Obesity predicts greater changes in Ki67 after neoadjuvant aromatase inhibitor therapy in early-stage ER+ breast cancer

Background: Nearly 70% of breast cancers are ER positive (ER+), and anti-estrogen therapy, such as tamoxifen and aromatase inhibitors (AI), are a mainstay of treatment. Neoadjuvant endocrine therapy (NET) with aromatase inhibitors is effective at reducing tumor burden and may be predictive of better long-term outcomes. A significant decrease in Ki-67 is prognostic but additional predictive clinical factors for improved response to NET are not well understood. Preliminary data from our post-menopausal cohort of women with ER+ early-stage breast cancers treated with NET presented at the San Antonio Breast Cancer Symposium 2025, showed correlation between larger tumor sizes and greater radiographic response to NET with 68% of tumors exhibiting a radiographic response. Women with higher BMI have a higher risk of breast cancer recurrence and mortality, hypothesized to be due to incomplete suppression of aromatase but specific data on response to NET is lacking. Objective: Determine the association between BMI and change in Ki67 expression after NET in patients with early-stage breast cancer. Methods: 150 post-menopausal women with Stage I-III ER+, HER2- breast cancer were treated with an aromatase inhibitor for 7-168 days (mean 42.83 days) prior to surgery and had BMI, pre- and post-NET Ki67 immunohistochemistry available. Digital Ki-67 analysis on the diagnostic biopsy before NET was compared to Ki-67 on the surgical specimen. Statistical analysis determined p-values from the pairwise t-test. Control group analysis is in progress. Results: The mean Ki-67 prior to NET was 18.62% (range 0.69%- 61.56%). The mean Ki-67 after NET was 4.17% (range 0.04%- 46.07%). The mean radiographic baseline tumor size 20.9 mm. We found that both BMI and the baseline tumor size significantly correlated with Ki-67 expression difference (p=0.038 and p= 0.026, respectively). For example, based on our analysis, it is expected that women with a BMI = 30, there will be a two-fold decrease in post-NET Ki-67 expression. There was no significant correlation between change in Ki-67 and number of days on NET. Discussion: In our cohort, higher BMI was associated with a greater decrease in Ki-67 expression compared to women with BMI <30, suggesting greater suppression of cell proliferation by NET in obese women. Suppression of Ki-67 is considered a good prognostic indicator, therefore this preliminary data contradicts the hypothesis that poorer outcomes for women with breast cancer and a BMI >30 are due to insufficient response to aromatase inhibitors. Additional research is needed to further elucidate these findings and validate this data against long-term AI adherence and other predictors of outcomes.