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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
Serial expression analysis of breast tumors during neoadjuvant chemotherapy reveals changes in cell cycle and immune
Mark Jesus M Magbanua1,2, Denise M Wolf3, Christina Yau4,5,6
1Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. mark.magbanua@ucsf.edu.
Introduction:
The molecular biology involving neoadjuvant chemotherapy (NAC) response is poorly understood. To elucidate the impact of NAC on the breast cancer transcriptome and its association with clinical outcome, we analyzed gene expression data derived from serial tumor samples of patients with breast cancer who received NAC in the I-SPY 1 TRIAL.
Methods:
Expression data were collected before treatment (T1), 24-96 hours after initiation of chemotherapy (T2) and at surgery (TS). Expression levels between T1 and T2 (T1 vs. T2; n = 36) and between T1 and TS (T1 vs. TS; n = 39) were compared. Subtype was assigned using the PAM50 gene signature. Differences in early gene expression changes (T2 - T1) between responders and nonresponders, as defined by residual cancer burden, were evaluated. Cox proportional hazards modeling was used to identify genes in residual tumors associated with recurrence-free survival (RFS). Pathway analysis was performed with Ingenuity software.
Results:
When we compared expression profiles at T1 vs. T2 and at T1 vs. TS, we detected significantly altered expression of 150 and 59 transcripts, respectively. We observed notable downregulation of proliferation and immune-related genes at T2. Lower concordance in subtype assignment was observed between T1 and TS (62 %) than between T1 and T2 (75 %). Analysis of early gene expression changes (T2 - T1) revealed that decreased expression of cell cycle inhibitors was associated with poor response. Increased interferon signaling (TS - T1) and high expression of cell proliferation genes in residual tumors (TS) were associated with reduced RFS.
Conclusions:
Serial gene expression analysis revealed candidate immune and proliferation pathways associated with response and recurrence. Larger studies incorporating the approach described here are warranted to identify predictive and prognostic biomarkers in the NAC setting for specific targeted therapies.
Clinical Trial Registration:
ClinicalTrials.gov identifier: NCT00033397 . Registered 9 Apr 2002.
Insights
Neoadjuvant chemotherapy (NAC) alters breast cancer gene expression, impacting response and recurrence. Early changes in proliferation and immune genes predict outcomes, highlighting potential biomarkers for targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Neoadjuvant chemotherapy (NAC) response mechanisms in breast cancer remain unclear.
- Understanding NAC's impact on the tumor transcriptome is crucial for improving clinical outcomes.
- The I-SPY 1 TRIAL provided serial tumor samples to analyze gene expression changes during NAC.
Purpose of the Study:
- To investigate the impact of NAC on the breast cancer transcriptome.
- To associate gene expression changes with clinical outcomes, including response and recurrence-free survival (RFS).
- To identify potential predictive and prognostic biomarkers for NAC treatment.
Main Methods:
- Gene expression profiling of serial tumor samples (before treatment, early post-chemo, at surgery).
- Comparison of expression levels at different time points (T1 vs. T2, T1 vs. TS).
- Analysis of early gene expression changes (T2-T1) and their association with response and RFS using Cox modeling.
Main Results:
- Significant alterations in 150 (T1 vs. T2) and 59 (T1 vs. TS) transcripts were observed.
- Early downregulation of proliferation and immune genes at T2; decreased cell cycle inhibitor expression linked to poor response.
- Increased interferon signaling and high proliferation gene expression in residual tumors associated with reduced RFS.
Conclusions:
- Serial gene expression analysis identified candidate immune and proliferation pathways linked to NAC response and recurrence.
- Early and residual tumor gene expression changes offer insights into treatment efficacy.
- Further research is needed to validate these findings as predictive biomarkers for targeted NAC therapies.
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