CDK4/6 inhibitors in advanced breast cancer Improving treatment strategies and patient outcomes

As treatment options for advanced breast cancer continue to expand, patients and clinicians face important questions about how to optimally sequence treatments to maximize patient benefit in terms of quality of life and overall survival, while minimizing toxicity and other potential negative aspects of treatments such as costs. This thesis describes the results of the phase 3 SONIA trial, which investigated the optimal timing of adding CDK4/6 inhibitors to endocrine therapy in hormone receptor-positive, HER2-negative advanced breast cancer. The trial demonstrates that first-line CDK4/6 inhibitor use does not improve progression-free survival after two treatment lines or overall survival compared with second-line use, but does increase toxicity for patients and leads to substantially higher drug expenditures for societies (part I). Several predefined and post-hoc subgroups were evaluated to assess whether any subgroup benefits from first-line CDK4/6i use. In addition, the SONIA trial highlights the importance of study designs that include mandatory crossovers when evaluating optimal treatment sequencing. Part II investigates resistance mechanisms to both CDK4/6 inhibitor treatment and endocrine therapy and shows that both cell line models and circulating tumor DNA can provide valuable insights into acquired resistance pathways.