Abstract 5923: The genetic landscape of metastatic breast cancer reflected in circulating tumor DNA

Abstract

Abstract Tissue biopsies of breast tumors only provide a snapshot of the evolution of the disease and may miss potential therapeutic targets, especially in the metastatic setting. Plasma-derived cell-free tumor DNA constitutes a potential surrogate for tumor DNA obtained from tissue biopsies to potentially capture inter-and intra-tumoral heterogeneity present in metastatic breast cancer. We aimed to investigate to what extent variants identified in the primary tumor and metastases are reflected in plasma. We performed whole-exome sequencing on tumor DNA from primary and metastatic lesions and plasma-derived circulating tumor DNA of eight patients with metastatic breast cancer. Our results show that metastases most often follow parallel evolution, given the low levels of stem mutations detected between primary tumors and matched metastases and mutational events private to the primary tumor. Furthermore, we demonstrated that ctDNA mainly reflected old stem mutations shared between primary tumor and metastasis, and less often, genetic alterations found solely in primary tumor or metastasis. Lastly, clinically relevant variants, e.g., resistance mutations detected in primary tumor and metastasis, were to some extent reflected in ctDNA, including affected genes MET, MTOR, CDK6, PIK3CA, and GATA3. However, mutations in MED1, NCOR1, and NCOR2 were only found in tumor tissues. These findings support the importance of a metastatic deposit biopsy to guide treatment decisions. Together, our results have implications for future ctDNA studies. For monitoring tumor burden using ctDNA, our results suggest that truncal mutations are the best candidates, as they are highest in circulating levels. For confident tracking of subclonal mutations in ctDNA, liquid biopsies are not yet to substitute metastatic tissue biopsies and instead demonstrate support to the current gold standard. Citation Format: Stephanie Kavan. The genetic landscape of metastatic breast cancer reflected in circulating tumor DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5923.