General Session 2

T. Kühn¹, M. Banys-Paluchowski², N. Ditsch³, E. Stickeler⁴, M. Hauptmann⁵, J. Schroth⁵, G. Karadeniz Cakmak⁶, M. Hahn⁷, M. Thill⁸, T. Reimer⁹, S. Fröhlich¹⁰, E. Schmidt¹⁰, M. Lux¹¹, H. Kolberg¹², I. Rubio¹³, M. Gasparri¹⁴, M. Kontos¹⁵, E. Bonci¹⁶, L. Niinikoski¹⁷, D. Murawa¹⁸, D. Pinto¹⁹, F. Peintinger²⁰, E. Schlichting²¹, H. Nina²², H. Valiyeva²³, M. Vanhoeij²⁴, L. Rebaza²⁵, B. Aktas Sezen²⁶, K. Jursik²⁷, G. Kadayaprath²⁸, L. Dostalek²⁹, A. Kothari³⁰, A. Perhavec³¹, T. Ivanov³², D. Zippel³³, S. Thongvitokomarn³⁴, B. Adamczyk³⁵, M. Gurleyik³⁶, D. Watermann³⁷, M. Porpiglia³⁸, S. Grasshoff³⁹, S. Loibl⁴⁰, D. Krug⁴¹, A. Lebeau⁴², R. Di Micco⁴³, O. Gentilini⁴⁴, J. de Boniface⁴⁵, S. Hartmann⁴⁶, AXSANA study group; ¹Breast Cancer Center / Department of Gynecology and Obstetrics, Die Filderklinik gGmbH / University of Ulm, Ulm, GERMANY, ²Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, GERMANY, ³Department of Gynecology and Obstetrics, University Hospital Augsburg, Augsburg, GERMANY, ⁴Clinic for Gynecology and Obstetrics, University Hospital RWTH Aachen, Aachen, GERMANY, ⁵Institute for Biometrics and Registry Research, Medizinische Hochschule Brandenburg, Neuruppin, GERMANY, ⁶General Surgery Department, Breast and Endocrine Unit, Zonguldak BEUN The School of Medicine, Zonguldak, TURKEY, ⁷Department for Women’s Health, University of Tübingen, Tübingen, GERMANY, ⁸Clinic for Gynecology and Gynecologic Oncology, AGAPLESION Markus Krankenhaus, Frankfurt am Main, GERMANY, ⁹Gynecologic oncology, Klinikum Südstadt Rostock, Rostock, GERMANY, ¹⁰Gynecology unit, Klinikum Südstadt Rostock, Rostock, GERMANY, ¹¹Department of Gynecology and Obstetrics, St. Louise Frauen- und Kinderklinik, St. Vincenz Krankenhaus, Paderborn, GERMANY, ¹²Clinic for Gynecology, Obstetrics, Senology and Gynecologic Oncology, Marienhospital Bottrop, Bottrop, GERMANY, ¹³Breast Surgical Unit, Clinica Universidad de Navarra, Madrid, SPAIN, ¹⁴Department of Gynecology and Obstetrics / Faculty of Biomedicine, Ente Ospedaliero Cantonale, Ospedale Regionale di Lugano / University of the Italian Switzerland (USI), Lugano, SWITZERLAND, ¹⁵Department of Surgery, Laiko Hospital, National and Kapodistrian University of Athens, Athens, GREECE, ¹⁶Department of Surgical Oncology / Department of Oncological Surgery and Gynecological Oncology, ”Prof. Dr. Ion Chiricuță” Institute of Oncology / “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, ROMANIA, ¹⁷Breast Surgery Unit, Comprehensive Cancer Center, Helsinki University Hospital, University of Helsinki, Helsinki, FINLAND, ¹⁸Surgery and Oncology Collegium Medicum / Department of General Surgery and Surgical Oncology, University of Zielona Góra / The Regional Hospital in Poznan – The Greater Poland Specialist Center, Zielona Gora / Poznan, POLAND, ¹⁹Breast Unit, Champalimaud Clinical Center, Champalimaud Foundation, Lisboa, PORTUGAL, ²⁰Department of Gynecology and Obstetrics / Institute of Pathology, Medical University of Graz / Medical University of Graz, Graz, AUSTRIA, ²¹Department for Breast and Endocrine Surgery, Oslo University Hospital, Oslo, GERMANY, ²²Department of Surgery, Oncology Hospital, Tirana, ALBANIA, ²³Breast Cancer Center / Department of Gynecology and Obstetrics, Oncologig Clinic of Azerbaijan Medical University, Baku, AZERBAIJAN, ²⁴Breast Unit, Universitair Ziekenhuis Brussel, Brussel, BELGIUM, ²⁵Breast Surgery, Oncosalud, San Borja – Lima, PERU, ²⁶EUBREAST e.V., EUBREAST e.V. / MSD Sharp & Dohme GmbH, Esslingen / Munich, GERMANY, ²⁷EUBREAST GmbH, EUBREAST GmbH, Gladenbach, GERMANY, ²⁸Medical and diagnostic research centre, MAX Hospital, Patparganj, New Delhi, INDIA, ²⁹35 Gynecologic Oncology Center, Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University, General University Hospital, Prague, CZECH REPUBLIC, ³⁰Breast Cancer Unit, Guy’s & St Thomas NHS Foundation Trust, London, UNITED KINGDOM, ³¹Center for Breast Diseases, Institute of Oncology Ljubljana, Ljubljana, SLOVENIA, ³²Breast Cancer Center / Department of Gynecology and Obstetrics, Heart and Brain Hospital, Pleven, BULGARIA, ³³Surgical Oncology Unit, Chaim Sheba Medical Centre, Tel Aviv, ISRAEL, ³⁴Queen Sirikit Centre for Breast Cancer, King Chulalongkorn Memorial Hospital, Bangkok, THAILAND, ³⁵Breast Cancer Unit, Greater Poland Cancer Centre, Poznan, POLAND, ³⁶Department of General Surgery, Istanbul Haydarpasa Numune Training and Research Hospital, University