Estradiol Levels According to Body Mass Index in Premenopausal Patients With Breast Cancer (SIMPEC-E2)

This is a multicenter, prospective, observational cohort study designed to evaluate the association between body mass index (BMI) and serum estradiol levels in premenopausal women with hormone receptor-positive invasive breast cancer receiving adjuvant endocrine therapy with an aromatase inhibitor combined with pharmacologic ovarian suppression using a gonadotropin-releasing hormone analog.

All endocrine treatments will be prescribed as part of routine clinical care. Participation in the study will not determine the selection, dose, schedule, continuation, or modification of anticancer treatment. No experimental intervention, treatment allocation, or randomization is planned.

Approximately 172 participants will be enrolled. For the primary analysis, participants will be classified according to World Health Organization BMI categories and grouped as having normal BMI or overweight/obesity. At enrollment, demographic, anthropometric, clinical, and oncologic information will be collected, including tumor characteristics, previous cancer treatment, type and timing of aromatase inhibitor and ovarian suppression therapy, concomitant medications, physical activity, and use of glucagon-like peptide-1 receptor agonists.

Weight and height will be measured to calculate BMI. Serum estradiol will be assessed using an ultrasensitive laboratory method. A baseline estradiol measurement may be obtained when applicable, depending on the timing of enrollment. The main estradiol assessment will be performed after approximately three months of combined aromatase inhibitor therapy and pharmacologic ovarian suppression, within a protocol-defined visit window of plus or minus 14 days. If a result suggests inadequate estrogen suppression, an additional measurement may be requested within 14 days using a different laboratory method, according to institutional practice and local availability.

The primary outcome is the proportion of participants with inadequate estrogen suppression, defined as a serum estradiol concentration greater than 2.72 pg/mL after approximately three months of treatment. This proportion will be compared between participants with normal BMI and those with overweight/obesity.

Secondary and exploratory analyses will evaluate absolute estradiol concentrations across BMI categories, the correlation between BMI and serum estradiol, a potential BMI cutoff associated with inadequate estrogen suppression, and clinical characteristics associated with inadequate suppression. Exploratory subgroup analyses will consider previous chemotherapy, physical activity, and use of glucagon-like peptide-1 receptor agonists.

The primary comparison will use a chi-square test or Fisher's exact test, as appropriate. Binary logistic regression will assess the association between BMI and inadequate estrogen suppression, with BMI evaluated as both a categorical and continuous variable and adjustment for clinically relevant potential confounders. Continuous outcomes will be analyzed using parametric or nonparametric methods according to their distributions. The relationship between BMI and estradiol concentration will also be assessed using Spearman correlation, and receiver operating characteristic curve analysis will be used to explore a potential BMI cutoff associated with inadequate estrogen suppression.