General Session 1

E. Hamilton¹, G. Curigliano², M. Martin³, F. Lerebours⁴, J. Tsurutani⁵, M. Savard⁶, K. Jerzak⁷, X. Hu⁸, L. Martins de Aquino Pimentel⁹, C. O’Sullivan¹⁰, E. Tokunaga¹¹, A. Okines¹², C. Huang¹³, W. Jacot¹⁴, J. Sohn¹⁵, E. Cronemberger Silva¹⁶, V. Mueller¹⁷, S. Yang¹⁸, G. Granata¹⁹, Q. Shen²⁰, L. Santarpia²¹, V. Dieras²²; ¹Medical Oncology, Sarah Cannon Research Institute, Nashville, TN, ²European Institute of Oncology, IRCCS, Milan, Italy, and Hemato-Oncology, University of Milano, Milano, ITALY, ³Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Universidad Complutense, CIBERONC, GEICAM, Madrid, SPAIN, ⁴Institut Curie, Saint-Cloud, Paris, FRANCE, ⁵Advanced Cancer Translational Research Institute, Showa Medical University Hospital, Tokyo, JAPAN, ⁶Department of Medicine, The Ottawa Hospital Cancer Centre, Ottawa, ON, CANADA, ⁷Sunnybrook Odette Cancer Centre, Department of Medicine, University of Toronto, Toronto, ON, CANADA, ⁸Department of Medical Oncology, Department of Medical Oncology, Fudan University Shanghai Cancer Center,, Shanghai, CHINA, ⁹Medical Oncology, Liga Norte-Rio Grandense Contra o Câncer, Natal, BRAZIL, ¹⁰Medical Oncology, Mayo Clinic, Rochester, MN, ¹¹Department of Breast Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, JAPAN, ¹²Medical Oncology, The Royal Marsden NHS Foundation Trust, London, UNITED KINGDOM, ¹³Breast Care Center, National Taiwan University Hospital, Taipei, TAIWAN, ¹⁴Département d’Oncologie Médicale, Institut Regional du Cancer de Montpellier, Montpellier, FRANCE, ¹⁵Division of Medical Oncology, Department of Internal Medicine, Severance Hospital, Yonsei University Health System, Seoul, KOREA, REPUBLIC OF, ¹⁶Medical Oncology, Centro Regional Integrado de Oncologia (CRIO), Fortaleza, BRAZIL, ¹⁷Department of Gynecology and University Breast Center, Universitaetsklinikum Hamburg-Eppendorf, Hamburg, GERMANY, ¹⁸Biostatistics, Pfizer Inc., Bothell, WA, ¹⁹Oncology Late Stage Development, Pfizer AG, Zug, SWITZERLAND, ²⁰Oncology, Research and Development, Pfizer Inc., Collegeville, PA, ²¹Oncology, Research and Development, Pfizer AG, Zug, SWITZERLAND, ²²Medical Oncology Department, Centre Eugene Marquis, Rennes, FRANCE.

Background: The current standard of care for first-line (1L) treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) consists of induction chemotherapy combined with trastuzumab (TRAS) and pertuzumab (PERT) followed by maintenance therapy with TRAS + PERT. Although this regimen has been associated with sustained disease control, most patients eventually experience disease progression. The HER2CLIMB-05(NCT05132582) study is investigating the efficacy and safety of adding tucatinib to TRAS + PERT as maintenance therapy in patients with HER2+ MBC after completion of 1L chemotherapy-based induction therapy. Methods: Patients with centrally confirmed HER2+MBC without evidence of progression after 1L induction therapy with 4 to 8cycles of a taxane combined with TRAS + PERT, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, and no or asymptomatic brain metastases (BM) were enrolled in HER2CLIMB-05. Contrast-enhanced brain magnetic resonance imaging was performed at screening and regular intervals during the study. Patients were randomly assigned 1:1 to receive either tucatinib 300 mg or placebo twice daily, in combination with either TRAS (6 mg/kg IV or 600 mg SC) plus PERT (420 mg/kg IV) or a SC fixed-dose combination of TRAS, PERT, and hyaluronidase administered every 21 days. Endocrine therapy was permitted for patients with hormone receptor-positive tumors. The primary endpoint is investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints include overall survival (OS), PFS by blinded independent central review, investigator-assessed central nervous system (CNS)-PFS, and safety. Results: Between March 2022 and July 2024, 654 patients were randomly assigned to receive tucatinib (n = 326) or placebo (n = 328) with1L maintenance therapy. All patients were female (median age: 54 years [range, 24-83]);45.0% were White, 35.2% were Asian, 2.9% were Black/African American, and 19.3%were Hispanic/Latino(a)/Spanish origin. Most patients had ECOG PS of 0 (64.1%)and de novo metastatic disease (69.3%). At baseline, 12.4% of patients had presence or history of BM and 52.6% had hormone receptor-positive MBC. As of September5, 2025, PFS was statistically significantly improved with the addition of tucatinib versus placebo to 1L maintenance therapy (hazard ratio [HR] = 0.641 [95%confidence interval (CI), 0.514-0.799]; 2-sided P < 0.0001). All prespecified patient subgroups demonstrated a PFS benefit with tucatinib combination 1L maintenance therapy consistent with the overall population and regardless of presence or absence of BM at baseline or hormone-receptor status. OS is still immature (observed number of deaths = 51;tucatinib arm versus control arm HR = 0.539 [95% CI, 0.303-0.957; 2-sided P= 0.032]). In the safety analysis set, the most common treatment-emergent adverse events (TEAEs) in the tucatinib arm (n = 326) were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (alanine aminotransferase: 28.2%; aspartate aminotransferase:25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1% were, respectively, grade ≥ 3. In the tucatinib arm, 13.5% of patients discontinued tucatinib due to TEAEs. Conclusions: In the HER2CLIMB-05 trial, the addition of tucatinib to TRAS + PERT as 1L maintenance therapy demonstrated a statistically significant and clinically meaningful improvement in PFS with a manageable safety profile in patients with HER2+ MBC.

