Comparative efficacy of first- versus second-line CDK4/6 inhibition in hormone receptor-positive, HER2-negative metastatic breast cancer and Genomic biomarkers of ipatasertib response for hormone receptor-positive metastatic breast cancer in the TAKTIC trial

Abstract

In our first project, we evaluated the comparative effectiveness of first-line (1L) versus second-line (2L) use of CDK4/6i in HR+/HER2-mBC using a systematic review and reconstructed individual patient data meta-analysis of 7,602 patients. We found that deferring CDK4/6i to the second-line setting was associated with worse PFS2 in the overall population; however, no significant difference in OS was observed between treatment strategies. Notably, when analyses were restricted to randomized clinical trials, both PFS2 and OS were similar between 1L and 2L use, challenging the assumption that earlier use of CDK4/6i universally improves outcomes. These findings have important clinical implications. Early use of CDK4/6i is associated with increased treatment duration, higher toxicity, and substantial cost, without clear survival benefit. Together, these results question the “always first-line” paradigm and highlight the need for more tailored treatment strategies. In selected patients, initial endocrine therapy alone may be a reasonable approach, reserving CDK4/6i for later lines of therapy. In our second project, we investigated genomic biomarkers of response and resistance to the AKT inhibitor, ipatasertib, in endocrine-resistant metastatic breast cancer using data from the phase Ib TAKTIC trial. Among 47 heavily pretreated patients, median progression-free survival was 5.72 months. PI3K/AKT pathway alterations were associated with improved outcomes specifically in patients receiving triplet therapy (ipatasertib, endocrine therapy, and CDK4/6i), but not in the overall cohort. In contrast, ESR1 mutations, FGFR1 amplifications, and EGFR alterations were associated with shorter PFS. Paired ctDNA analyses further demonstrated the emergence of genomic alterations at disease progression, suggesting potential mechanisms of acquired resistance. These findings highlight the dynamic nature of tumor evolution and the potential role of ctDNA in the identification of novel therapeutic targets. Overall, this thesis addresses two critical challenges in metastatic breast cancer: optimizing treatment sequencing and advancing biomarker-driven precision oncology. Together, these studies support a more individualized approach to therapy, emphasizing that effective treatment depends not only on selecting the right drug, but also on identifying the right timing and the right patient.