Understanding metastasis mixed-treatment responses through genomic analyses

Area of Science:

• Oncology
• Genomics
• Immunology

Background:

• Metastatic breast cancer (MBC) presents genomic heterogeneity within patients.
• Treatment response in MBC can be variable across different metastatic sites, known as mixed response.
• The influence of tumor characteristics and microenvironment on this intrapatient treatment variability is not well understood.

Purpose of the Study:

• To investigate the genomic underpinnings of mixed treatment responses in metastatic breast cancer.
• To identify specific genomic and cellular markers associated with differential drug sensitivity across metastases within the same patient.

Main Methods:

• Genomic analysis of multiple metastases from six individual metastatic breast cancer patients exhibiting mixed responses.
• Assay of gene expression (e.g., CDKN2A, KRAS) and immune cell infiltration (e.g., T regulatory cells, CD8 T cells) within distinct metastatic lesions.

Main Results:

• Higher expression of regulatory T cells (T reg) and the CDKN2A gene were associated with non-response in specific metastases.
• Increased KRAS gene expression, KRAS amplicon, and CD8 T cells correlated with positive treatment response in individual metastases.
• Identified distinct genomic profiles correlating with differential drug sensitivity within the same patient.

Conclusions:

• Genomic heterogeneity of metastatic lesions significantly influences intrapatient treatment response variability in breast cancer.
• Specific molecular markers, including T cell populations and gene expression profiles (CDKN2A, KRAS), may predict differential sensitivity to therapy.
• These findings offer insights into personalized treatment strategies for metastatic breast cancer by explaining mixed clinical responses.