M. Lambertini¹, F. Samy², E. Agostinetto³, L. Arecco⁴, P. Freire⁵, A. Sonnenblick⁶, G. Arpino⁷, L. Del Mastro⁸, A. Choudhury⁹, N. Harbeck¹⁰, I. Vaz-Luis¹¹, V. Kaklamani¹², A. Wolff¹³, A. Partridge¹⁴, S. Loi¹⁵, S. Fielding¹⁶, M. Piccart¹⁷, S. Di Cosimo¹⁸, E. de Azambuja¹⁷; ¹Medical Oncology, University of Genova – IRCCS Ospedale Policlinico San Martino, Genoa, ITALY, ²Statistics, Frontier Science Scotland, Kingussie, UNITED KINGDOM, ³Oncology, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B) and Université Libre de Bruxelles (U.L.B.), Brussels, BELGIUM, ⁴Oncology, Department of Oncology, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B) and Université Libre de Bruxelles (U.L.B.), Brussels, BELGIUM, ⁵Medical Oncology, Oncologia D’Or Hospital de Câncer de Pernambuco, Recife, BRAZIL, ⁶Medical Oncology, The Oncology Division, Tel Aviv Sourasky Medical Center, Grey Faculty of Medicine, Tel Aviv University, Tel Aviv, ISRAEL, ⁷Medical Oncology, Università di Napoli Federico II, Naples, ITALY, ⁸Medical Oncology, University of Genova – IRCCS Ospedale Policlinico San Martino, Genova, ITALY, ⁹-, Novartis, Hyderabad, INDIA, ¹⁰Oncology, Dept. OB&GYN and CCC Munich, LMU University Hospital, Munich, GERMANY, ¹¹Medical Oncology, Institut Gustave Roussy, Villejuif, FRANCE, ¹²Medical Oncology, UTH San Antonio, San Antonio, TX, ¹³Medical Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, ¹⁴Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, ¹⁵Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, AUSTRALIA, ¹⁶Stat, Frontier Science Scotland, Kingussie, UNITED KINGDOM, ¹⁷Medical Oncology, Department of Oncology, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B) and Université Libre de Bruxelles (U.L.B.), Brussels, BELGIUM, ¹⁸Medical Oncology, Istituto Nazionale dei Tumori (INT), Milano, ITALY.

Background: The optimal adjuvant endocrine therapy (ET) for patients (pts) with hormone receptor-positive (HR+)/HER2-positive (HER2+) early breast cancer (EBC) remains controversial. The present analysis investigated the efficacy of different types of ET in pts with centrally tested HR+/HER2+ EBC treated with modern chemotherapy (CT) and trastuzumab (T)-based regimens at 10-year follow-up. Patients and methods: ALTTO (BIG 2-06) is an international phase 3 trial in pts with HER2+ EBC randomized to 4 adjuvant anti-HER2 treatments with CT: T alone, lapatinib (L) alone, their sequence (T->L) or their combination (T+L). Pts in the L alone arm, pts with HR-/HER2+ disease and pts with HR+ tumours who did not start adjuvant ET were excluded from the analysis. HER2 and HR status were centrally tested for all pts. Disease-free survival (DFS), time to distant recurrence (TTDR) and overall survival (OS) were compared between pts who received a selective estrogen receptor modulator (SERM) vs. those who received an aromatase inhibitor (AI). To avoid the risk of immortal time bias, pts with HR+/HER2+ disease who switched from one ET to another during the follow-up were excluded. A pre-planned subgroup analysis according to menopausal status at baseline was performed. Among premenopausal women, a comparison was made between SERM alone, SERM + ovarian function suppression (OFS) and AI±OFS (depending on post-CT menopausal status). Multivariable Cox proportional hazards regression models were used to model survival outcomes with adjuvant ET as the predictor. Other covariates in the model were CT timing (concurrent/sequential), tumour grade (G1/2, G3, GX), age (continuous) and tumour size (T, continuous) and a strata variable of axillary lymph node (N0, N1-3, N>=4 nodes, N/A). SERM were used as the reference category for adjusted hazard ratios (aHR). Results: This analysis included 2,651 pts with HR+/HER2+ of whom 1,518 (57.3%) received SERM (99.5% tamoxifen) and 1,133 (42.7%) AI. Among 1,259 premenopausal pts, 903 (71.7%) received SERM alone, 238 (18.9%) SERM+OFS and 118 (9.4%) AI±OFS. Median follow-up was 9.9 years (IQR 7.0-10.0 years). Overall, 10-year DFS was 80.1% and 76.5% in the AI and SERM groups, respectively (aHR 0.65; 95% CI 0.52-0.82). Compared to pts treated with SERM, those who received AI had fewer local (0.9% vs. 2.4%) and distant (9.3% vs. 12.1%) recurrences. In subgroup analyses, AI was superior to SERM irrespective of pts (age, menopausal status, body mass index), tumor (T, N, G, HR+ levels, HER2 FISH ratio) and treatment (anti-HER2 arm, CT type and timing) characteristics. In the AI and SERM groups, 10-year TTDR was 85.7% and 83.1% (aHR 0.65; 95% CI 0.50-0.85), and 10-year OS was 88.9% and 89.1% (aHR 0.73; 95% CI 0.53-1.00), respectively. Among premenopausal pts only, 10-year DFS was 90.0%, 77.3% and 77.6% with AI±OFS, SERM+OFS and SERM, respectively (AI±OFS vs. SERM: aHR 0.44; 95% CI 0.23-0.85; SERM+OFS vs. SERM: aHR 0.87; 95% CI 0.61-1.23). In the AI±OFS, SERM+OFS and SERM groups, 10-year TTDR was 92.8%, 82.9% and 85.1% (AI±OFS vs. SERM: aHR 0.57; 95% CI 0.27-1.18; SERM+OFS vs. SERM: aHR 0.94; 95% CI 0.62-1.41), and 10-year OS was 95.6%, 88.7% and 91.3% (AI±OFS vs. SERM: aHR 0.68; 95% CI 0.27-1.73; SERM+OFS vs. SERM: aHR 0.98; 95% CI 0.58-1.66), respectively. Conclusions: In this large 10-year follow-up analysis of pts with centrally tested HR+/HER2+ EBC treated with modern CT+anti-HER2-based therapy in the ALTTO trial, the use of AI was associated with significantly improved DFS and TTDR without differences in OS. The DFS benefit of AI was observed in both premenopausal and postmenopausal pts. These data may help optimizing adjuvant ET choices in pts with HR+/HER2+ EBC and shed light on the need of designing ad hoc clinical trials in this setting.

