Systemic cytokine dynamics during neoadjuvant chemotherapy versus endocrine therapy and CDK4/6 inhibition in high-risk luminal breast cancer: Results from the GEICAM/2019-01-CARABELA trial.
Year: 2026
Type: conference-abstract
Abstract: 619 Background: Chemotherapy (CT) and CDK4/6 inhibitors modulate antitumor immunity primarily within the tumor microenvironment. Whether these effects are reflected systemically during neoadjuvant therapy, differ by treatment, or are associated with response remains unclear. Methods: CARABELA is a randomized neoadjuvant trial comparing letrozole (ET) + the CDK4/6 inhibitor abemaciclib vs standard CT in high-risk HR+/HER2− breast cancer. Plasma cytokines were measured at baseline (BL), 2 weeks (wks), 12 wks, and end of treatment (EOT) using multiplex proximity extension assay (Olink Target 96 Immuno-Oncology panel). Analyses included: (1) BL cytokine profiles by menopausal status, Oncotype DX Breast Recurrence Score test result (RS ≤25 vs >25), and Ki67 (<40% vs ≥40%); (2) longitudinal cytokine changes (BL to 2 and 12 wks, Δ) by residual cancer burden (RCB 0/I vs II/III), overall and by treatment; (3) EOT cytokine profiles by RCB. Group comparisons were adjusted by false discovery rate (FDR) threshold of 5% controlled by the q-value method. Multivariable logistic regression models were adjusted for menopausal status. Treatment–cytokine interactions were evaluated. Results: At BL, 40 cytokines were differentially expressed by menopausal status, with most showing higher levels in postmenopausal patients, including myeloid-associated inflammatory chemokines (CXCL9, CXCL10, MCP-1, MCP-4), angiogenic/matrix-remodeling factors (VEGFA, HGF, MMP7, MMP12), and TNF-related/immune regulatory molecules (TNFRSF12A, TNFRSF9, Galectin-9), indicating chronic systemic inflammation, without enrichment of cytotoxic immune effector programs. No BL cytokine differences met FDR threshold by RCB, RS or Ki67. Early cytokine changes (BL-2 wks) were not associated with RCB. In the ET + abemaciclib arm, no significant changes were observed between BL and 12 wks. In the CT arm, 25 cytokines had a significant increase (BL-12 wks) in patients with RCB II/III with respect to patients with RCB 0/I. These included inflammatory chemokines (IL8, CXCL1, CXCL5, CCL3, CCL4, MCP-3, MCP-4), angiogenic/growth factors (VEGFA, ANGPT1, EGF, PDGF-B), and stress-/TNF-related signaling molecules (CASP-8, TNFSF14, ADA). These cytokines were associated with RCB II/III in multivariable models adjusted for menopausal status. Cytokine–treatment interaction tests did not meet FDR threshold. Conclusions: Postmenopausal women display a distinct cytokine profile consistent with chronic systemic inflammation. Neoadjuvant CT induces pronounced systemic cytokine changes, while ET + CDK4/6 inhibition does not. Increased inflammatory and angiogenic cytokines during CT are associated with residual disease, supporting longitudinal systemic immune profiling as a marker of treatment resistance in high-risk luminal breast cancer. Clinical trial information: NCT04293393 .
Source: Journal of Clinical Oncology
Authors: Angel Guerrero-Zotano, Miguel Martin, Maria Eva Perez-Lopez, Noelia Martinez-Jañez, Juan David Cardenas, Miguel Gil Gil, Manuel Ruiz-Borrego, Pedro Sanchez-Rovira, Sonia Del Barco, Begoña Bermejo, Raquel Andrés, Jose Juan Ponce-Lorenzo, Eduardo Martínez-De Dueñas, Jesús Herranz, Rosalia Caballero, Marta Portela, Maria M. Caffarel, Federico Rojo, Maria Jose Lallena, Emilio Alba
Institutions: Fundación Instituto Valenciano de Oncología, GEICAM – Spanish Breast Cancer Group, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Cáncer, Instituto de Investigación Sanitaria Gregorio Marañón, Complexo Hospitalario Universitario A Coruña, Hospital Universitario Ramón y Cajal, Hospital Universitario de Toledo, Institut d'Investigació Biomédica de Bellvitge, Institut Català d'Oncologia, Hospital Universitario Virgen del Rocío, Complejo Hospitalario de Jaén, Universitat de València, Hospital Clínico Universitario de Valencia, INCLIVA Health Research Institute, Hospital Clínico Universitario Lozano Blesa, Hospital General Universitario de Alicante Doctor Balmis, Consorcio Hospitalario Provincial de Castellón, Ikerbasque, Biogipuzkoa Health Research Institute, Centro de Investigación Biomédica en Red, Hospital Universitario Fundación Jiménez Díaz, Eli Lilly (Spain), Hospital Clínico Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W7162533979
Cites:
Cited by:
Related to: