Body mass index in postmenopausal women with estrogen receptor-positive, HER2-negative early breast cancer: An exploratory analysis of the LORELEI trial.

BACKGROUND

Phosphoinositide 3-kinase (PI3K) pathway, involved in obesity-related signalling, may influence efficacy and toxicity of PI3K inhibitors (PI3Ki). We explored associations between body mass index (BMI) and objective response rate (ORR), safety, molecular features, and breast density in the LORELEI trial.

METHODS

LORELEI (NCT02273973) was a randomized trial evaluating neoadjuvant PI3Ki taselisib plus letrozole vs placebo plus letrozole in patients with estrogen receptor-positive/HER2-negative early breast cancer. Patients were classified as normal weight (BMI 18.5-24.9 kg/m²), overweight (25-29.9 kg/m²), or obese (≥30 kg/m²). Logistic regression tested BMI by treatment arm, adverse events were analysed descriptively by BMI category. Immune composition and gene expression profiles were evaluated by RNA sequencing.

RESULTS

Of 329 patients, 98 (29.8%) were classified as normal weight, 125 (38%) as overweight, and 106 (32.2%) as obese. In the placebo arm, higher BMI was associated with lower ORR [odds ratio (OR) 0.90, 95% CI 0.83-0.97]; no association was observed in the taselisib arm [OR 1.03, 95% CI 0.96-1.11; interaction p = 0.007 (unadjusted), p = 0.013 (adjusted)]. In patients with obesity the incidence of hyperglycaemia and diarrhoea was 15.1% and 24.5%, respectively. Higher levels of pS6, a downstream effector of the PI3K pathway, were associated with increased ORR in patients with obesity in the placebo arm (interaction p = 0.011). Patients with obesity had lower baseline breast density (p < 0.001), not associated with ORR. Obesity was associated with increased IL6 expression, immune cell infiltration, and fatty acid metabolism signature.

CONCLUSIONS

Obesity was associated with lower ORR with letrozole alone, whereas this association was not observed in patients treated with taselisib.