2273P - Influence of body mass index (BMI) on the response to chemotherapy in patients with HER2+ breast cancer: Role of the leptin axis

Background

Obesity is associated with T-cell dysfunction and high PD-1 expression, resulting in paradoxical benefit from check-point inhibitor therapy. This effect is driven, in part, by leptin that exerts its action through binding to the leptin receptor (Ob-R), which is highly expressed in HER2+ BC. High tumor infiltrating lymphocytes (TILs) counts correlate with pathological response and long-term outcomes in BC, but the precise mechanism is not known. The aim of this study was to investigate the role of BMI in modulating TILs and pathological responses in early HER2+ BC patients who received neoadjuvant systemic treatment (NST).

Methods

Women with HER2+ BC receiving anti-HER2-based NST followed by surgical resection were included. Patient age, menopausal status, and height/weight (to calculate BMI) were recorded. Based on biopsy findings, tumors were categorized as HER2+/HR+ and HER2+/HR-. Ob-R expression was also measured and classified as over-expressed if there were >50% positive cells with weak or strong staining. TILs and PD-1 expression were determined centrally using pre-treatment biopsies. TILs were considered as continuous variables and binary, <30 vs ≥30%, and PD-1 as positive (>1%). Associations with pathological complete response (pCR) were assessed statistically.

Results

27 of 85 HER2+ BC patients were overweight/obese (BMI ≥25kg/m²). Patients with high BMI tended to have tumors with higher hormone receptor expression than lean patients (85 vs 64%; p=0.078). No differences were found in median Ki67 between the high or low BMI groups. A greater number of high BMI patients were menopausal (63 vs. 36%; p=0.038). Patients with high BMI had a significantly greater expression of Ob-R vs lean patients (78 vs 55%; p=0.045) and at the same time had a significantly higher expression of TILs (median 23 vs 16%; p=0.007). Despite having higher TIL counts, pCR were similar (63.0 vs 58.6%; p= 0.704). However, PD-1 expression was significantly higher in patients with high BMI (median 4 vs 1; p=0.012).

Conclusions

Our study shows for the first time how obesity, through the Ob-R/leptin axis, might activate TILs. However, this was not translated into higher CR; probably due to high PD-1 expression as exhaustion feature.

Clinical trial identification

Editorial acknowledgement

Editorial assistance was provided by Content Ed Net (Madrid, Spain).

Legal entity responsible for the study

The authors.

Funding

Roche, ACS Foundation.

Disclosure

J. Pérez García: Financial Interests, Personal, Advisory Role: Lilly, Roche, Eisai, Daiichi Sankyo, AstraZeneca, Seattle Genetics, Gilead; Financial Interests, Personal, Other, Travel expenses: Roche. J. Cortés: Financial Interests, Personal, Advisory Role: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, GEMoaB, Gilead, Menarini, Zymework; Financial Interests, Personal, Funding: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, Daiichi Sankyo, AstraZeneca; Non-Financial Interests, Institutional, Research Funding: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F. Hoffmann-La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, PIQUR Therapeutics, Puma C, Queen Mary University of London; Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Pharmaceuticals, Leuko (relative); Other, Personal, Other, Travel, accommodation, expenses: Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca, Gilead; Financial Interests, Personal, Other, Patents: Pharmaceutical Combinations of A Pi3k Inhibitor and A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. Issued. L. García Estevez: Financial Interests, Personal, Advisory Role: Roche, AstraZeneca, Daiichi Sankyo, Gilead. All other authors have declared no conflicts of interest.