A new study led by WEHI researchers has developed a blood test capable of detecting drug resistance to PARP inhibitors (PARPi) in ovarian cancer patients harboring BRCA1 mutations. This breakthrough addresses a significant challenge in cancer treatment, where resistance to PARPi therapy often leads to relapse. The study, for the first time, identifies and detects DNA changes caused by a 'splicing trick' in the blood, offering a potential turning point for personalized cancer treatment.
Splicing Mechanism and Drug Resistance
PARPi therapy has revolutionized the treatment of ovarian and breast cancers, particularly in patients with homologous recombination deficiency (HRD) caused by BRCA1 or BRCA2 mutations. However, drug resistance remains a major obstacle. The process of splicing allows cancer cells with BRCA1 mutations to bypass the mutation targeted by the drug, effectively removing the drug's vulnerability and causing resistance.
Dr. Ksenija Nesic, a lead researcher at WEHI, explained, "It's been known for a while that splicing creates drug resistance. What we didn't know was how the cancer cells do this and whether we could detect, measure, and predict it in patients."
Detecting Resistance Through Blood Tests
The study demonstrates that this form of drug resistance can be detected in a subset of ovarian cancer patients through a blood test or by examining the patient's tumor. Specifically, the research team identified this resistance mechanism in ovarian cancer patients with mutations in the BRCA1 gene.
"This could be transformative for the cohort of ovarian cancer patients who have mutations in the BRCA1 gene, and potentially for other ovarian cancer patients too," Dr. Nesic noted. The team is optimistic that further research will uncover similar splicing mechanisms in BRCA2 and other genes related to HRD.
Clinical Implications and Future Directions
Homologous recombination deficiency (HRD) is present in approximately 50% of ovarian cancer patients, with about half of these patients having mutations in the BRCA1 or BRCA2 genes. The ability to detect splicing changes could revolutionize patient care by enabling doctors to monitor for resistance and make informed treatment decisions.
"The discovery is profound because it opens up an avenue to monitor for drug resistance, where clinicians can in the future easily detect altered splicing of genes for BRCA1 and potentially for other genes involved in HRD, as their patient stops responding to therapy," said Dr. Nesic.
Existing tests that show these changes are currently being used in research settings. These include DNA sequencing of a patient’s tumor or detecting cancer DNA in the blood. Soon clinicians will be able to order these tests directly and look out for this form of resistance.
The hope is that testing for this type of resistance, potentially through a simple blood test, will become standard practice in both clinical and research settings. This would allow for earlier detection of resistance, enabling patients to be moved onto the next best therapy more promptly.
"While there are many types of resistance to PARP inhibitors, being able to identify those patients who are no longer going to respond to PARPi treatment early, enables better decision-making – meaning patients can be moved onto the next best therapy," Dr Nesic concluded. "The ultimate goal is to stop drug resistance in its tracks, for PARPi and for other types of drug resistance too. This research brings us closer to achieving this."