S. S. Badve¹, F. Zhao², N. Tung³, Y. Gokmen-Polar¹, C. C. O’Sullivan⁴, A. Prat⁵, E. P. Winer⁶, J. L. Wright⁷, A. Recht³, A. C. Weiss⁸, J. A. Tjoe⁹, S. M. Feldman¹⁰, G. B. Rocque¹¹, M. Smith¹², N. Unni¹³, S. Sardesai¹⁴, S. Tang¹⁵, S. Modi¹⁶, W. J. Irvin¹⁷, P. Villagrassa⁵, C. Battelli¹⁸, A. K. Krie¹⁹, N. Bagegni²⁰, M. A. George²¹, M. L. Telli²², V. F. Borges²³, N. D’Abreo²⁴, P. Shah²⁵, K. D. Miller²⁶, A. H. Partridge²⁷, L. A. Carey²⁸, A. M. DeMichele²⁵, A. C. Wolff²⁹, ECOG-ACRIN; ¹Pathology, Emory School of Medicine, Atlanta, GA, ²Biostatistics, DFCI, Boston, MA, ³Hem Onc, Beth Israel Deaconess Medical Center, Boston, MA, ⁴Hem Onc, Mayo Clinic, Rochester, MN, ⁵Reveal Genomics, Reveal Genomics, Barcelona, SPAIN, ⁶Hem Onc, Yale University, New Haven, CT, ⁷Hem Onc, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, ⁸Oncology, University of Rochester Medical Center, Rochester, NY, ⁹Hem Onc, Green Bay Oncology, Neenah, WI, ¹⁰Hem Onc, Montefiore Einstein Center for Cancer Care, Bronx, NY, ¹¹Hem Onc, O’Neal Comprehensive Cancer Center at UAB, Birmingham, AL, ¹²Patient Advocacy, Research Advocacy Network, Naperville, IL, ¹³Hem Onc, UT Southwestern Medical Center, Dallas, TX, ¹⁴Hem Onc, The James Cancer Hospital at Ohio State University, Columbus, OH, ¹⁵Hem Onc, Louisiana State University Health Sciences Center, New Orleans, LA, ¹⁶Hem Onc, Memorial Sloan Kettering Cancer Center, New York, NY, ¹⁷Hem Onc, Bon Secours Health System, Marriottsville, MD, ¹⁸Hem Onc, New England Cancer Specialists, Scarborough,, GA, ¹⁹Hem Onc, Allina Health, Minneapolis,, MN, ²⁰Hem Onc, Washington University School of Medicine, St. Louis, MO, ²¹Hem Onc, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, ²²Hem Onc, Stanford University School of Medicine, Stanford, CA, ²³Hem Onc, University of Colorado Anschutz Medical Campus, Aurora, CO, ²⁴Hem Onc, NYU Winthrop Hospital, Mineola, NY, ²⁵Hem Onc, University of Pennsylvania/Abramson Cancer Center, Philadelphia, PA, ²⁶Hem Onc, Indiana Univ/Melvin and Bren Simon Cancer Center, Indianapolis, IN, ²⁷Hem Onc, Dana-Farber Cancer Institute, Boston, MA, ²⁸Hem Onc, Lineberger Comprehensive Cancer Center, , Chapel Hill, NC, ²⁹Hem Onc, Johns Hopkins Univ/Sidney Kimmel Cancer Center, Baltimore, MD.

Background: The association of TILs with pathologic complete response (pCR) and survival in HER2+ breast cancer is not well established with several prior studies showing inconsistent results. In this secondary analysis of EA1181, we evaluated the association between stromal TILs (sTILs) and pCR rates. Methods: EA1181 (NCT04266249) enrolled patients (pts) with anatomic clinical stage II/III HER2+ breast cancer who preoperatively received 4 cycles of trastuzumab and pertuzumab with 12 weeks of paclitaxel or docetaxel q3w x 4 (THP), followed by surgery. sTILs density was assessed on full-face hematoxylin and eosin (H&E)-stained tumor biopsy sections. sTILs scores were analyzed per protocol as a continuous variable (every 10% increment) and as a categorical variable (60% as per Denkert et al, 2018), and also with an exploratory 30% cutoff commonly used in TNBC. Cox proportional hazards models were used to examine the association between sTILs and pCR, adjusting for available baseline factors. The associations between sTILs (by category) and clinicopathologic characteristics were examined using Fishers’ exact test. Results: Among 2141 pts with HER2+ BC treated on EA1181, H&E slides were available for 1328 (62%). The study population evaluated for sTILs was comparable to the overall population. pCR rates were 44.5% overall, 64% for HER2+/ER- and 33% for HER2+/ER+ disease. sTILs distribution was: 623 (47%) 60%, which led us to merge the latter two groups (705 [53%] had ≥10% sTILs). In univariable and multivariable analyses, increasing sTILs (as a continuous variable) were associated with increasing pCR rates in both HER2+/ER+ and HER2+/ER- disease (p<0.001; Table). sTILs analyzed as a categorical variable (<10% vs ≥10%) were significantly associated with pCR for all patients (combined) and for those with HER2+/ER+ disease. In exploratory analysis using a cutoff of <30% vs ≥30% sTILs, an association with pCR was also seen in univariable analysis for both HER2+/ER+ disease (p30% remained a significant predictor for pCR only in HER2+/ER+ disease. Additional exploratory analysis with other molecular biomarkers, intrinsic subtypes, and immune signatures will be presented. Conclusion: sTILs were associated with pCR after THP, further supporting the important role of immune mechanisms in HER2+ breast cancer, and highlighting a potentially robust predictive tool to assess pathologic response. Baseline sTILs could potentially inform the preoperative design of future trials of therapy optimalization. Association of baseline sTILs with recurrence free survival in EA1181 will be reported in the future.

