Background: The impact of obesity on the efficacy of endocrine treatment (ET) in patients with estrogen receptor positive (ER+) breast cancer (BC) is poorly investigated. Several neoadjuvant trials, using changes in Ki67 as biomarker of anti-proliferative response, have demonstrated that neoadjuvant ET improves surgical and clinical outcomes. A recent study has shown that the subgroup of patients with an anti-proliferative response to neoadjuvant aromatase inhibition has a better prognosis as compared to the other patients (Smith et al., The Lancet 2020). However, it is unclear if obesity, and mammary adiposity are associated with anti-proliferative response. Material and Methods: We included 56 post-menopausal patients with ER+ BC that were treated with 4 months of neoadjuvant letrozole in a single institution. Body mass index (BMI) was categorized according to the WHO criteria and considered both as categorical and continuous variable. Centralized Ki67 assessment was performed as per study protocol. Consistently with previous neoadjuvant clinical trials, Ki67 index was dichotomized (<14% and ≥14%) identifying three groups of patients according to Ki67 at baseline (Ki67bl) - Ki67 at surgery (Ki67srg) (“high - high”, “high - low”, “low - low”). Anti-proliferative response was defined as “high - low”, absence of response as “high - high” while “low - low” were excluded from the response analysis. Digital assessment of mammary adipocytes (distant from the tumor and cancer-associated adipocytes - CAAs) and assessment of tumor infiltrating lymphocytes (TILs) were performed on scanned H&E BC slides, derived from surgical specimens. We performed univariate and multivariable logistic regressions adjusted for Ki67bl to evaluate the association of BMI, adipocyte size, TILs (dichotomized at 10%) with response to ET. The Wilcoxon rank-sum test was performed to evaluate the association between adipocyte size and histology. Results: 13 (23.2%), 20 (35.7%), and 23 (41.1%) patients were lean, overweight and obese, respectively. BMI did not show any significant association with the standard clinico-pathological characteristics. A significantly higher proportion of tumors with an anti-proliferative response was observed in obese patients as compared to lean and overweight patients (86%, 25%, 80% respectively, p = 0.03). A significant association between BMI (obese vs lean) and anti-proliferative response, was observed by the multivariable analysis (odds ratio (OR): 13.76, 95% Confidence Interval : 95%CI: 1.48 - 207.63, p = 0.02). A similar trend was observed when considering BMI as a continuous variable (OR: 1.19, 95%CI: 1.00 - 1.50, p = 0.04). Larger distant adipocyte size (diameter and area) was further identified as an independent predictor of anti-proliferative response (OR: 11.75, 95%CI: 10.02 - 17.02, p = 0.04, OR: 100.15, 95%CI: 100.01 - 100.55, p = 0.02). At the exploratory level, we showed an association between low TILs (< 10%) and anti-proliferative response, although not significantly (OR: 0.16, 95%CI: 0.01 - 1.20, p = 0.06). Finally, we showed that lobular BC patients (n = 10) had smaller CAAs diameter and area compared to ductal BC patients (n = 25; median diameter 44.00 µm and 49.32 µm; median area 1681 µm2 and 2122 µm2; respectively, p = 0.04) reflecting a possible differential tumor cell/adipocyte interaction according to the BC histology. Conclusions: This study suggests that anti-proliferative response to neoadjuvant aromatase inhibition might be more frequent in patients with increased adiposity as compared to lean patients. These observations, which need to be confirmed in larger series of patients, highlight the need of investigating treatment efficacy and BC biology according to the adiposity of the patient.

Citation Format: Edoardo Isnaldi, François Richard, Maxim De Schepper, Sophia Leduc, Marion Maetens, Tatjana Geukens, Karen Van Baelen, Ha-Linh Nguyen, Ghizlane Rouas, Gabriele Zoppoli, Fatima Cardoso, Christos Sotiriou, Denis Larsimont, Giuseppe Floris, Elia Biganzoli, Christine Desmedt. The association between adiposity and anti-proliferative response to neoadjuvant endocrine therapy with letrozole in post-menopausal patients with estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-02-02.