of Health Sciences Turkey, Istanbul, TURKEY, ³⁷Department of Gynecology and Obstetrics, Ev. Diakoniekrankenhaus, Freiburg, GERMANY, ³⁸Department of Gynecology and Obstetrics, Breast Unit S. Anna Hospital, Torino, ITALY, ³⁹Department of Gynecology and Obstetrics, Harzklinikum Dorothea Christiane Erxleben, Quedlinburg, GERMANY, ⁴⁰GBG Forschungs GmbH, GBG Forschungs GmbH, Neu-Isenburg, GERMANY, ⁴¹University Hospital Hamburg-Eppendorf, Department of Radiotherapy and Radiooncology, Hamburg, GERMANY, ⁴²Institute of Pathology / Private Group Practice for Pathology, University Hamburg-Eppendorf, Hamburg / Lübeck, GERMANY, ⁴³Breast Surgery Unit, IRCCS Ospedale San Raffaele, Milan, ITALY, ⁴⁴Breast Surgery Unit, IRCCS Ospedale San Raffaele / Vita-Salute San Raffaele University, Milan, ITALY, ⁴⁵Department of Surgery, Breast Center / Department of Medical Epidemiology and Biostatistics, Capio St. Göran’s Hospital / Karolinska Institutet, Stockholm, SWEDEN, ⁴⁶Department of Gynecology and Obstetrics, University Hospital Rostock, Rostock, GERMANY.

Introduction In breast cancer patients converting from clinically positive (cN+) to negative (ycN0) lymph node status after neoadjuvant chemotherapy (NACT), surgical staging by axillary lymph node dissection (ALND) is increasingly replaced by less invasive procedures like targeted axillary dissection (TAD) or sentinel lymph node biopsy (SLNB), possibly followed by completion ALND or regional radiotherapy if positive. Prospective data comparing oncologic safety of different procedures as a primary approach after NACT are currently scarce. We report 3-year axillary recurrence-free survival (ARFS) as the first primary endpoint analysis of the AXSANA/EUBREAST 3(R) study (NCT04373655, www.eubreast.org/axsana), initiated by the European Breast Cancer Research Association of Surgical Trialists (EUBREAST e.V.). Methods In an international multicenter cohort study, patients with cN+ breast cancer who receive at least four cycles of NACT and convert to ycN0 are eligible. Axillary staging after NACT is performed according to institutional routine. Grouping of patients was based on the primary staging procedure, not on final axillary surgery, e.g., completion ALND following a positive SLNB was classified as SLNB. Co-primary endpoints are ARFS, invasive breast cancer-specific survival (iBCSS), and patient-reported quality of life. Data entry is systematically monitored. Less extensive axillary staging procedures as first surgery after NACT (TAD, SLNB, targeted lymph node biopsy (TLNB)) are considered non-inferior to staging by ALND if the lower bound of a two-sided 90% confidence interval (CI) around 3-year ARFS exceeds 97%. 750 patients were required per group (TAD/SLNB/TLNB vs ALND). Results From June 2020 to April 2025, 6,474 patients (26 countries, 288 study sites) were enrolled, 2,632 of whom had completed surgery by December 31, 2023 and were selected for analysis. Primary staging procedure was ALND in 799 patients (30.4%) and less invasive procedures (419 SLNB, 1399 TAD, 15 TLNB) in 1,833 (69.6%). Nodal complete pathological response was reported in 1,345 patients (51.1%): 423 (31.4%) after ALND and 922 (68.6%) after TAD/SLNB/TLNB. 2489 patients (94.6%) received post-NACT nodal radiotherapy: 759 (95.0%) after ALND and 1730 (94.4%) after TAD/SLNB/TLNB. After a median follow-up of 2.0 years (range, 0.01-4.5), 15 axillary recurrences occurred after TAD/SLNB/TLNB and 4 after ALND (4.2 vs 2.5 events/1000 person-years, p=0.351). 3-year ARFS was 99.2% (95% CI 98.2-100.0) after ALND and 98.8% (95% CI 98.1-99.5) after TAD/SLNB/TLNB. For TAD/SLNB/TLNB, the lower bound of a 90% CI was 98.2%. After SLNB, 1 axillary recurrence occurred and 14 after TAD (1.2 vs 5.1 events/1000 person-years, p=0.132). Results were similar upon controlling for clinicopathological risk factors and neoadjuvant treatment or exclusion of 143 patients without radiotherapy. iBCSS at 3 years was 85.7% (95% CI 82.6-89.0) for ALND and 88.2% (95% CI 86.0-90.3) for TAD/SLNB/TLNB. Conclusion In patients who convert from clinically node-positive to node-negative breast cancer, the AXSANA study showed that less invasive surgical staging procedures are associated with a low axillary recurrence rate, not inferior to ALND after 3 years, regardless of initial tumor stage or subtype. These findings reinforce efforts to minimize surgical morbidity without compromising oncologic outcomes.

