More than 1700 women are diagnosed with ovarian cancer and over 20,000 people are diagnosed with breast cancer in Australia every year.
PARPi therapy has been a breakthrough for treating ovarian and breast cancers. In high-income countries, most patients with a DNA repair deficiency known as HRD – which can be caused by BRCA1 or BRCA2 mutations – are now receiving this treatment.
However, drug resistance remains a major challenge in PARPi therapy, with the majority of patients eventually experiencing relapse.
The process of splicing can cause cancer cells with mutations in genes, such as BRCA1, to become resistant to PARPi treatment. This means cancer cells with mutated BRCA1 genes can ‘skip over’ the mutation that the drug exploits, removing the drug vulnerability and causing the cancer to become resistant.
A new WEHI-led study has been able to detect DNA changes that cause this ‘splicing trick’ in the blood for the first time.
Co-first author and WEHI ovarian cancer researcher Dr Ksenija Nesic said the findings solve a long-standing ‘blind spot’ in cancer research and could mark a turning point for cancer treatment.
“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,” Dr Nesic said.
The findings show, for the first time, 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 tumour itself. Specifically, the study identified this drug resistance in ovarian cancer patients who have 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 said. “We are hopeful that further research will reveal similar splicing mechanisms in BRCA2 and other genes that relate to HRD.”
HRD (homologous recombination deficiency) is found in approximately 50% of ovarian cancer patients. Among these patients, about half have mutations in the BRCA1 or BRCA2 genes.
“The findings could revolutionise patient care, as doctors will now know they can look for splicing changes and more importantly, how to look,” Dr Nesic said.
Existing tests that show these changes are currently being used in research settings. These include DNA sequencing of a patient’s tumour 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.
It is hoped that testing for this type of resistance, in the form of a simple blood test, will eventually become standard practise in clinical as well as research settings.
“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,” Dr Nesic said.
“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.
“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.”
