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Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer: a clinical and
Haoyu Wang1, Zhengyuan Wang2, Zheng Wang1
1Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Abstract:
p53 is mutated in half of cancer cases. However, no p53-targeting drugs have been approved. Here, we reposition decitabine for triple-negative breast cancer (TNBC), a subtype with frequent p53 mutations and extremely poor prognosis. In a retrospective study on tissue microarrays with 132 TNBC cases, DNMT1 overexpression was associated with p53 mutations (P = 0.037) and poor overall survival (OS) (P = 0.010). In a prospective DEciTabinE and Carboplatin in TNBC (DETECT) trial (NCT03295552), decitabine with carboplatin produced an objective response rate (ORR) of 42% in 12 patients with stage IV TNBC. Among the 9 trialed patients with available TP53 sequencing results, the 6 patients with p53 mutations had higher ORR (3/6 vs. 0/3) and better OS (16.0 vs. 4.0 months) than the patients with wild-type p53. In a mechanistic study, isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53. In the DETECT trial, decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line (upregulation by 16-fold) and the most responsive patient with TNBC. Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.
Insights
Decitabine shows promise for treating triple-negative breast cancer (TNBC) with p53 mutations. This study found decitabine increased response rates and survival, suggesting its potential repurposing for TNBC.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- p53 mutations occur in half of all cancers, yet no p53-targeting drugs are approved.
- Triple-negative breast cancer (TNBC) frequently harbors p53 mutations and has a poor prognosis.
- DNA methyltransferase 1 (DNMT1) overexpression is linked to p53 mutations and poor survival in TNBC.
Purpose of the Study:
- To investigate the efficacy of repurposing decitabine for p53-mutated TNBC.
- To evaluate decitabine's impact on survival, response rates, and immune responses in TNBC patients.
- To explore IRF7 as a potential biomarker for decitabine-based therapies in TNBC.
Main Methods:
- Retrospective analysis of 132 TNBC tissue microarrays.
- Prospective DETECT trial (NCT03295552) evaluating decitabine with carboplatin in stage IV TNBC.
- TP53 sequencing, DNMT1 expression analysis, and mechanistic studies in isogenic TNBC cell lines.
Main Results:
- DNMT1 overexpression correlated with p53 mutations and poorer overall survival (OS) in TNBC.
- The DETECT trial showed a 42% objective response rate (ORR) with decitabine and carboplatin in stage IV TNBC.
- Patients with p53 mutations exhibited higher ORR and improved OS compared to those with wild-type p53.
- Decitabine treatment upregulated IRF7, indicating a potential role in immune response activation.
Conclusions:
- Decitabine shows potential for repurposing in p53-mutated TNBC treatment.
- Decitabine, in combination with carboplatin, demonstrated efficacy in a phase II trial.
- IRF7 may serve as a predictive biomarker for decitabine-based therapies in TNBC patients.
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