A new Prostate Cancer Foundation (PCF)-funded study published today in the scientific journal Cell has identified a new subtype of advanced prostate cancer – one which may be treatable with checkpoint immunotherapy, a type of treatment that can produce long-term remissions and even cures in many cancer types, but has not yet been optimized in prostate cancer.

Checkpoint immunotherapy is a type of cancer treatment that activates a person’s own immune system to target and kill their cancer.  In some types of cancers such as melanoma and lung cancer, checkpoint immunotherapy has been highly effective and can even result in apparent cures for some patients. Researchers have found that for this type of treatment to work, tumors must first look like foreign or dangerous objects to the immune system, and being covered in mutated proteins is the best way to do this.  Prostate cancer however, typically does not have a lot of mutated proteins.  Instead, prostate cancer is primarily driven by gene amplifications and deletions – meaning the genes retain their normal form, but there is just way more or way less (even complete loss) of certain important ones.   Unfortunately, the immune system tends to ignore these tumors.  Thus, with the exception of the small fraction of prostate tumors that are hyper-mutated due to mutations in “MMR” genes, checkpoint immunotherapy has not been highly effective in prostate cancer.

About 3% of advanced prostate cancers have mutations in MMR genes, which result in extremely high levels of mutations (a phenomenon called microsatellite instability, MSI).  In 2017, the FDA approved the checkpoint immunotherapy pembrolizumab for treatment of all solid tumors with MMR mutations or MSI, including prostate cancer.

The PCF-International Dream Team, led by Dr. Arul Chinnaiyan of the University of Michigan, has been studying the mutations that occur in advanced prostate cancer and using this information to identify treatments that will work for individual patients based on their unique tumor mutations.  Dr. Chinnaiyan and team have now reported the discovery of a new and highly unique subset of metastatic prostate cancers (comprising 5-7% of patients), which have deleted and/or mutated the CDK12 gene.

CDK12-mutant tumors were completely unique from all other prostate cancer subtypes, including those with MMR mutations.  CDK12-mutant tumors expressed a unique set of genes, and had a unique pattern of mutations, including a high level of mutations that altered the form of proteins.  This finding led DR. Chinnaiyan and team to hypothesize that these tumors may be visible as “bad apples” to the immune system – and that immunotherapy may work for these patients.

To investigate this theory, Dr. Chinnaiyan and team examined the treatment and clinical histories of eleven patients with CDK12-mutant tumors identified in the University of Michigan MI-ONCOSEQ program.  Of four patients who had been exposed at some time to the checkpoint immunotherapy anti-PD1, two had exhibited exceptional declines in PSA levels, one of whom also had shrinkage of metastatic tumors on scans and remains on therapy.  A third patient did not have a significant PSA decline, but remains on therapy without progression.

These results suggest that CDK12-mutations may be a biomarker to identify patients who may benefit from checkpoint immunotherapy.  While these results are highly promising, a clinical trial is necessary to prove efficacy in a controlled setting.

“Mutation of CDK12 is a new way tumors can create altered proteins which might trigger the immune system,” said Dr. Chinnaiyan.  “This is an exciting finding which defines a subset of advanced prostate cancer patients who could benefit from immunotherapy.”

Dr. Chinnaiyan also presented these results at the 2018 American Association for Cancer Research (AACR) Annual Meeting, which was held from April 14-18, 2018, in Chicago, IL.

About 3% of advanced prostate cancers have mutations in MMR genes, which result in extremely high levels of mutations (a phenomenon called microsatellite instability, MSI).  In 2017, the FDA approved the checkpoint immunotherapy pembrolizumab for treatment of all solid tumors with MMR mutations or MSI, including prostate cancer.
Dr. Andrea Miyahira has a PhD in cancer immunology, and is Director of Research at the Prostate Cancer Foundation.