14 years
Number of Axillary Lymph Node Dissection (ALND)	Evaluation of the number of ALNDs performed	Day 0
Number of Tailored Axillary Dissection (TAD)	Evaluation of the number of TAD performed	Day 0
Number of additional micrometastases	Evaluation of the number of additional micrometastases removed by ALND	Day 0
Number of additional macrometastases	Evaluation of the number of additional macrometastases removed by ALND	Day 0

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regional recurrence	Evaluation of the number of regional recurrence	Up to 14 years
Locoregional recurrence	Evaluation of the number of locoregional recurrence	Up to 14 years
Invasive recurrence	Evaluation of the number of invasive recurrence	Up to 14 years

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Collaborators: Memorial Sloan Kettering Cancer Center
• Investigators: Principal Investigator: Walter P. Weber, MD, University Hospital, Basel, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2023
• Primary Completion (Actual): December 31, 2023
• Study Completion (Actual): December 31, 2024

Study Registration Dates

• First Submitted: June 12, 2024
• First Submitted That Met QC Criteria: June 12, 2024
• First Posted (Actual): June 18, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 16, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Neoadjuvant chemotherapy; Axillary lymph node dissection; Isolated tumor cells
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Recurrence
• Other Study ID Numbers: 2023-00418: bb23Weber

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No