T. Reimer¹, A. Stachs¹, K. Veselinovic², T. Kühn³, J. Heil⁴, S. Polata⁵, F. Marmé⁶, E. K. Trapp⁷, T. Müller⁸, G. Hildebrandt⁹, D. Krug¹⁰, B. Ataseven¹¹, R. Reitsamer¹², S. Ruth¹³, H. Strittmatter¹⁴, C. Denkert¹⁵, I. Bekes¹⁶, N. Stahl¹⁷, D. Zahm¹⁸, M. Thill¹⁹, M. Golatta⁴, J. Holtschmidt²⁰, M. Knauer²¹, V. Nekljudova²⁰, S. Loibl²², B. Gerber¹; ¹Department of Obstetrics and Gynecology, University of Rostock, Rostock, GERMANY, ²Department of Obstetrics and Gynecology, University of Ulm, Ulm, GERMANY, ³Department of Obstetrics and Gynecology, University Hospital Ulm, The Filderhospital, Filderstadt-Bonlanden, GERMANY, ⁴Department of Gynecology and Obstetrics, University of Heidelberg, Breast Center, St. Elisabeth Hospital, Heidelberg, GERMANY, ⁵Department of Obstetrics and Gynecology, Evangelical Forest Hospital Spandau, Berlin, GERMANY, ⁶Faculty of Medicine Mannheim, University Heidelberg, Mannheim, GERMANY, ⁷Department of Obstetrics and Gynecology, University Hospital Graz, Graz, AUSTRIA, ⁸Department of Obstetrics and Gynecology, Hanau City Hospital GmbH, Hanau, GERMANY, ⁹Department of Radiotherapy and Radiation Oncology, University Medicine Rostock, Rostock, GERMANY, ¹⁰Department of Radiotherapy and Radiation Oncology, University Hospital Hamburg-Eppendorf (UKE), Hamburg, GERMANY, ¹¹Department of Obstetrics and Gynecology, University of Bielefeld, Klinikum Lippe, Detmold, GERMANY, ¹²Department of Senology, University Hospital Salzburg, Salzburg, GERMANY, ¹³Department of Obstetrics and Gynecology, Johanniter-Hospital Genthin-Stendal, Stendal, GERMANY, ¹⁴Department of Obstetrics and Gynecology, Rems-Murr-Hospital, Winnenden, GERMANY, ¹⁵Institute of Pathology, Philipps-University Marburg and University Hospital Marburg (UKGM), Marburg, GERMANY, ¹⁶Department of Obstetrics and Gynecology, University Hospital Ulm, Germany, Breast center, HOCH Health Ostschweiz, Kantonsspital St. Gallen, Universitäres Lehr- und Forschungsspital, St. Gallen, SWITZERLAND, ¹⁷Breast Unit, Helios Clinic Schwerin, Schwerin, GERMANY, ¹⁸Department of Obstetrics and Gynecology, SRH Wald-Klinikum Gera GmbH, Gera, GERMANY, ¹⁹Department of Gynecology and Gynecological Oncology, Agaplesion Markus Hospital, Frankfurt am Main, GERMANY, ²⁰Medicine and Research Departement, GBG c/o GBG Forschungs GmbH, Neu-Isenburg, GERMANY, ²¹Breast Center, Tumor and Breast Center Eastern Switzerland, St. Gallen, SWITZERLAND, ²²Medicine and Research Departement, GBG c/o GBG Forschungs GmbH, Neu Isenburg, Goethe University Frankfurt, Frankfurt am Main, GERMANY.

