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Predicting chemotherapy resistance in breast and ovarian cancer with BRCA epigenetics

New research discovers genomic and epigenomic BRCA alterations that can predict chemotherapy resistance in breast and ovarian cancers.  

A new study, published in Science Translational Medicine, investigated the heterogeneity in BRCA1 alterations and their differing responses to chemotherapy in triple negative breast cancer (TNBC) and ovarian carcinomas (OvCas).  

TNBC and OvCas are some of the most challenging types of cancer to treat. They can be aggressive and often go undetected until their later stages. Although many cancers are initially susceptible to chemotherapy, resistance can often arise. TNBCs and OvCas with BRCA mutations can have varying responses to chemotherapies, and understanding these mixed outcomes could help design safer and more effective treatments.  

Researchers at the Jackson Laboratory research institute in the United States investigated why promoter methylated BRCA1 alterations responded poorly to alkylating agents, compared to BRCA1 mutants.  

The authors said, “The mechanistic heterogeneity of response to DNA-damaging chemotherapy across the different BRCA states can explain many of the inconsistencies seen in clinical trials.”  

Defining signatures that correlate with treatment response could inform efforts to predict the impact of platinum chemotherapy in patients and reduce the use of ineffectual treatments.  

Same genomic mutational signatures but different therapeutic response 

Researchers used genomic analysis to confirm high TDP1 activity, an indicator of homologous repair deficiency (HRD). They compared this in both promoter methylated BRCA1 patients and BRCA1 mutants, with results suggesting no difference in mutational signatures.  

Mouse models with early TNBC were then used to compare tumour sizes after a short course of platinum-based therapy across the different BRCA state groups. Researchers found that the BRCA1 methylated model showed no decrease in tumour growth, whilst mutated BRCA1 models did.  

BRCA1 mutations and resistance to platinum-based chemotherapy  

Using methylation-specific droplet digital PCR (MS-ddPCR), researchers found a loss of BRCA1 methylation and reactivation of BRCA1 gene expression after platinum-based therapy.  

The authors said, “BRCA1 methylated tumours would undergo demethylation after even short exposure to chemotherapy which is associated with acquired resistance to platinum-based therapy.” 

Similar results seen in OvCa cohorts showed that BRCA deficiency by pathogenic mutations was significantly associated with improved response to platinum-based therapy. However, this was not seen with BRCA1 promoter methylation sets.  

This study shed light on the inconsistencies previously observed in predicting outcomes using HRD status in TNBC and OvCa clinical trials. This research demonstrated that BRCA methylation is a functionally plastic state within the cancer cell and that it can be rapidly lost upon chemotherapy exposure.  

The authors wrote, “The ability to de-escalate a toxic combination (of checkpoint inhibitors and chemotherapy) in a subset of patients with TNBC and OvCas potentially identified by our decision tree would have a meaningful impact on cancer survivors.” 

Written by Harry Yuen, Science Writer Intern

Image Credit: Canva