New research has discovered a subset of men with prostate cancer who have specific faults in their tumours that significantly worsen their chances of survival, but could mean they are more likely to benefit from immunotherapy.
The team – led by scientists at The Institute of Cancer Research, London, and the Dana-Farber Cancer Institute in the US – found that 8.1 percent 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 7.0 years for those with advanced disease and no detectable mismatch repair defects.
Cancers with ‘mismatch repair’ gene mutations are not able to correct single-letter mistakes in their DNA code and so are considered genetically unstable. They develop an increasing number of mutations as they grow and rapidly evolve drug resistance, thus leaving patients in dire need of new treatment options.
However, the researchers also found that that half of tumours with mismatch repair mutations had high levels of PD-L1, compared with only 9.8 percent without – suggesting that they are much more likely to benefit from treatment with a checkpoint inhibitor drug.
It was also found that over half of tumours with mismatch repair mutations had been invaded by T cells from the patient’s immune system, which further indicates that immunotherapy may well be effective for these patients.
The researchers are now developing tests to identify men with mismatch repair mutations in their tumours, while new clinical trials led by The Institute of Cancer Research (ICR) and The Royal Marsden are evaluating the effectiveness of checkpoint inhibitor immunotherapies in this group of patients, on the back of these findings.
“We are seeing a revolution in cancer treatment as immunotherapy becomes an important option for many types of the disease,” said Professor Paul Workman, chief executive of The ICR.
“Immunotherapy is an unusual treatment in working best in cancers that have a lot of mutations. 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.”
The research, published today in the Journal of Clinical Investigation, was funded by the Prostate Cancer Foundation, Movember Foundation, Prostate Cancer UK, Stand Up to Cancer, V Foundation, the Stewart J. Rahr Foundation, Cancer Research UK, the Experimental Cancer Medicine Centre and NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The ICR.