Background: Axillary nodal status is an important prognostic factor in early breast cancer (eBC), guiding systemic treatment and postoperative radiotherapy. As axillary surgery does not significantly affect BC mortality itself, it is considered as a staging procedure in clinically node-negative (cN0) patients (pts). The Intergroup-Sentinel-Mamma (INSEMA) trial investigated the avoidance of sentinel lymph node biopsy (SLNB) in cN0 pts (Rando1) or the omission of completion axillary lymph node dissection (cALND) in pN1a(sn) pts (Rando2). The analysis of the first randomization demonstrated non-inferiority of omitting SLNB in cN0 patients undergoing breast-conserving surgery (BCS) concerning invasive disease-free survival (iDFS), meeting the trial’s primary endpoint. Here we report the analysis of the second randomization. Study Design: The INSEMA trial was conducted between 2015 and 2019 in Germany and Austria. The first randomization of this prospective trial compared no axillary surgery with SLNB in pts with invasive eBC (tumor size ≤ 5 cm; c/iN0) scheduled for BCS, including postoperative whole-breast irradiation (WBI). This randomization was carried out in a 4:1 allocation (SLNB vs. no SLNB). Pts with 1-3 macrometastases in the SLNB arm underwent a second randomization in a 1:1 ratio, to either SLNB alone or cALND. The aim was to assess whether SLNB alone is non-inferior to cALND in terms of iDFS. The analysis of Rando2 was based on the per-protocol (PP) set. Due to fewer SLNB-positive patients than expected, the iDFS analysis for the second randomization was downgraded from a co-primary to a key secondary outcome following protocol amendment #5 (December 2018). The non-inferiority margin was defined as 5-year iDFS > 76.5% (hazard ratio (HR) < 1.271) for SLNB alone, compared to an expected 5-year iDFS of 81% for the cALND arm. Results: 485 pts were recruited for Rando2 (intention-to-treat (ITT) set: N=243 with cALND vs. N=242 with SLNB alone). After excluding 99 pts (mainly due to axillary surgery performed not per randomized arm), 386 pts (cALND: N=169, SLNB alone: N=217) were included in the PP set. The median follow-up (FU) is 74.2 months. The cALND cohort is characterized by higher rates for postoperative chemotherapy (39.8% vs. 33.6%, p=0.239), conventionally fractionated WBI (87.0% vs. 75.1%, p=0.004), tumor bed boost (88.8% vs. 80.6%, p=0.035), and regional nodal irradiation (36.0% vs. 20.6%, p=0.019) compared to the SLNB alone cohort. Analysis in the PP set was unable to demonstrate non-inferiority for SLNB alone compared to cALND, with an HR of 1.69 (95% CI: 0.98-2.94). Estimated 5-year iDFS rates are 86.6% (81.0%-90.7%) in the SLNB alone arm and 93.8% (88.7%-96.6%) in the cALND arm (log-rank p=0.058). Estimated 5-year overall survival (OS) rates are 94.9% (90.6%-97.2%) in the SLNB alone arm and 96.2% (91.7%-98.3%) in the cALND arm (log-rank p=0.663). Among the ITT set, there was also no difference in iDFS between the arms, with an HR of 1.26 (0.80-1.99) for SLNB alone compared to cALND. Estimated 5-year iDFS rates (ITT set) are 86.0% (80.6%-90.0%) with SLNB alone and 89.3% (84.3%-92.8%) with cALND, respectively (log-rank p=0.314). Locoregional recurrences (LRR) were infrequent, with 5-year cumulative incidence rates of 1.1% vs. 0.0% (p=0.405) in the SLNB alone arm compared to cALND. The safety analysis demonstrates that patients who underwent SLNB alone benefited in terms of lymphedema rate, arm mobility, and reduced arm and shoulder pain. Conclusion: No significant differences were observed between SLNB alone vs. cALND in both subsets (PP, ITT) for iDFS, OS, and LRR. These findings after a 6-year FU are representative of cN0 pts with positive SLNB and BCS; the 10-year FU data will be presented in 2029.

