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Genetic signature of treatment resistance in breast cancer identified

Researchers have discovered a genetic signature that can identify drivers of poor outcomes in advanced oestrogen-receptor positive (ER+) breast cancer.

Breast cancer

The majority of breast cancers (~70%) are initially diagnosed as oestrogen receptor-alpha positive (ERα+). In these instances, endocrine therapies (ET) are used to either induce oestrogen deprivation or directly target the ERα ligand binding domain (LBD). However, acquired resistance to these therapies is common and is typically associated with somatic mutations in the gene encoding Erα, ESR1. The most well studied are point mutations within the LBD, including Y537S and D538G.

More recently, there has been evidence that has identified multiple chromosomal translocations involving the ESR1 gene that can also drive ET-resistance. In these cases, chimeric transcription factors are formed that have constitutive activity.

A diagnostic genetic signature for breast cancer

In a recent study, published in Cancer Research, a multi-institution team of researchers functionally screened 15 ESR1 fusions. They identified 10 that promoted oestradiol-independent cell growth, motility, invasion, epithelial-mesenchymal transition and resistance to fulvestrant (an endocrine therapy).

The team used RNA-Seq to understand the transcriptional reprogramming induced by active ESR1 fusions. From this, they identified a gene expression pattern that was specific to functionally active ESR1 gene functions. This was then reduced to a diagnostic 24-gene signature.

This signature was subsequently examined in 20 ERα+ patient-derived xenografts (PDXs) and in 55 ERα+ metastatic breast cancer samples. The signature was able to successfully identify cases harbouring ESR1 gene fusions. Interestingly, it was also able to accurately identify the presence of activating ESR1 LBD point mutations. The team gave the signature the name ‘MOTERA’ for Mutant or Translocated Estrogen Receptor Alpha.

Overall, these findings showcase that the 24-gene signature represents an efficient approach to screening samples for the presence of diverse ESR1 mutations and translocations that drive treatment failure. This is significant in the field of precision medicine as these findings could provide specific details about a person’s tumour that could guide the selection of more effective treatments.

Co-author, Dr Charles E. Foulds, said:

“In the future, a patient’s cancer cells could be analysed and, once the MOTERA score indicates the presence of an ER mutation or translocation, then the tumour cells would be further studied to more precisely determine what kind of ER mutant or translocation is present. This would help guide the selection of a personalised, optimal treatment.”

Image credit: canva