R. Salgado¹, L. E. Lara Gonzalez¹, F. Giudici², F. Rojo³, L. Comerma⁴, S. Wienert⁵, J. Palacios⁶, Z. Kos⁷, S. L. De Haas⁸, A. Rodriguez Lescure⁹, G. Viale¹⁰, Y. Zheng¹¹, D. Gao⁷, A. Kiermaier¹², F. Andre¹³, S. Loibl¹⁴, M. J. PIccart¹⁵, R. Gelber¹⁶, D. Cameron¹⁷, I. E. Krop¹⁸, P. Savas¹, T. O. Nielsen⁷, C. Denkert¹⁹, S. Michiels²⁰, S. Loi¹, APHINITY Steering Committee and Investigators, The International Immuno-Oncology Biomarker Working Group.; ¹Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, AUSTRALIA, ²Unit of Cancer Epidemiology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, ITALY, ³Department of Pathology, Fundacion Jimenez Diaz University Hospital Health Research Institute (IIS-FJD, UAM)—CIBERONC, Madrid, SPAIN, ⁴Pathology Department, Hospital del Mar, Barcelona, SPAIN, ⁵Institute of Pathology, Universitätsmedizin Berlin (a corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin), Berlin, GERMANY, ⁶Pathology Department, University Hospital Ramón y Cajal, IRYCIS, CIBERONC, Universidad de Alcala, Madrid, SPAIN, ⁷Department of Pathology and Lab Medicine, University of British Columbia and BC Cancer, Vancouver, BC, CANADA, ⁸NA, F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, ⁹Medical Oncology Department, Elche General University Hospital, Alicante, SPAIN, ¹⁰Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, ITALY, ¹¹Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, ¹²Product Development Data Sciences, F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, ¹³Department of Medical Oncology, Gustave Roussy Cancer Campus, ClinicObiome, Villejuif, France; Université Paris-Saclay, Ile-de-France, Paris, FRANCE, ¹⁴NA, GBG Forschungs GmbH, Neu-Isenburg, GERMANY, ¹⁵NA, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Bruxelles, BELGIUM, ¹⁶Harvard T.H. Chan School of Public Health, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, ¹⁷Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UNITED KINGDOM, ¹⁸Medical Oncology, Yale Cancer Center, New Haven, CT, ¹⁹Institute of Pathology, Philipps University Marburg, Marburg, GERMANY, ²⁰Service de Biostatistique et d’Epidémiologie, Gustave Roussy, Villejuif Cedex, FRANCE.

Background: Stromal tumor-infiltrating lymphocytes (sTILs) are prognostic and predictive biomarkers for HER2-targeted therapy in early-stage HER2-positive breast cancer (BC). Manual sTIL scoring demonstrates high reproducibility but may underrepresent immune infiltration. Digital pathology and artificial intelligence (AI) offer automated sTIL quantification and spatial assessment but require validation against clinical endpoints. Aim: To compare manual, digital (non-AI), and AI-based sTIL quantification methods, including AI-derived spatial metrics in the phase III APHINITY trial. Objectives included interobserver reproducibility, method concordance, prognostic performance for invasive disease-free survival (iDFS) and overall survival, enhancement of prognostic models by AI, and identification of patients benefiting from adjuvant pertuzumab. Methods: Of 4,804 APHINITY trial participants, 4,306 (90%) had evaluable archival H&E whole-slide images for all methods. Manual scoring was performed by an experienced pathologist (RS), with reproducibility assessed on 262 slides independently reviewed by five pathologists using international TIL guidelines. Digital quantification used a standard image-analysis algorithm, and AI-percentage lymphocyte scoring employed Case45’s zero-shot deep-learning biomarker pipeline. Two AI-derived spatial metrics were computed: density of lymphocytes adjacent to cancer nests and quantification of dense lymphoid aggregates (immune hotspots). High-TIL status was defined as ≥75th percentile for percentage scores and ≥50th percentile for spatial metrics. Concordance was measured using intraclass correlation coefficient (ICC) and pairwise agreement. Prognostic and predictive performance were assessed via multivariable Cox regression adjusted for treatment arm, age, chemotherapy regimen, hormone-receptor status, nodal status, tumor size, and grade, with likelihood-ratio tests for incremental prognostic gains. Predictive benefit was evaluated by treatment-by-TIL interaction hazard ratios (HR) for iDFS in high-TIL groups. Results: Manual scoring reproducibility was excellent (ICC 0.87). Continuous sTIL quantification showed modest to moderate concordance across methods (ICC 0.37-0.62), with digital and AI consistently scoring lower than manual. High/low TIL classification achieved 80% overall agreement. Every 10% increment in sTIL was associated with reduced recurrence risk (HR: manual 0.93, digital 0.92, AI 0.87; all p < 0.001). AI spatial immune hotspots outperformed percentage metrics (HR = 0.41; p < 0.001) and, when combined with manual scores, provided the greatest additional discrimination (p < 0.001). In high-TIL patients, pertuzumab reduced iDFS events by 64% (manual HR = 0.36; p int = 0.003), 52% (digital HR = 0.48; p int = 0.025), and 54% (AI HR = 0.46; p int = 0.01). Manual scoring alone identified 562/2,573 (22%) node-positive patients as high-TIL and likely pertuzumab-responsive, whereas AI-percentage lymphocyte identified 625 (24%) thus contributing to further detect 253 node-positive patients who would benefit from addition of pertuzumab (a 10% larger group). AI spatial metrics were not predictive. Conclusions: Despite modest concordance, manual, digital and AI-derived sTIL assessments independently demonstrated prognostic and predictive value for identifying HER2-positive BC patients benefiting from adjuvant pertuzumab. AI-driven sTIL quantification matches and slightly improves prognostic accuracy, importantly both AI and manual sTIL can identify a larger group of pertuzumab-responsive patients. Integrating AI-derived quantitative and spatial metrics into multiparameter models can further individualize HER2-targeting therapy.

