The Subclonal Architecture of Metastatic Breast Cancer: Results from a Prospective Community-Based Rapid Autopsy...

Area of Science:

• Oncology
• Genomics
• Cancer Biology

Background:

• Understanding cancer genome evolution is crucial for improving patient outcomes.
• Genomic assays offer potential for personalized breast cancer medicine.
• The evolution of cancer genomes and disease profiles at death remain largely unknown.

Purpose of the Study:

• To investigate the genomic landscape of advanced breast cancers leading to lethal disease.
• To characterize the evolution of the cancer genome from primary to metastatic sites.
• To understand treatment-driven genomic changes in metastatic breast cancer.

Main Methods:

• Rapid autopsy was performed on four patients with advanced breast cancer.
• Paired tumor-normal whole exome sequencing and SNP arrays were conducted on multiple metastatic sites and primary tumors.
• Subclonal architectures were inferred by jointly analyzing all patient samples.

Main Results:

• Significant inter-case differences in mutational burden, driver mutations, and copy number variation were observed.
• Intra-case heterogeneity was dramatic, with significant differences between primary and metastatic sites, and among metastatic sites.
• Treatment was found to drive subclonal diversification and the evolution of treatment resistance, including parallel evolution and driver augmentation.

Conclusions:

• Metastatic breast cancer genomes are shaped by diverse mechanisms, emphasizing the value of studying advanced disease.
• Treatment significantly drives genomic heterogeneity, impacting disease monitoring and treatment selection in personalized medicine.