G. Hildebrandt¹, A. Stachs², K. Veselinovic³, T. Kuehn⁴, J. Heil⁵, S. Polata⁶, F. Marmé⁷, D. Zierhut⁸, D. Krug⁹, B. Ataseven¹⁰, R. Reitsamer¹¹, S. Ruth¹², C. Denkert¹³, J. Kaiser¹⁴, I. Bekes¹⁵, D. Zahm¹⁶, M. Thill¹⁷, M. Golatta⁵, J. Holtschmidt¹⁸, M. Knauer¹⁹, V. Nekljudova¹⁸, S. Loibl²⁰, B. Gerber², T. Reimer²; ¹Department of Radiotherapy and Radiation Oncology, University Medicine Rostock, Rostock, GERMANY, ²Department of Obstetrics and Gynecology, University of Rostock, Rostock, GERMANY, ³Department of Obstetrics and Gynecology, University Hospital Ulm, Ulm, GERMANY, ⁴Department of Obstetrics and Gynecology, University Hospital Ulm, The Filderhospital, Filderstadt-Bonlanden, GERMANY, ⁵Department of Gynecology and Obstetrics, University of Heidelberg, Breast Center, St. Elisabeth Hospital, Heidelberg, GERMANY, ⁶Department of Internal Medicine, Hematology and Oncology, Evangelical Forest Hospital Spandau, Berlin, GERMANY, ⁷Department of Obstetrics and Gynecology, Faculty of Medicine Mannheim, University Heidelberg, Mannheim, GERMANY, ⁸Department of Radiotherapy, Hanau City Hospital, Hanau, GERMANY, ⁹Department of Radiotherapy and Radiation Oncology, University Hospital Hamburg-Eppendorf (UKE), Hamburg, GERMANY, ¹⁰Department of Obstetrics and Gynecology, University of Bielefeld, Klinikum Lippe, Detmold, GERMANY, ¹¹Department of Senology, University Hospital Salzburg, Salzburg, AUSTRIA, ¹²Department of Obstetrics and Gynecology, Johanniter-Hospital Genthin-Stendal, Stendal, GERMANY, ¹³Institute of Pathology, Philipps-University Marburg and University Hospital Marburg (UKGM), Marburg, GERMANY, ¹⁴Department of Radiotherapy, Salzburg University Hospital – Salzburger Landeskliniken, Paracelsus Medical University, Salzburg, AUSTRIA, ¹⁵Department of Obstetrics and Gynecology, University Hospital Ulm, Breast center, HOCH Health Ostschweiz, Kantonsspital St. Gallen, Universitäres Lehr- und Forschungsspital, St. Gallen, SWITZERLAND, ¹⁶Department of Obstetrics and Gynecology, SRH Wald-Klinikum Gera GmbH, Gera, GERMANY, ¹⁷Department of Gynecology and Gynecological Oncology, Agaplesion Markus Hospital, Frankfurt am Main, GERMANY, ¹⁸Medicine and Research Departement, GBG c/o GBG Forschungs GmbH, Neu-Isenburg, GERMANY, ¹⁹Breast Center, Tumor and Breast Center Eastern Switzerland, St. Gallen, SWITZERLAND, ²⁰Medicine and Research Departement, GBG c/o GBG Forschungs GmbH, Goethe University Frankfurt, Frankfurt am Main, GERMANY.

Background: The de-escalation of axillary surgery during breast-conserving surgery (BCS) must be considered alongside radiotherapy to accurately interpret oncological outcomes. The INSEMA trial demonstrated that omitting axillary sentinel lymph node biopsy (SLNB) in clinically node-negative early breast cancer (BC) patients (pts) undergoing BCS is oncologically safe regarding 5-year invasive disease-free survival (iDFS). Analysis from other de-escalation trials (ACOSOG Z0011, SENOMAC) revealed that a significant percentage of pts received regional nodal irradiation (RNI). INSEMA documented dose distribution in ipsilateral axillary levels I-III and captured RNI. This study investigates how pts parameters, surgical axillary extent, and radiation techniques affect ipsilateral axillary dose distribution. Material and methods: INSEMA (NCT02466737), a surgical trial on SLNB omission in early invasive BC and BCS, randomized 5502 pts between September 2015 and April 2019 in Germany and Austria. The protocol mandated whole-breast irradiation (WBI) while RNI was only permitted in patients with 4 or more involved lymph nodes. This pre-planned secondary analysis includes 5154 pts from 108 radiotherapy (RT) facilities. Contouring of the ipsilateral axilla (level I-III) followed the Radiation Therapy Oncology Group consensus definitions. Dose parameters are presented as relative doses (in % of the prescribed breast dose) to avoid different absolute doses between conventionally and hypofractionated cases. Results: Of 5154 pts, 4890 (95.7%) received postoperative WBI per INSEMA protocol. The majority of pts (N=2800, 58.0%) were treated with 3D-conformal RT-technique using standard tangential fields, other pts received various modern intensity-modulated radiotherapy techniques. Deep inspiration breath-hold was used in 102 pts (2.1%). Conventional fractionation was more common (N=3163, 66.0%) than moderate hypofractionation (N=1630, 34.0%). A tumor bed boost was applied in 3807 pts (74.9%), delivered either simultaneously (N=1973, 52.6%) or sequentially (N=1781, 47.4%); 257 pts (6.8%) received an intraoperative boost irradiation. No differences were observed between randomized groups regarding the technique used, fractionation schedule, and boost application. Median and average dose for each axillary level differed significantly between arms with higher median doses in the SLNB arm compared to the no SLNB arm for level I (91.4% vs. 86.3%; p<0.001), level II (37.8% vs. 24.3%; p 50% of patients, level I unintentionally received a median dose of ≥ 85% of the prescribed breast dose. RNI including supra-/infraclavicular and/or parasternal nodes was performed in N=87, 4.0% of pts with SLNB versus a rate of N=5, 0.9% for no SLNB pts (p<0.001). Among 264 pts without postoperative RT, iDFS did not differ significantly between arms (hazard ratio for no SLNB to SLNB = 1.43 [95% CI: 0.75-2.72], p=0.28). Conclusions: Approximately 50% of all INSEMA pts received a potentially therapeutic dose in level I. A higher incidental axillary dose and an increased use of RNI were observed in the SLNB arm compared to no SLNB pts. In the no SLNB-arm, RNI was applied in < 1% of patients.

