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Researchers in the U.S. and U.K. have identified a new subtype of prostate cancer that is characterized by loss of both copies of the CDK12 gene, and which an early clinical study showed can respond to immune checkpoint inhibitor drugs that commonly aren’t effective against prostate cancer. The new tumor subtype occurs in about 7% of patients with metastatic castration-resistant prostate cancer (mCRPC), although only about 1% of patients with earlier-stage disease.

“Because prostate cancer is so common, 7% is a significant number,” says research lead Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology, at the University of Michigan. “The fact that immune checkpoint inhibitors may be effective against this subtype of prostate cancer makes it even more significant. This is an exciting prospect for patients who have CDK12 alterations and may benefit from immunotherapy.”

In the team’s reported pilot clinical study, two out of four late-stage patients with CDK12-mutant prostate cancer responded to the immunotherapy drug pembrolizumab and were still alive when the report was written. The study follows on from a clinical trial led by the Institute for Cancer Research, and the Royal Marsden NHS Foundation Trust in the U.K., which found that pembrolizumab could be of benefit to some patients with advanced prostate cancer who had no further treatment options.

Chinnaiyan is senior author of the team’s report, published today in Cell, describing idenitifcation of the new prostate cancer subtype and reporting on data from the four pembrolizumab-treated patients. The paper is entitled “Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer.

Prior studies have identified common genetic drivers of prostate cancer, as well as distinct molecular subtypes in both primary and metastatic disease, the researchers write. CDK12 is a cyclin-dependent kinase that is involved in regulating key cellular processes and has also been implicated in controlling genomic stability through regulating genes involved in the DNA damage response.

The University of Michigan team had previously reported that 4.7% of mCRPC patients carried changes to both copies of the CDK12 gene. For their studies described in Cell, the team working with collaborators in the U.S. and with scientists in the U.K. at The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust London, analyzed DNA and RNA sequencing data from 360 mCRPC samples, obtained from the Mi-ONCOSEQ study, and from the Stand Up to Cancer-Prostate Cancer Foundation Dream Team.

They identified CDK12 mutations in 25/360 mCRPC patients (6.9%), but in only 6/498 patients with primary prostate cancer. “All patients showed biallelic inactivation of CDK12,” they note, while “strikingly,” the CDK12 mutations were mutually exclusive to all of the already known primary genetic drivers (PGDs) analysed, including ETS fusions, SPOP mutations, HRD (homologous recombination-deficiency, ATM mutations and mismatch repair-deficiency (MMRD).“

Primary prostate cancers are largely diploid, whereas metastatic tumors often show loss of heterozygosity, aneuploidies, and a significant increase in mutational burden, the authors note. In contrast, they found that CDK12-mutated mCRPC tumors exhibited a “distinctive genomic landscape” that was similar to that identified in a subset of ovarian cancers. “The prototype CDK12 mutant tumor was baseline diploid and had few arm-level copy-number aberrations except gain of 8q, but notably, hundreds of focal copy-number gains were dispersed across the gnome,” they state. “All cases with CDK12 inactivation, and only cases with CDK12 mutation, exhibited this form of genome instability in both the metastatic and primary cohorts.”

The CDK12 mutants in addition exhibited a distinct transcriptional phenotype and a shift from oxidative to glycolytic metabolism, which is a hallmark of many types of cancer, but is generally not characteristic of most prostate cancers, they add. The CDK12 mutant tumors also displayed characteristic copy number and mutational signatures, which characterized the tumors as distinct from the HRD or MMRD type of prostate cancer. “In particular, CDK12-mutants are different from tumors with HRD, which was previously presumed to be the pathway through which CDK12 regulated genomic instability,” they point out.

Significantly, CDK12-mutated tumors also harbored higher numbers of surface neoantigens, which act to recruit immune-fighting T cells, a finding that may explain why this subtype of cancer is more susceptible to immune checkpoint blockade, and so why some patients do benefit from immune checkpoint blockade, the team suggests. Identifying specific mutation-associated neoantigens could thus feasibly lead to the development of personalized tumor vaccines. 

“Perhaps most importantly for translational purposes, CDK12 mutant cases exhibit a characteristic immunophenotype.…CDK12 mutant tumors show high overall immune infiltration, increased levels of tumor-infiltrating lymphotyces, and altered chemokine signalling. This immunological phenotype may be influenced by the elevated neoantigen burden in CDK12 mutant tumors.”

“Immunotherapy works for a relatively small group of men with advanced prostate cancer—but when it works, it really works,” notes Johann de Bono, M.D., Regius Professor of Cancer Research at The Institute of Cancer Research. “If we can identify in advance who will benefit, then it should accelerate the passage of immunotherapy into routine use for patients. Our new study has revealed a distinct group of men with advanced prostate cancer whose tumors have biological features that could make them likely to respond to immunotherapy drugs such as pembrolizumab. We now need larger clinical studies to further study the benefit of immunotherapy in this group of patients. In the future, a genetic test could help pick out men with this particular set of genetic changes, so that they can be considered for immunotherapy.”

Researchers at the University of Michigan Rogel Cancer Center are to lead a multisite clinical trial to assess checkpoint inhibitor therapy in patients with metastatic prostate cancers that exhibit loss of CDK12.

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