Identification of genetic signatures similar to BRCA1/BRCA2 mutations in patients without the mutation could make it possible to treat 1 in 5 patients with breast cancer with PARP inhibition, according to study published in Nature Medicine.1
“In the past, clinical trials for PARP inhibitors have focused mainly on the 1% to 5% of women with breast cancer. However, 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. 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,” said Dr. Serena Nik-Zainal, lead author on the study, in a press release.2
According to the paper, 1% to 5% of breast cancers are related to hereditary mutations in the BRCA1 or BRCA2 genes. Tumors with BRCA1/BRCA2 mutations rely on poly(ADP-ribose) polymerase (PARP) for DNA repair allowing PARP inhibitors as a treatment option.
Researchers from the Wellcome Trust Sanger Institute sought to identify “mutational signatures” such as insertion/deletion, rearrangements, and somatic substitutions that were associated with dysfunctions in the BRCA1/BRCA2 genes. They developed the HRDetect model which was found to accurately identify samples that were BRCA1/BRCA2-deficient with a sensitivity of 98.7%.
The HRDetect model was applied a cohort of 560 patients with breast cancer of which there were 22 patients with a known BRCA1 or BRCA2 germline mutation. This model identified an additional 47 cases of functional BRCA1/BRCA2 deficiency and 22 cases of somatic BRCA1/BRCA2 loss in patients who did not have detectable BRCA1/BRCA2 mutations.
Although the results would need to be confirmed with clinical trials, these results suggest the possibility of treatment with PARP inhibitors in up to 20% of patients with breast cancer.1
“From the mutational signatures we were able to spot many more tumors with defects in their DNA repair machinery that we couldn’t see before. This was only possible by sequencing the entire genome of these cancers. Further work needs to be done as there could be tumors with the same mutational signature elsewhere in the body that may respond to these drugs,” said Dr Helen Davies, co-author on the study. in a statement.2