M. Carausu¹, A. De Caluwé², D. Gacquer¹, D. Venet¹, S. Majjaj¹, Z. Denis¹, X. Wang¹, F. Libert³, A. Lefort³, I. Desmoulins⁴, A. Gombos⁵, D. T’Kint De Roodenbeke⁵, P. Aftimos⁵, F. Lebrun⁵, D. De Valeriola⁵, I. Veys⁶, C. Pop⁶, S. Drisis⁷, D. Larsimont⁸, M. Ignatiadis⁵, M. Piccart⁵, F. Rothé¹, E. Romano⁹, L. Buisseret¹⁰, C. Sotiriou¹; ¹Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Brussels, BELGIUM, ²Department of Radiotherapy, Institut Jules Bordet, Brussels, BELGIUM, ³BRIGHTcore, Campus Erasme – IRIBHM, Université Libre de Bruxelles, Brussels, BELGIUM, ⁴Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, FRANCE, ⁵Department of Medical Oncology, Institut Jules Bordet, Brussels, BELGIUM, ⁶Department of Surgery, Institut Jules Bordet, Brussels, BELGIUM, ⁷Department of Medical Imagery, Institut Jules Bordet, Brussels, BELGIUM, ⁸Department of Anatomical Pathology, Institut Jules Bordet, Brussels, BELGIUM, ⁹Department of Medical Oncology, Institut Curie, Paris, FRANCE, ¹⁰Department of Medical Oncology, Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Brussels, BELGIUM.

BackgroundLuminal B breast cancer is considered immunologically “cold”, with low pathological complete response (pCR) rates after neoadjuvant chemotherapy (NACT). The phase II Neo-CheckRay trial (NCT03875573) tested immune-priming strategies by combining NACT with stereotactic body radiotherapy (SBRT) and immune checkpoint (ICB)/adenosine blockade. Adding durvalumab (arm 2) ± oleclumab (arm 3) to SBRT+NACT (arm 1) doubled pCR rates (from 16.7% to 33.3% and 31.1%). We performed single-cell RNA-sequencing of longitudinal samples from patients included in the Neo-CheckRay trial to elucidate mechanisms of action and identify immune correlates of pCR. MethodsWe profiled 78 tumor and axillary lymph node (LN) samples at baseline, week 6 (post-SBRT), and at surgery from 28 patients treated at Institut Jules Bordet, using 10X Genomics 5′ platform. Following sequencing and quality control, cells were batch-corrected and annotated using canonical markers. Wilcoxon tests were used to assess changes in cell fractions and gene expression.ResultsIn ICB-treated arms (2+3), high baseline CXCL13+ myeloid cells (p = 0.034) and IL2RA+ T cells (p = 0.002) predicted pCR. Additionally, Arm 3 showed a unique vascular adenosine priming with high CD39/ADORA2A (p = 0.036) on endothelial cells and low ADORA2B (p = 0.017) on endothelial cells.By week 6, SBRT+NACT acted as an in situ vaccine, promoting antigen presentation and T cell priming. Migratory (mDCs, p = 0.002) and conventional DCs (cDC1s, p = 0.02), proliferative myeloids (p = 0.002), early-activated (p = 0.023) and follicular-helper CD4+ T cells (p = 0.006) increased in lymph nodes, while immunosuppressive lipid-associated macrophages decreased (SPP1+TREM2+ LAM p = 0.005, APOC1-LAM p = 0.04). In tumors, arm 1 showed broad immune contraction, T cell exhaustion, and a drop in the effector memory compartment (p = 0.021), while arm 3 displayed rebalanced immunity, with reduced Tregs (p = 0.034) and an increased cytotoxic-to-Treg ratio. ICB responders maintained CXCL13+ myeloids (p = 0.016) and showed enhanced antigen presentation and T cell recruitment via cGAS-STING and IFN signaling, with elevated CXCL10 expression in myeloids (p = 0.018). In arm 3, reduced T-cell exhaustion scores on pericytes (p = 0.013), lower immunosuppression in T cells (p = 0.038), higher MHC II scores on epithelial cells (p = 0.024), and an M1-like myeloid signature indicated successful immune activation.Most strikingly, we observed divergent adenosine pathway remodeling by response and treatment. Arm 3 responders showed redistribution of CD73/CD39 from immune/tumor cells to pericytes/vasculature (p = 0.036, p = 0.01), coupled with increased ADA/ADK expression on immune cells (p = 0.01), enabling active adenosine degradation. In contrast, non-responders and arm 1 accumulated CD73 on myeloids (p = 0.009), CAFs (p = 0.05), and epithelium (p = 0.024) while lacking degradation enzymes, maintaining suppression.ConclusionIn immune-cold luminal B breast cancer, effective therapy likely requires: pre-existing immune organization (CXCL13+ myeloid), anti-tumor priming by SBRT+NACT, sustained T-cell activity via PD-L1 blockade, and relief of adenosine-mediated suppression via CD73 blockade. Notably, our data suggest oleclumab’s efficacy may stem not from mere CD73 inhibition, but from its redistribution to the vascular niche, where it may preserve perfusion and immune accessibility, without triggering the immunosuppressive effects seen with CD73 upregulation on myeloid, CAF, or epithelial cells.

