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Understanding metastasis mixed-treatment responses through genomic analyses
Susana Garcia-Recio1, Paola Zagami2,3, Brooke M Felsheim4
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Abstract:
Early-stage and metastatic breast cancers (MBC) can exhibit genomic heterogeneity, even within the same individual. Response to therapy in metastatic breast cancer patients with multiple metastases can also be heterogeneous, with different degrees of responsiveness to the same drug(s) across metastatic sites, termed "mixed response," within the same patient. Whether this treatment response variability is influenced by factors such as intrinsic tumor characteristics of metastatic lesions and/or the microenvironment is unknown. Through genomic analysis of multiple metastases from the same patient, assayed in 6 different patients who had exhibited mixed response on imaging, we identified that higher regulatory T cells (T reg) and CDKN2A gene expression values correlate with non-response, while the KRAS gene, KRAS amplicon, and CD8T cells were associated with response in individual metastases. These genomic features may explain mixed clinical responses and provide valuable insights into intrapatient variations in treatment sensitivity.
Insights
Genomic analysis reveals distinct features in breast cancer metastases. Higher regulatory T cells and CDKN2A gene expression correlate with non-response, while KRAS gene and CD8T cells indicate treatment response.
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.
