BRCA gene complex

BRCA gene complex

The Poly ADP Ribose Polymerase (PARP) inhibitors currently used to treat a small percentage of patients with breast cancer may be an effective treatment for as many as 1 in 5 breast cancer cases, new research has found. The study, published in Nature Medicine yesterday, found that BRCA-like mutational signatures were found in many more breast tumours than previously thought.

“Our study shows that there are many more people who have cancers that look like they have the same signatures and same weakness as patients with faulty BRCA1 and BRCA2 genes. We should explore if they could also benefit from PARP inhibitors,” said Serena Nik-Zainal, senior author of the paper and researcher at the Wellcome Trust Sanger Institute. “The results suggest that clinical trials now need to look at cancer patients who share the same genetic signature in their cancer. This could change how clinical trials are designed in the future.”

The research involved the creation of a weighted mathematical model based on the genomic sequences of breast cancer tumours that the team dubbed HRDetect. Using the training sequence data, the model was taught to recognise the mutational signatures of Homologous Recombination (HR) mediated double strand break repair, a widespread characteristic of BRCA1 and/or BRCA2 germline mutations.

“Unlike most biomarkers, these multiple mutational signatures are the direct consequence of abrogation of repair pathways,” the authors wrote. “Thus, in the current analysis, we exploit this observation to quantitatively define the genomic features of BRCA1/BRCA2 deficiency and present a WGS-based predictor with remarkable performance for detection of HR deficient tumors.”

Initially, the team demonstrated that HRDetect could identify BRCA-related repair deficient tumours in almost 99% of samples when Whole Genome Sequencing (WGS) data was available. They then applied the model to assess 560 samples from different individuals, finding 22 cases with inherited BRCA mutations (germline), and another 22 that displayed somatic alterations to the genes. However, the model also flagged 47 apparently BRCA-free samples as displaying the same mutational signature.

Further analysis involving data from patients with breast, ovarian, or pancreatic cancer discovered that the signature may occur in up to 20% of breast cancer tumours. In contrast, germline BRCA mutations only occur in 1-5% of breast cancer cases. Highlighting this difference, the research team argued that there was merit in the idea of testing whether or not PARP inhibitors, currently reserved for patients with BRCA mutations, could be of use in treating a much larger subset of patients.

“This work uses mutational signatures to identify the complete set of cancers that will respond to certain drugs that are already known to be effective in a subset,” said Michael Stratton, co-author, Director of the Wellcome Trust Sanger Institute, and CEO of the Wellcome Genome Campus. “To translate these results into treatments, further sequencing of cancer genomes and more clinical trials are urgently needed, but this is a most promising start.”

The paper also noted that the sensitivity of the model decreased dramatically when applied to exome data instead of genome data, although retraining the model with exome sequences did increase the sensitivity again slightly. Of significant clinical relevance was that the model seemed amenable to Formalin-Fixed Paraffin Embedded (FFPE) samples and needle biopsy samples, both of which are common in clinical settings but which have proven difficult to utilise in the past.