Related Experiment Video
Updated: Jun 11, 2025
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Genomic and transcriptomic profiling of pre- and postneoadjuvant chemotherapy triple negative breast cancer tumors
Tomomi Nishimura1, Ravi Velaga2, Norikazu Masuda2
1Department of Next-generation Clinical Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Abstract:
Our understanding of neoadjuvant treatment with microtubule inhibitors (MTIs) for triple negative breast cancer (TNBC) remains limited. To advance our understanding of the role of breast cancer driver genes' mutational status with pathological complete response (pCR; ypT0/isypN0) prediction and to identify distinct gene sets for MTIs like eribulin and paclitaxel, we carried out targeted genomic (n = 50) and whole transcriptomic profiling (n = 64) of TNBC tumor samples from the Japan Breast Cancer Research Group 22 (JBCRG-22) clinical trial. Lower PIK3CA, PTEN, and HRAS mutations were found in homologous recombination deficiency (HRD)-high (HRD score ≥ 42) tumors with higher pCR rates. When HRD-high tumors were stratified by tumor BRCA mutation status, the pCR rates in BRCA2-mutated tumors were higher (83% vs. 36%). Transcriptomic profiling of TP53-positive tumors identified downregulation of FGFR2 (false discovery rate p value = 2.07e-7), which was also the only common gene between HRD-high and -low tumors with pCR/quasi-pCR treated with paclitaxel and eribulin combined with carboplatin, respectively. Differential enrichment analysis of the HRD-high group posttreatment tumors revealed significant correlation (p = 0.006) of the glycan degradation pathway. FGFR2 expression and the differentially enriched pathways play a role in the response and resistance to MTIs containing carboplatin treatment in TNBC patients.
Insights
Neoadjuvant microtubule inhibitors improve pathological complete response (pCR) in triple-negative breast cancer (TNBC). Lower PIK3CA, PTEN, HRAS mutations and higher BRCA2 mutation status correlate with pCR in HRD-high tumors. FGFR2 and glycan degradation pathways influence treatment response.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Neoadjuvant treatment with microtubule inhibitors (MTIs) for triple-negative breast cancer (TNBC) has limited understanding.
- Predicting pathological complete response (pCR) to MTIs requires further investigation into the role of gene mutations.
Purpose of the Study:
- To investigate the association between gene mutational status and pCR prediction in TNBC patients receiving neoadjuvant MTIs.
- To identify distinct gene sets associated with MTI response, specifically eribulin and paclitaxel.
Main Methods:
- Targeted genomic and whole transcriptomic profiling of TNBC tumor samples from the JBCRG-22 clinical trial (n=64).
- Analysis of mutation status (PIK3CA, PTEN, HRAS, BRCA1/2, TP53) and homologous recombination deficiency (HRD) scores.
- Transcriptomic profiling to identify differentially expressed genes and enriched pathways post-treatment.
Main Results:
- Lower PIK3CA, PTEN, and HRAS mutations were observed in HRD-high tumors with higher pCR rates.
- HRD-high tumors with BRCA2 mutations showed significantly higher pCR rates (83%) compared to non-BRCA2 mutated tumors (36%).
- TP53-positive tumors exhibited FGFR2 downregulation; FGFR2 and glycan degradation pathways correlated with MTI response/resistance.
Conclusions:
- Gene mutational status, particularly BRCA2, and HRD levels are predictive of pCR in TNBC patients treated with neoadjuvant MTIs.
- FGFR2 expression and glycan degradation pathway alterations are implicated in response and resistance to MTIs combined with carboplatin.
- These findings offer insights into personalized treatment strategies for TNBC based on genomic profiles.