H. Iwata¹, C. Kanbayashi², T. Toyama³, A. Yoshimura⁴, T. Sakai⁵, Y. Bando⁶, K. Watanabe⁷, K. Terata⁸, T. Morimoto⁹, E. Tokunaga¹⁰, T. Sangai¹¹, M. Kitahara¹², T. Kuwayama¹³, A. Matsui¹⁴, T. Fujisawa¹⁵, F. Hara⁴, R. Kajikawa¹⁶, T. Shibata¹⁶, K. Sasaki¹⁷, T. Shien¹⁸; ¹Advanced Clinical Research and Development, Nagoya City University Graduate School of Medical Sciences, Nagoya, JAPAN, ²Breast Oncology, Niigata Cancer Center Hospital, Niigata, JAPAN, ³Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, JAPAN, ⁴Breast Oncology, Aichi Cancer Center, Nagoya, JAPAN, ⁵Breast Surgical Oncology, Breast Oncology Center, The Cancer Institute Hospital of JFCR, Tokyo, JAPAN, ⁶Breast and Endocrine Surgery, University of Tsukuba Hospital, Tsukuba, JAPAN, ⁷Breast Oncology, Hokkaido Cancer Center, Sapporo, JAPAN, ⁸Breast and Endocrine Surgery, Akita University Hospital, Akita, JAPAN, ⁹Breast Surgery, Yao Municipal Hospital, Yao, JAPAN, ¹⁰Breast Oncology, NHO Kyushu Cancer Center, Fukuoka, JAPAN, ¹¹Breast and Thyroid Surgery, Kitasato University Hospital, Sagamihara, JAPAN, ¹²Breast Surgery, Ibaraki Prefecture Central Hospital, Ibaraki, JAPAN, ¹³Breast Surgery, Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, JAPAN, ¹⁴Breast Surgery, National Hospital Organization Tokyo Medical Center, Tokyo, JAPAN, ¹⁵Breast Oncology, Gunma Prefectural Cancer Center, Ota, JAPAN, ¹⁶JCOG Data Center, National Cancer Center Hospital, Tokyo, JAPAN, ¹⁷JCOG Operations Office, National Cancer Center Hospital, Tokyo, JAPAN, ¹⁸Breast and Endocrine Surgery, Okayama University Hospital, Okayama, JAPAN.

Background: The frequency of ductal carcinoma in situ (DCIS) has increased due to the screening program. The standard treatment for DCIS is still resection. A prospective study of no surgery for low grade DCIS showed positive outcomes in 2024. However, due to the short observation period, no surgery therapy is not even a recommended treatment option. Methods: The LORETTA trial (Low-risk DCIS with Endocrine Therapy Alone-TAM; JCOG1505) is a single-arm confirmatory trial of endocrine therapy alone for estrogen receptor positive, low-risk DCIS. The study population were women seeking treatment for DCIS at one of the JCOG Breast Cancer Study Group institutions in Japan. Eligible participants were 40 and over age with low-risk DCIS defined as nuclear grade (NG) 1 or 2 without comedo necrosis, estrogen receptor positive, HER2-negative on core biopsy without microinvasive or invasive cancer. The maximum tumor diameter does not exceed 25 mm with no finding of invasive cancer on all imaging (MMG, US, and MRI). Tamoxifen (TAM) 20 mg/day is mandatory without surgery in all patients. The primary endpoint was 5-year cumulative incidence proportion of ipsilateral invasive cancer (CIPIC). The secondary endpoints include contralateral breast disease-free survival, overall survival (OS), surgical proportion/timing, and safety. The analysis assumed a 5 year CIPIC threshold of 7% and an expected of 2.5%, with a one-sided α of 2.5% and 95% power. A total of 340 patients was required. The efficacy of TAM alone without surgery is considered confirmed when the upper limit of the 95% confidence interval is less than or equal to 7%. Results: From Jul 2017 to Jan 2024, 341 pts were enrolled. In Jan 2025, early termination was recommended by DSMC as interim monitoring showed 5Y CIPIC exceeded 7%. Median follow up is 36 (range: 0-80.4) months. The patient’s characteristics: median age 53 (range: 40-85) years, PS 0/1:340/1, NG1/2:238/103, PgR 0/weak/strong: 11/17/313, HER2 0/1/2: 66/186/76, pre/post menopause: 162/173. Among 341 pts, 18 pts were found to have ipsilateral invasive cancer. 5Y CIPIC is 9.8% (95% confidence interval [CI]:5.2-16.1%). In the subgroup analysis, imaging-defined tumor diameter was associated with the occurrence of invasion: MMG (p=0.0278), US (p=0.0433), MRI (p=0.0530). No significant association with NG, HER2, PgR, or age. Contralateral breast disease-free survival: 97.5% (4 patients). 5Y OS: 98.8% (2 deaths, unrelated). Surgical proportion: 9.7% (33/341); 5Y surgery-free survival: 82%. Grade ≥3 adverse events occurred in 3.8% of patients. Conclusion: The primary endpoint did not meet the predefined threshold. However, the incidence of ipsilateral invasive breast cancer and the surgical proportion were low at 5 years. TAM alone without surgery therapy might be an option in carefully selected low-risk DCIS with ER-positive HER2-negtaive.

