Evolutionary history of metastatic breast cancer reveals minimal seeding from axillary lymph nodes

Area of Science:

• Oncology
• Genomics
• Cancer Evolution

Background:

• Metastatic breast cancer remains incurable, necessitating a deeper understanding of tumor progression.
• Characterizing the evolutionary dynamics of metastasis is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the genomic evolutionary landscape of metastatic breast cancer.
• To determine the role of axillary lymph nodes (ALNs) in seeding distant organ metastasis.
• To elucidate evolving mutational processes during cancer progression.

Main Methods:

• Comprehensive genomic analysis of primary tumors and metastatic lesions from 20 breast cancer patients (99 samples).
• Evolutionary modeling to infer tumor spreading and seeding patterns.
• Analysis of mutational processes, including APOBEC-associated mutagenesis.

Main Results:

• Identified diverse evolutionary patterns, including linear and parallel evolution to distant metastatic sites.
• Demonstrated polyclonal seeding, with multiple subclones originating from primary tumors and/or metastases.
• Found that synchronous ALN metastasis does not contribute to distant seeding, suggesting hematogenous dissemination.
• Observed co-occurrence of clonal evolution with new driver alterations and increased APOBEC-associated mutagenesis.

Conclusions:

• Axillary lymph node metastasis is not a significant route for seeding distant organ metastasis in breast cancer.
• Hematogenous spread is a primary mechanism for distant cancer dissemination.
• Genomic evolution during metastasis involves changing mutational landscapes and driver alterations.