HINXTON, U.K.—A team of British researchers has uncovered genetic indicators suggesting that a greater number of breast cancer cases than previously thought are treatable with existing PARP inhibitors. Scientists from the Wellcome Trust Sanger Institute and their collaborators determined that patterns of mutations—mutational signatures—in some breast cancer tumors were similar to mutations found in people with malfunctioning BRCA1 and BRCA2 genes. These findings suggest that 20 percent more breast cancer patients may benefit from PARP inhibitors currently used to treat BRCA1/BRCA2-related cancers.
In the U.K.-based study, researchers analyzed the breast cancer genomes of 560 patients and looked for every single type of mutation they possibly could. The team developed a new computer-based tool called HRDetect able to discriminate between tumors with and without the BRCA1/BRCA2 mutation, based on the appearance of their genome. Cancer genomes without a mutation in the BRCA1 and BRCA2 genes are neat and organized, they say, whereas genomes with BRCA1/BRCA2-deficiency are chaotic.
HRDetect sees the tumor profile as if it is reading an X-ray, the researchers explain, and it can be applied across all tumors. The scientists discovered that many breast cancer patients had mutational signatures that were identical to people with faulty BRCA1 and BRCA2 genes, even though they had not inherited the mutations.
Dr. Helen Davies, joint first author from the Wellcome Trust Sanger Institute, said: “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.”
The results were published in March in Nature Medicine and open up the possibility of one in five more women being treated with PARP inhibitors, a class of drug previously only thought to be effective for women with an inherited BRCA1 or BRCA2 mutation. This would need to be tested through a systematic clinical trial on a wider set of patients to see if they might also be responsive to the drugs, with participants being selected based on the mutational signatures of their tumor.
Sir Mike Stratton, director of the Sanger Institute, said: “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. 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.”
PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP). Several forms of cancer are more dependent on PARP for DNA repair than regular cells, making it an attractive target for cancer therapy. PARP proteins are known as DNA binding and repair proteins. When activated by DNA damage, these proteins recruit other proteins that do the actual work of repairing DNA. Under normal conditions, PARP proteins are released from DNA once the repair process is underway.
PARP inhibitors have been designed to specifically treat tumors with faulty BRCA1 and BRCA2 genes in breast and ovarian cancers, and their use against prostate cancer is currently being investigated. They appear to work in two ways. For cancers that are BRCA1/BRCA2-deficient, PARP is an alternative DNA repair mechanism that the cancer cells rely on. The drugs work by blocking the PARP DNA repair mechanism in BRCA1/BRCA2-deficient cancer cells, so damaged DNA is not mended, leading to cancer cell death. In addition, PARP inhibitors act to trap proteins on DNA strands, which are more toxic to cells than the unrepaired single-strand DNA breaks that accumulate in the absence of PARP activity, indicating that PARP inhibitors act as PARP poisons.
“In the past, clinical trials for PARP inhibitors have focused mainly on the [small percentage] of women with breast cancer related to faulty BRCA1 and BRCA2 genes. 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,” says Dr. Serena Nik-Zainal, lead author from the Wellcome Trust Sanger Institute. “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.”