Multiplexed high-throughput immune cell imaging in patients with high-risk triple negative early breast cancer: Analysis from the International Breast Cancer Study Group (IBCSG) Trial 22-00

S Rusakiewicz; S Tyekucheva; S Tissot-Renaud; K Chaba; M Imbimbo; F Benedetti; R Kammler; J Hornfeld; E Munzone; L Gianni; B Thurlimann; I Láng; G Pruneri; K P Gray; M R Regan; S Loi; M Colleoni; G Viale; L Kandalaft; G Coukos; Giuseppe Curigliano

doi:10.1016/j.ejca.2024.113535

Multiplexed high-throughput immune cell imaging in patients with high-risk triple negative early breast cancer: Analysis from the International Breast Cancer Study Group (IBCSG) Trial 22-00

Eur J Cancer. 2024 Mar:200:113535. doi: 10.1016/j.ejca.2024.113535. Epub 2024 Jan 24.

Authors

S Rusakiewicz¹, S Tyekucheva², S Tissot-Renaud¹, K Chaba¹, M Imbimbo³, F Benedetti¹, R Kammler⁴, J Hornfeld¹, E Munzone⁵, L Gianni⁶, B Thurlimann⁷, I Láng⁸, G Pruneri⁹, K P Gray¹⁰, M R Regan¹¹, S Loi¹², M Colleoni¹³, G Viale¹⁴, L Kandalaft¹, G Coukos¹, Giuseppe Curigliano¹⁵

Affiliations

¹ Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland; Center of Experimental Therapeutics, Department of Oncology, University Hospital of Lausanne, 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, Switzerland.
² International Breast Cancer Study Group Statistical Center, Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³ Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
⁴ Translational Research Coordination, International Breast Cancer Study Group, a division of ETOP IBCSG Partners Foundation, Bern, Switzerland.
⁵ Division of Medical Senology, IEO, European Institute of Oncology, IRCCS, Milan, Italy.
⁶ Department of Medical Oncology, Ospedale Infermi, AUSL Della Romagna, Rimini, Italy.
⁷ Kantonsspital St. Gallen, St Gallen, Switzerland; Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland.
⁸ Clinexpert-research, Budapest, Hungary.
⁹ Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; University of Milan, School of Medicine, Milan, Italy.
¹⁰ Division of General Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Biostatistics and Research Design Core, Institutional Centers of Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA.
¹¹ International Breast Cancer Study Group Statistical Center, Division of Biostatistics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
¹² Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Cancer Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; International Breast Cancer Study Group, a division of ETOP IBCSG Partners Foundation, Bern, Switzerland.
¹³ Division of Medical Senology, IEO, European Institute of Oncology, IRCCS, Milan, Italy; Department of Pathology and Laboratory Medicine, IEO, European Institute of Oncology, IRCCS, Milan, Italy.
¹⁴ Division of Medical Senology, IEO, European Institute of Oncology, IRCCS, Milan, Italy; Department of Pathology and Laboratory Medicine, IEO, European Institute of Oncology, IRCCS, Milan, Italy; European Institute of Oncology, IRCCS, Milan, Italy.
¹⁵ European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy. Electronic address: giuseppe.curigliano@ieo.it.

PMID: 38309015
DOI: 10.1016/j.ejca.2024.113535

Abstract

Background: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer (BC) subtype, with dismal prognosis and limited option in advanced settings, yet stromal tumor infiltrating lymphocytes (sTILs) in this subtype has a predictive role.

Patients and methods: The International Breast Cancer Study Group (IBCSG) Trial 22-00 is a randomized phase III clinical trial testing the efficacy of low-dose metronomic oral Cyclophosphamide-Methotrexate (CM) maintenance following standard adjuvant chemotherapy treatment for early-stage hormone receptor-negative breast cancer patients. A case-cohort sampling was used. We characterized immune cells infiltrates in patients with TNBC by 6 plex immunofluorescence (IF) staining for CD4, FOXP3, CD3, cytokeratine and CD8 RESULTS: We confirmed that high immune CD3⁺ T cells as well as stromal and intra-epithelial Tregs (CD4⁺Foxp3⁺ T cells) infiltrates were associated with a better Distant Recurrence-Free Interval (DRFI), especially in LN+ patient, regardless of the treatment. More importantly, we showed that the spatial distribution of immune cells at baseline is crucial, as CM maintenance was detrimental for T cells excluded LN+ TNBC patients.

Conclusions: immune spatial classification on immune cells infiltrates seems crucial and could help patients' selection in clinical trial and greatly improve responses to specific therapies.

Keywords: Multiplexed analysis; Multispectral Imaging; Triple negative breast cancer; Tumor infiltrating lymphocytes.

MeSH terms

Biomarkers, Tumor / analysis
Clinical Trials, Phase III as Topic
Cyclophosphamide
Disease-Free Survival
Female
Forkhead Transcription Factors
Humans
Lymphocytes, Tumor-Infiltrating
Methotrexate
Prognosis
Randomized Controlled Trials as Topic
Triple Negative Breast Neoplasms* / diagnostic imaging
Triple Negative Breast Neoplasms* / drug therapy

Substances

Biomarkers, Tumor
Cyclophosphamide
Forkhead Transcription Factors
Methotrexate