A. Llombart-Cussac¹, J. Pérez-García², M. Ruiz-Borrego³, A. Stradella⁴, B. Bermejo⁵, S. Escrivá-de-Romaní⁶, C. Reboredo⁷, N. Ribelles⁸, A. Cortés-Salgado⁹, C. Albacar¹⁰, M. Colleoni¹¹, G. Antonarelli¹², G. Notini¹³, M. Gion¹⁴, J. García-Mosquera¹⁵, L. Sanz¹⁶, E. Martínez-García¹⁷, P. González-Alonso¹⁷, A. Amaya-Garrido¹⁸, J. Guerrero¹⁹, J. Rodríguez-Morató¹⁸, L. Mina¹⁹, G. Martrat²⁰, M. Quintana²¹, F. Riva²², D. Dustin²², H. Zhang²², M. Mancino¹⁷, J. Cortés²³; ¹Oncology, Hospital Arnau de Vilanova; Translational Oncology Group, Facultad de Ciencias de la Salud, Universidad Cardenal Herrera-CEU; Medica Scientia Innovation Research (MedSIR), Valencia, SPAIN, ²Oncology, International Breast Cancer Center (IBCC), Pangaea Oncology,  Quiron  Group;Medica Scientia Innovation Research (MedSIR), Barcelona, SPAIN, ³Oncology, Hospital Universitario Virgen del Rocío, Sevilla, SPAIN, ⁴Oncology, Institut  Català  d’Oncologia, Barcelona, SPAIN, ⁵Oncology, Hospital Clínico Universitario de Valencia, Biomedical Research Institute INCLIVA; Oncology Biomedical Research National Network (CIBERONC-ISCIII), Madrid, Valencia, SPAIN, ⁶Oncology, Vall  d’Hebron  University Hospital, Vall  d’Hebron  Institute of Oncology (VHIO), Barcelona, SPAIN, ⁷Oncology, Complejo Hospitalario Universitario A Coruña (CHUAC), A Coruña, SPAIN, ⁸Oncology, Hospital Universitario Virgen de la Victoria; Instituto de Investigaciones Biomédicas de Málaga (IBIMA), Málaga, SPAIN, ⁹Oncology, Medical Oncology Department, Hospital Universitario Ramon y Cajal (YRYCIS), Madrid, SPAIN, ¹⁰Oncology, Institut d’Oncologia de la Catalunya Sud (IOCS), Hospital Universitari Sant Joan de Reus, IISPV, Reus, SPAIN, ¹¹Oncology, Instituto Europeo di Oncologia (IEO), IRCCS, Milano, ITALY, ¹²Oncology and Hemato-Oncology (DIPO), University of Milan; European Institute of Oncology, IRCCS, Milan, ITALY, ¹³Oncology, Medica Scientia Innovation Research (MedSIR), Barcelona, SPAIN, ¹⁴Oncology, Hospital Ramón y Cajal; IOB Madrid, Hospital Beata María Ana, Madrid, SPAIN, ¹⁵Oncology, Hospital Universitari Dexeus; Medica Scientia Innovation Research (MedSIR), Barcelona, SPAIN, ¹⁶Oncology, IOB Madrid, Hospital Beata María Ana, Madrid, SPAIN, ¹⁷Translational, Medica Scientia Innovation Research (MEDSIR), Barcelona, SPAIN, ¹⁸Scientific Impact, Medica Scientia Innovation Research (MEDSIR), Barcelona, SPAIN, ¹⁹Data Analytics, Medica Scientia Innovation Research (MEDSIR), Barcelona, SPAIN, ²⁰Scientific, Medica Scientia Innovation Research (MEDSIR), Barcelona, SPAIN, ²¹Strategic Services, Medica Scientia Innovation Research (MEDSIR), Barcelona, SPAIN, ²²Oncology, Guardant Health, Palo Alto, CA, ²³Oncology, International Breast Cancer Center (IBCC), Pangaea Oncology,  Quiron  Group; IOB Madrid; Hospital Beata María Ana; Universidad Europea de Madrid; Hospital Universitario Torrejón, Ribera Group; Medica Scientia Innovation Research (MedSIR), Madrid, SPAIN.

