Multimodal liquid biopsy approach for the identification of predictive biomarkers for CDK4/6 inhibitor therapy in patients with breast cancer

• Applicant: Dr. Corinna Keup
• Subject Area: Gynaecology and Obstetrics ; Hematology, Oncology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 493185725

CDK4/6 inhibitors are still a relatively new treatment option for patients with metastatic hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC). However, predictive markers to differentiate patients with higher vs. lower response probability are not known.The liquid biopsy analytes circulating tumor cells (CTCs), cell-free DNA (cfDNA), and extracellular vesicles (EVs) reflect the tumoral heterogeneity. We have previously demonstrated the feasibility of a multimodality liquid biopsy approach in HR+/HER2- BC patients. The multimodal strategy planned here includes four dimensions of information: mutation (established) and methylation (to be established) analysis of cfDNA and controls (buffy coat) by targeted next generation sequencing (NGS), and parallel analysis of EVs and their mRNA (established) and miRNA (to be established) by multimarker qPCR. Blood samples from 80 patients prior to first-line therapy with CDK4/6 inhibitors will now be studied to identify novel predictive biomarkers for resistance to CDK4/6 inhibitors using multimodal liquid biopsy (primary endpoint). In addition, paired blood samples from the same 80 patients will be exploratively analyzed after six months of CDK4/6 inhibitor therapy to investigate the translation of the identified predictive markers for therapy success monitoring. The specificity of the identified predictive biomarkers with respect to line of therapy and CDK4/6 inhibitor therapy will also be exploratively tested with two additional cohorts (n=40 in second or more line of therapy and n=20 treated with endocrine monotherapy). Multimodal liquid biopsy will be accompanied by genomic analysis of paired metastatic tissue.

• DFG Programme: Research Grants