Title: Adding Adjuvant Drugs From Distinct Breast Cancer Trials.

Studies conducted in perioperative settings have recently expanded the treatment options for early-stage operable breast cancer. These studies have different inclusion criteria, however they are not entirely mutually exclusive. It results that multiple treatment options may be available to the same patient, making the choice of therapy a significant challenge. The concurrent or sequential administration of these therapies has been suggested by expert panels or international guidelines. Yet combining therapeutic strategies that have been independently tested can be problematic. It is possible that the same subset of patients benefits from each therapy individually, meaning that combining them might offer no additional benefit. Moreover, the toxicity of those combinations - short and long-term - has not been assessed in phase 3 trials. Whether these toxicities and dose reductions offset gains is unknown. Here, we offer clinical scenario where this could happen, like combining pembrolizumab plus olaparib in triple-negative breast cancer, or olaparib plus CDK4/6 inhibitors in hormone receptor-positive disease. Although each therapy has shown efficacy in individual trials, the net gain of their combined or sequential use in the peri-operative setting remains unproven in phase 3 trials. This dilemma extends well beyond breast cancer as a growing number of agents continue to be approved in neoadjuvant or adjuvant space. A cautious evidence-driven approach is needed to ensure these strategies truly benefit patients. This could have important policy implications, including regulatory enforcement for combination trials rather than extrapolating from monotherapy data.