IntroductionHER2-directed therapies have dramatically improved the outcome of patients (pts) with HER2[+]EBC, leading to the investigation of different de-escalation approaches. ctDNA is an emerging tool for risk stratification and real-time monitoring in EBC, offering the potential to personalize treatment decisions. The PHERGain study showed the feasibility of a FDG positron emission tomography (PET)-guided, pathological complete response (pCR)-adapted strategy to safely omit chemotherapy (CT) in pts with stage I-IIIA HER2[+] EBC undergoing neoadjuvant dual HER2 blockade with trastuzumab and pertuzumab (HP). The PET- and pCR-guided approach allowed omission of CT in 37.9% of pts, achieving a 3-year invasive-disease free survival (iDFS) rate (94.8%) in the overall adaptive group. In this sub-study, we assess a tumor-uninformed epigenomic-based ctDNA assay for minimal residual disease detection to improve the prediction of pCR and 3-year iDFS, thereby enabling more tailored (neo)adjuvant treatment strategies for HER2[+] EBC pts within the framework of the PHERGain study. MethodsDetails of the trial design and study population have been previously reported. Out of 356 randomized pts, 63 in group A (standard treatment) and 267 in group B (adaptive treatment) proceeded to surgery. The primary objective of the PHERGuide sub-study was to assess the correlation between ctDNA clearance after two treatment cycles and pCR (ypT0/is ypN0) in all included pts. Secondary objectives evaluated the association between ctDNA levels and patient outcomes. Blood samples were collected at baseline, after cycle 2 of neoadjuvant treatment, and pre-surgery. A total of 932 samples from 351 pts (336 baseline, 311 cycle 2, and 285 pre-surgery) were analyzed using Guardant Reveal^TM, a tumor-uninformed epigenomic assay that provides a binary ctDNA detection result along with an estimated tumor fraction. ctDNA clearance was defined as detectable ctDNA at baseline but undetectable at a subsequent time point. Categorical variables were analyzed using logistic regression models, and survival outcomes were assessed with Cox proportional hazards regression. ResultsOf the 932 samples, 801 were eligible for this sub-study (161 in group A and 640 in group B). ctDNA was detected in 204 of 288 (71%) baseline samples suitable for analysis. Detection rates were significantly correlated with disease stage: 33% (9/27) in stage I, 73% (154/217) in stage II, and 93% (41/44) in stage III tumors (p < 0.001). A total of 126/167 (75.4%) and 124/149 (83.2%) pts with detectable baseline ctDNA showed ctDNA clearance after two treatment cycles and prior to surgery, respectively. ctDNA clearance after two treatment cycles (p = 0.003) and at the pre-surgical time point (p < 0.001) was significantly associated with achieving a pCR. No significant correlation was observed between baseline ctDNA status and pCR (p = 0.583). No patient with detectable ctDNA prior to surgery (n = 25) achieved a pCR. ctDNA positivity at baseline was associated with worse 3-year iDFS (92.5% vs. 100%, HR 0.20; 95%CI 0.02-0.98; p = 0.046). ConclusionsThese findings demonstrate a significant correlation between ctDNA clearance and pCR in HER2[+] EBC pts undergoing neoadjuvant HER2-targeted therapy. Moreover, detectable ctDNA at baseline is associated with inferior 3-year outcomes. Further prospective studies are needed to confirm these results.

J. A. Sparano¹, V. Wang², R. J. Gray², D. F. Makower³, K. S. Albain⁴, D. F. Hayes⁵, C. E. Geyer⁶, E. C. Dees⁷, M. P. Goetz⁸, J. A. Olson⁹, S. S. Badve¹⁰, T. J. Saphner¹¹, T. J. Whelan¹², M. Radovich¹³, V. G. Kaklamani¹⁴, G. W. Sledge¹⁵; ¹Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, ²ECOG-ACRIN Biostatistical Center, Dana Farber Cancer Institute, Boston, MA, ³Department of Oncology, Montefiore Medical Center, New York, NY, ⁴Department of Medicine, Stritch School of Medicine at Loyola University, Maywood, IL, ⁵Department of Medicine, University of Michigan, Ann Arbor, MI, ⁶Department of Medicine, University of Pittsburgh, Pittsburgh, PA, ⁷Department of Medicine, University of North Carolina, Chapel Hill, NC, ⁸Department of Oncology, Mayo Clinic, Rochester, MN, ⁹Department of Surgery, Washington University, Saint Louis, MO, ¹⁰Department of Pathology, Emory University, Atlanta, GA, ¹¹Hematology and Medical Oncology, Aurora Cancer Care, Marinette, WI, ¹²Department of Radiation Oncology, McMaster University, Hamilton, ON, CANADA, ¹³Chief Scientific Officer, Caris Life Sciences, Irving, TX, ¹⁴Department of Medicine, University of Texas at San Antonio, San Antonio, TX, ¹⁵Chief Medical Officer, Caris Life Sciences, Irving, TX.

Background: The TAILORx trial established that adjuvant endocrine therapy (ET) is non-inferior to chemotherapy plus ET (CET) in T1-2N0 HR+/HER2-negative early breast cancer(EBC) with an Oncotype DX (ODX) 21-gene recurrence score (RS) of 11-25, RS 0-10is associated with low distant recurrence (DR) rates with ET alone, and RS26-100 is associated with higher DR rates despite CET. Although ODX is prognostic for 10-year DR, it has limited value for late DR >5 years. In order to develop improved DR risk prognostication, we developed multimodal AI models integrating clinical, molecular, and histopathology features to provide prognostic information for early (5 years), and overall DR at 15 years using primary tumor samples and clinical data from volunteers who participated in TAILORx.Methods: Digitized H&E slides were generated and nucleic acids extracted and sequenced from~5000 primary tumor samples using Caris MI Tumor Seek-Hybrid, of which 2,808(56%) were used for model training and 5-fold nested cross validation (60/20/20split). Models included single-modality (clinical [C], image [I], molecular [M:ODX genes]), dual-modality (CM, IC), and multimodal (ICM). An expanded molecular model (M+) model was also derived from expanded molecular inputs derived from whole transcriptome sequencing (WTS) data, including 5 commercial gene signatures (ODX, MammaPrint, Prosigna, EndoPredict, BCI) and 57 high-variance genes; only EndoPredict, BCI, and ODX gene signatures were retained for model M+. Model-CM+ combined clinical plus expanded molecular features, while ICM/ICM+ integrated image, clinical, and (expanded) molecular inputs. Risk scores were dichotomized into high vs. low risk groups using thresholds chosen to yield risk group proportions closely matching those defined by the ODX RS cutoff of 25 for distinguishing high vs. low genomic risk. The primary endpoint was distant recurrence (DR). Prognostic performance was assessed using truncated concordance index (C-index, 90th percentile of event times), hazard ratios (HRs), and log-rank tests. DNA-level whole exome sequencing (WES) features were also tested but did not provide additional prognostic information and thus excluded from final models. Results: The actual ODX continuous RS achieved a C-index of 0.625 for overall DR and 0.743early DR, but no prognostic value for late DR (0.52). Similar results for the C-index were observed for ODX+C for overall DR (0.619), early DR (0.724), and late DR (0.514). Of all models evaluated, model-ICM+ gave the best overall prognostic accuracy for overall DR (C-index0.713; hazard ratio [HR] 3.56 for comparison of high vs. low risk, p<0.001)and late DR (C-index 0.655; HR 2.36, p<0.001), and ranked second for early DR (C-index 0.772; HR 6.59, p<0.001) behind the CM+ model (C-index 0.782). Among single-modality models, Model-M+ improved early DR prognostication compared with a molecular model including only ODX genes(C-index 0.767 vs 0.744 for M),whereas Model-I was strongest for late DR prognostication (C-index 0.635).. Conclusions Molecular features primarily drove prognostic accuracy for early DR within 5 years, whereas histopathology features strengthened the prognostic accuracy for late DR after 5 years. Multimodal models captured these complementary signals, with ICM+ giving the best overall accuracy for individualized prognostic assessment. Additional validation of the optimized ICM+ model and other models is being performed in an intendent validation sample of 2000 TAILORx volunteers, with results to be presented at the meeting. Supported by the Breast Cancer Research Foundation and the U.S. NIH/NCI U10CA180820 and 5U24CA196172, and the U.S. Postal Service Breast Cancer Stamp Fund.