B. H. Chua¹, E. K. Link², I. A. Olivotto³, I. Kunkler⁴, T. Whelan⁵, P. Deseyne⁶, G. Gruber⁷, BIG 3-07/TROG 07.01 trial investigators; ¹University of New South Wales, Sydney, Australia, ²Peter MacCallum Cancer Centre, Melbourne, Australia, ³University of Calgary, Calgary, AB, Canada, ⁴University of Edinburgh, Edinburgh, United Kingdom, ⁵McMaster University, Hamilton, ON, Canada, ⁶University Medical Center Groningen, Groningen, Netherlands, ⁷Klinik Hirslanden, Zurich, Switzerland

Background: Whole breast irradiation (WBI) after breast conserving surgery for ductal carcinoma in-situ (DCIS) reduces local recurrence. We aimed to evaluate whether a tumor bed boost after WBI improved long-term outcomes, and examine radiation dose fractionation sensitivity for non-low-risk DCIS. Methods: The study was an international, randomized, unmasked, phase 3 trial involving 136participating centers from six clinical trials organizations in 11 countries. Eligible patients were women aged ≥18 years who had breast conserving surgery with ≥1 mm of clear radial resection margins for unilateral, histologically proven, non-low-risk DCIS defined as age <50 years or age ≥50 years plus at least one of the risk factors for local recurrence (palpable tumor, multifocal disease, tumor size ≥1.5cm, intermediate or high nuclear grade, central necrosis, comedo histology and/or surgical margin<10 mm). Patients were stratified by age (<50 years vs ≥50 years), planned endocrine therapy (yes or no) and treating center. They were randomized to one of four groups (1:1:1:1) of no boost versus boost after conventional versus hypofractionated WBI, or to one of two groups (1:1) of no boost versus boost after each center-prespecified conventional or hypofractionated WBI. The conventional WBI was 50 Gy in 25 fractions, and hypofractionated WBI was 42·5 Gy in 16 fractions. A boost dose of 16 Gy in eight fractions, if allocated, was delivered after WBI. The primary endpoint was time to local recurrence. Secondary endpoints were time-to-disease recurrence, overall survival and treatment toxicity. Cosmetic outcome and health-related quality of life will be reported separately. This trial is registered with ClinicalTrials.gov (NCT00470236). Results: Between June 25, 2007, and June 30, 2014, 1608 patients were randomly assigned to no tumor bed boost (805 patients) or boost (803 patients). Conventional WBI was given to 831 patients, and hypofractionated WBI was given to 777 patients. Endocrine therapy was used in 13% of patients. Median follow-up was 10.2 years. The 10-year free-from-local-recurrence rates were 87% (95% CI 84-89%) in the no-boost group and 93% (91-95%) in the boost group (hazard ratio 0.49; 0.34-0.69;p<0.001). Fifty-four percent and 58% of local recurrences were invasive in the no-boost and boost groups, respectively. There were no significant differences in the 10-year free-from-local recurrence rates between the conventional WBI and hypofractionated WBI groups in the 4-arm randomization category (90% vs. 89%, P=0.82) or in all randomized patients (89% vs. 91%, P=0.80). The test for interaction between boost and dose-fractionation was not significant in the 4-arm randomization category (P=0.39) or in all randomized patients (P=0.77). The 10-year free-from-disease recurrence rates were lower in the no-boost group (79%) than in the boost group (87%; hazard ratio, 0.67;0.52−0.86; p=0.002). There was no statistically significant difference in 10-year overall survival rates between the no-boost (94%) and boost (96%) groups (0·73; 0·47-1·14; p=0·17). The boost group had higher rates of grade 2 or higher breast induration (7% [5-9%] vs 17% [14-19%], p<0.001) and breast pain (11% [9-13%] vs 17% [14-20%], p=0·002), with no suggestion of interaction with WBI dose fractionation. Conclusions: Our results provide the first long-term randomized trial data to demonstrate the efficacy of tumor bed boost radiation after postoperative WBI on local recurrence in patients with non-low-risk DCIS with an associated increase in grade 2 or greater breast induration and pain. Within the limits of the trial design, moderately hypofractionated WBI was not associated with an increase in local recurrence or toxicity.