Association of Body Mass Index with Tumor-Infiltrating Lymphocytes and Treatment Response in Early HER2-Positive Breast Cancer

Rosa Sánchez Gómez,1,2 Belén Pérez-Míes,3– 6 José Palacios,3– 6 Gema Moreno Bueno,2,4,7,8 Isabel Calvo,1,2 José L Solorzano,9 Fernando Neria,10 María Fernandez-Abad,6,7,11 Silvia González-Martínez,3,4,12 Laura García-Estevez1,2,4 1Breast Cancer Department, MD Anderson Cancer Center, Madrid, Spain; 2MD Anderson Cancer Center Foundation, Madrid, Spain; 3Molecular Pathology of Cancer Group, Ramón Y Cajal Health Research Institute (IRYCIS), Madrid, Spain; 4Centre for Biomedical Research in Cancer Networks (CIBERONC), Carlos III Health Institute, Madrid, Spain; 5Department of Pathology, Ramón y Cajal University Hospital, Madrid, Spain; 6Faculty of Medicine, University of Alcalá, Madrid, 28801, Spain; 7Area 3 Cancer, Instituto Ramón Y Cajal de Investigación Sanitaria (IRYCIS), Madrid, 28034, Spain; 8Biochemistry Department, Universidad Autonoma de Madrid (UAM), Instituto de Investigaciones Biomedicas ‘Alberto Sols’ (CSIC-UAM), Madrid, Spain; 9Pathology Department, MD Anderson Cancer Center, Madrid, Spain; 10Faculty of Medicine, Universidad Francisco de Vitoria, Madrid, Spain; 11Breast Cancer Department, Hospital Ramon y Cajal, Madrid, Spain; 12“Contigo Contra el Cáncer de la Mujer” Foundation, Madrid, SpainCorrespondence: Laura García-Estevez, Breast Cancer Department, MD Anderson Cancer Center, C. de Arturo Soria, 270, Cdad. Lineal, Madrid, 28033, Spain, Email [email protected]: Immune-related biomarkers such as stromal tumor-infiltrating lymphocytes (TILs) are associated with response to neoadjuvant therapy in HER2+ breast cancer. Host-related factors, including BMI, may influence the tumor immune microenvironment and modify the predictive value of immune infiltration.Methods: In this retrospective cohort study, we evaluated associations between BMI, stromal TIL density, selected immune checkpoint markers (PD-1 and TIM-3), leptin receptor (Ob-R) expression, and pathological complete response (pCR) in patients with early-stage HER2+ breast cancer treated with neoadjuvant HER2-targeted therapy.Results: Of 101 patients analyzed, 48.0% had a BMI ≥ 25 kg/m2. Patients with BMI ≥ 25 kg/m2 exhibited higher stromal TIL density (p = 0.011), higher frequency of PD-1 positivity (p = 0.058), and higher Ob-R expression (p = 0.043). BMI was not directly associated with pCR. In multivariable analysis, hormone receptor positivity was inversely associated with pCR (odds ratio [OR] = 0.15; 95% confidence interval [CI], 0.04– 0.51; p = 0.004), whereas higher stromal TIL density was independently associated with increased odds of pCR (OR = 1.37; 95% CI, 1.03– 1.93; p = 0.048). A significant interaction observed between BMI and stromal TIL density (interaction OR = 0.99; 95% CI, 0.97– 1.00; p = 0.044) indicated that the association between immune infiltration and treatment response differed according to BMI. In early-stage HER2+ breast cancer, stromal TIL density and PD-1 expression are associated with response to neoadjuvant therapy, while BMI appears to modify the relationship between immune infiltration and pCR.Conclusion: Host-related factors, as captured by BMI, may influence the tumor immune microenvironment and predictive value of immune biomarkers in early-stage HER2-positive breast cancer. As the study was exploratory, these observations warrant further study.Keywords: body mass index, human epidermal growth factor receptor 2-positive breast cancer, obesity, treatment response, tumor-infiltrating lymphocytes