PARP inhibitors like Lynparza (olaparib) were designed to treat patients with inherited BRCA1 or BRCA2 mutations, but more women with breast cancer could benefit from these drugs, a study suggests.
The study, “HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures,” appeared in Nature Medicine. It argues that women with BRCA mutations have a faulty DNA repair machinery that makes them more susceptible to PARP inhibitors. Other mutations affecting this machinery could also make patients good candidates to be treated by those drugs. But clinical trials are needed to confirm this hypothesis.
“In the past, clinical trials for PARP inhibitors have focused mainly on the 1 to 5 percent of women with breast cancer,” Dr. Serena Nik-Zainal, lead author of the Wellcome Trust Sanger Institute, said in a press release. “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.”
She added: “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.”
Nik-Zainal and her team at the British research institute analyzed the genome of 560 patients with breast cancer, looking for every type of mutation possible — including insertions or deletions of small chunks of the DNA.
They developed a new computer-based tool, the HRDetect, to look at these mutations and identify mutational patterns in the tumors that made women have an abnormal BRCA function, even if they did not have any mutation in the BRCA genes.
The team found that up to 22 percent of breast cancer patients had mutations that led to a defective BRCA function — a much higher percentage than the 1 to 5 percent of women known to have BRCA mutations. While the results must be validated in future clinical trials, the findings suggest that a much larger percentage of breast cancer patients could benefit from already approved PARP inhibitors.
“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 Sir Mike Stratton, director of the Sanger Institute. “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.”