Men who suffer with an aggressive form of prostate cancer could have their life-expectancy increased by immunotherapy treatment.
Scientists discovered unstable prostate cancer tumours – so-called “ultra-mutant” cells – are also more likely to be recognised by the immune system.
They believe patients with these tumours could be more likely to respond to special “checkpoint inhibitor immunotherapy”, which helps the immune system attack cancer cells.
The team found men with prostate cancer who have specific faults in their tumours, which make their DNA error-prone and unstable, survive only half as long as other men with advanced disease.
But these patients are also more likely to benefit from new immunotherapy treatments which could add years to their lives.
Study lead Professor Johann de Bono, from the Institute of Cancer Research in London, said: “Our study found that some men with advanced prostate cancers have genomic mutations in their tumours that make the disease unstable, aggressive and resistant to standard therapies.
“These men with ‘mismatch’ repair mutations only live about half as long as others who also have advanced prostate cancer but whose tumours don’t carry such mutations.
“We made an exciting step forward in working out how to treat men with such aggressive, unstable tumours.
“We discovered that tumours with mismatch repair mutations have key hallmarks which make them particularly likely to respond to checkpoint inhibitor immunotherapy.
“We are now developing tests that could pick out patients with these mutations, and we’re running new clinical trials to see if immunotherapy can offer new hope for these men.”
The study, published in the Journal of Clinical Investigation, looked at 127 tumour biopsies from 124 patients and genomic information from a further 254 patients.
It found 8.1 per cent of men with advanced prostate cancer had evidence of mismatch repair mutations in their tumours.
These men survived only 3.8 years after beginning prostate cancer treatment, compared with seven years for men with advanced disease but no detectable mismatch repair defects.
The researchers explained cancers with ‘mismatch repair’ gene mutations can’t correct single-letter mistakes in their DNA code properly and so are genetically unstable.
They acquire more and more mutations as they grow and rapidly evolve drug resistance – which is why new treatment approaches are so badly needed.
But the researchers discovered these ultra-mutant cancer cells are also easy for the immune system to recognise because they look different from healthy cells.
They studied at the levels of a protein called PD-L1 on the surface of cancer cells as a way of indicating the likely response to checkpoint inhibitor immunotherapy.
Targeting PDL-1 activity with an immune checkpoint inhibitor takes the ‘brakes’ off the immune system, setting it free to attack cancer cells.
Professor Paul Workman, chief executive of the Institute of Cancer Research, said: “Prostate cancers normally tend to have fewer mutations than other cancer types, which may be why immunotherapy has so far only been successful in a small minority of patients.
“This new study is exciting in providing a way to pick out those men with prostate cancer who have the most aggressive, unstable disease and the worst survival – but who conversely might be the best responders to immunotherapy.
“It will be fascinating to see whether we can translate the theory into practice in the new clinical trials to test out immunotherapy in men with genetically unstable tumours.”
Scientists found that half of tumours with mismatch repair mutations had high levels of PD-L1, compared with only 9.8 per cent of those without – making men with these tumours much more likely to benefit from a checkpoint inhibitor drug.
They also found that over half of tumours with mismatch repair mutations had been invaded by T cells from the patient’s immune system, another indicator that immunotherapy may well be effective.
The researchers are now developing tests to identify men with mismatch repair mutations in their tumours.
Clinical trials to test the effectiveness of checkpoint inhibitor immunotherapies in this group of patients are also underway.
Dr Howard Soule, executive vice president and chief science officer of the Prostate Cancer Foundation, added: “This important study informs identification of prostate cancer patients whose disease is likely to respond to treatment with immune checkpoint inhibitors.”