K. L. Jhaveri¹, Y. Park², C. Barrios³, G. Curigliano⁴, H. Iwata⁵, J. Cortés⁶, D. Loirat⁷, T. Pascual⁸, Z. Shao⁹, C. Araneda¹⁰, T. Yamashita¹¹, M. Tapia¹², P. Cinar¹³, S. Lam¹³, X. Ren¹³, W. Verret¹³, J. Kwan¹³, K. Punie¹⁴, H. S. Rugo¹⁵; ¹Memorial Sloan Kettering Cancer Center (MSKCC); Weill Cornell Medical College, New York, NY, ²Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, KOREA, REPUBLIC OF, ³Latin American Cooperative Oncology Group (LACOG), Porto Alegre, BRAZIL, ⁴European Institute of Oncology, IRCCS Milano, University of Milano, Milano, ITALY, ⁵Nagoya City University Graduate School of Medical Sciences Medical School, Nagoya, JAPAN, ⁶International Breast Cancer Center (IBCC), Pangaea Oncology, Quiron Group, Barcelona, Spain; Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain; Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, SPAIN, ⁷Institut Curie, Medical Oncology Department and IHU Cancers des Femmes, Paris, FRANCE, ⁸Cancer Institute and Blood Disorders, Hospital Clínic de Barcelona, Translational Genomics and Targeted Therapies in Solid Tumors Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Universitat de Barcelona, SOLTI Cancer Research Group, Barcelona, SPAIN, ⁹Fudan University Shanghai Cancer Center; Shangai Medical College, Fudan University, Shanghai, CHINA, ¹⁰Bradford Hill Clinical Research Center, Santiago, CHILE, ¹¹Kanagawa Cancer Center, Yokohama, JAPAN, ¹²Hospital Clínico Universitario of Valencia; Biomedical Research Institute INCLIVA, Valencia, SPAIN, ¹³Gilead Sciences, Inc., Foster City, CA, ¹⁴Ziekenhuis aan de Stroom, Antwerp, BELGIUM, ¹⁵City of Hope Comprehensive Cancer Center Duarte, Duarte, CA.

Background: Patients with hormone receptor positive (HR+)/ human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (mBC) refractory to endocrine therapy (ET) have poor prognosis with short progression-free survival (PFS), low overall survival (OS) rate, and limited treatment options. In the phase 3 TROPiCS-02 trial, sacituzumab govitecan (SG) significantly improved median PFS and OS vs chemotherapy in participants with HR+/HER2− mBC who had received prior chemotherapy. We report primary results from the randomized phase 3 ASCENT-07 study (NCT05840211) in adults with HR+/HER2−, locally advanced unresectable or mBC who have received prior ET and are candidates for first chemotherapy. Methods: Participants were randomized 2:1 to receive SG 10 mg/kg IV or chemotherapy treatment of physician’s choice (TPC; capecitabine, nab-paclitaxel, or paclitaxel). Randomization was stratified by duration of prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) use in the metastatic setting, HER2 IHC status, and geographic region. The primary endpoint was PFS by blinded independent central review (BICR) per RECIST v1.1. Key secondary endpoints were OS, objective response rate (ORR) by BICR, and quality of life; other secondary endpoints were PFS and ORR by investigator assessment, duration of response (DOR) by BICR and investigator assessment, and safety. Results: Of 690 participants randomized, 456 received SG and 234 received TPC. Median age was 57 years; 424 (93%) participants in the SG group and 215 (92%) in the TPC group received prior CDK4/6i for mBC. With median follow-up of 15.4 months, SG did not show statistically significant improvement in PFS by BICR vs TPC (hazard ratio [HR], 0.85; 95% CI, 0.69-1.05; P = 0.130). PFS by investigator assessment showed numerical improvement with SG versus TPC (HR, 0.78; 95% CI, 0.64-0.93; nominal P = 0.008). Although OS data were not mature at the primary analysis (maturity rate, 27%), an early trend in improvement favoring SG was observed (HR, 0.72; 95% CI, 0.54-0.97; nominal P = 0.029). ORR by BICR was similar with SG (37%) than with TPC (33%) and median DOR by BICR was longer (12.1 vs 9.3 months for SG and TPC, respectively). The most common grade ≥ 3 treatment-emergent adverse event (TEAE) in both treatment groups was neutropenia (SG: 56%; TPC: 21%). Despite higher proportion of participants experiencing grade ≥ 3 TEAEs with SG vs TPC, rates of dose reduction were similar and treatment discontinuation was lower with SG vs TPC (Table). Conclusions: The study did not meet the primary endpoint of PFS by BICR in participants with HR+/HER2−, locally advanced unresectable or mBC who have received prior ET and are candidates for first chemotherapy. No new safety concerns were identified. An early trend in improvement of OS was observed, and the study will continue to further assess OS.

A. Bardia¹, P. Schmid², M. Martín³, S. Hurvitz⁴, K. Jung⁵, M. Rimawi⁶, S. Saji⁷, G. Werutsky⁸, N. Harbeck⁹, S. Loi¹⁰, A. Ogiya¹¹, M. Ruiz-Borrego¹², A. Alacacıoğlu¹³, J. Wu¹⁴, C. Ye¹⁵, M. Liste-Hermoso¹⁶, N. Withana¹⁶, T. Badovinac Crnjevic¹⁷, M. Shah¹⁸, P. Pérez-Moreno¹⁹, C. Geyer, Jr.²⁰; ¹University of California Los Angeles, Los Angeles, CA, ²Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, UNITED KINGDOM, ³Universidad Complutense, GEICAM, CIBERONC, Madrid, SPAIN, ⁴Department of Medicine, UW Medicine, Fred Hutchinson Cancer Center, Seattle, WA, ⁵Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, KOREA, REPUBLIC OF, ⁶Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, ⁷Department of Medical Oncology, Fukushima Medical University, Fukushima, JAPAN, ⁸Breast Cancer Program, Latin American Cooperative Oncology Group and Centro de Pesquisa em Oncologia, Hospital Sao Lucas PUCRS, Porto Alegre, JAPAN, ⁹Department of Obstetrics and Gynecology, LMU University Hospital, Munich, GERMANY, ¹⁰Division of Cancer Research, Peter MacCallum Cancer Centre and The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, AUSTRALIA, ¹¹Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, JAPAN, ¹²Breast Cancer Unit, Hospital Universitario Virgen del Rocío, Sevilla, SPAIN, ¹³Department of Oncology, İzmir Kâtip Çelebi University, Atatürk Training and Research Hospital, İzmir, TURKEY, ¹⁴Department of Breast Surgery, Cancer Hospital/Institute, Fudan University, Shanghai, CHINA, ¹⁵Department of Oncology Biostatistics, Genentech, Inc., South San Francisco, CA, ¹⁶Global Product Development – Clinical Science Oncology (PDOH), F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, ¹⁷PDO – Clinical Science Oncology, F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, ¹⁸Product Development Safety, Genentech, Inc., South San Francisco, CA, ¹⁹Product Development Oncology/Hematology (PDOH), Genentech, Inc., South San Francisco, CA, ²⁰Department of Medicine, University of Pittsburgh School of Medicine-UPMC Hillman Cancer Center, Pittsburgh, PA.

Background: Adjuvant (adj) endocrine therapy (ET) is the mainstay treatment (tx) for estrogen receptor-positive, HER2-negative early breast cancer (ER+ HER2- eBC). However, up to 1/3 of patients (pts) eventually experience recurrence. Clinically, there is an unmet need for more tolerable and efficacious ET to improve adherence and pt outcomes. Giredestrant, a next-generation oral selective estrogen receptor antagonist and degrader (SERD), was shown to be more potent than other SERDs (Liang 2021; Bardia 2023) and demonstrated superior antiproliferative activity vs anastrozole in the neoadj coopERA BC trial (Hurvitz 2023). Results of the prespecified interim analysis of the global, randomized lidERA BC trial (NCT04961996) are presented. Methods: Pts with Stage I-III ER+ HER2- eBC were randomized 1:1 to giredestrant 30 mg oral daily (with an LHRH agonist in pre- and peri-menopausal women, and men) or standard-of-care ET (tamoxifen or aromatase inhibitor) for 5 years (yr). The primary endpoint was invasive disease-free survival (IDFS). Key secondary endpoints were overall survival (OS), distant recurrence-free interval (DRFI), and safety. Results: 4170 pts were randomized (Aug 2021-Sep 2023): 2084 to giredestrant; 2086 to standard-of-care ET. Median age was 54.0 yr; 59.3% of pts were postmenopausal; 13.0%, 47.4%, and 39.6% had Stage I, II, and III BC, respectively. Median follow-up at clinical cutoff (Aug 8, 2025) was 32.3 months, with 336 IDFS events. Efficacy is shown in the table. Giredestrant demonstrated superior IDFS vs standard-of-care ET (hazard ratio [HR] 0.70; 95% confidence interval [CI], 0.57, 0.87; p = 0.0014). 3-yr IDFS rates were 92.4% and 89.6%, respectively. There was a trend towards OS improvement in the giredestrant arm vs the standard-of-care ET arm (HR 0.79; 95% CI, 0.56,1.12). The DRFI HR was 0.69 (95% CI, 0.54, 0.89). The most common adverse events (AEs) in the giredestrant vs standard-of-care ET arms, respectively, were arthralgia (48.0% vs 47.1%), hot flush (27.4% vs 28.8%), and headache (15.3% vs 13.2%); the most common Grade 3-4 AEs, hypertension (2.6% vs 2.0%) and arthralgia (1.5% vs 1.8%). Discontinuations due to AEs occurred in 5.3% with giredestrant vs 8.2% with standard-of-care ET. Conclusions: lidERA BC is the first Phase III trial to demonstrate benefit with an oral SERD in eBC. Giredestrant tx resulted in a statistically significant and clinically meaningful IDFS improvement vs standard-of-care ET in ER+, HER2- eBC. OS trended in favor of the giredestrant arm, and DRFI was improved vs standard-of-care ET. The safety profile was favorable and consistent with known profiles, and the discontinuation rate was slightly lower with giredestrant compared with standard-of-care ET. Overall, the results support giredestrant as a potential new standard for pts with HR+ eBC.