Abstract
A recent study established that patients with metastatic castration-resistant prostate cancer who had mutations that inactivated both CDK12 alleles also exhibited other genetic changes. Results of a small, related study suggest these genetic changes may make tumors more responsive to PD-1 inhibitors.
Patients with prostate cancer and specific genetic alterations may be more likely to respond to immunotherapy: In a recent study, researchers determined that men with metastatic castration-resistant prostate cancer (mCRPC) who had mutations that inactivated both CDK12 alleles also exhibited other genetic changes that might make them more responsive to a PD-1 inhibitor (Cell 2018;173:1770–82).
“Checkpoint immunotherapy in general has not done well in patients with prostate cancer” compared with melanoma and lung cancer, possibly because prostate cancer has a comparatively low tumor mutational burden, says Arul Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology at the University of Michigan in Ann Arbor, and one of the study's senior authors.
In a 2015 study, Chinnaiyan and others established a landscape of molecular alterations in prostate cancer by sequencing tumor biopsies from 150 men with mCRPC (Cell 2015;161:1215–28). In the process, they discovered a small percentage of patients with mutations that inactivated both CDK12 alleles.
To further investigate, Chinnaiyan and his team performed a comprehensive genomic analysis of tumor samples from 360 men with mCRPC. They found that 7% of these men had mutations that inactivated both CDK12 alleles, and this inactivation was associated with genomic instability, tandem duplications throughout the genome, gene fusions, and higher levels of neoantigens. The researchers also found increased T-cell infiltration in the tumors.
A related retrospective study examined four patients with mCRPC who harbored CDK12 mutations and who did not respond to conventional treatments. When treated with the PD-1 inhibitor pembrolizumab (Keytruda; Merck), two experienced a decrease in PSA, one of whom also demonstrated a radiographic response.
The findings suggest that such patients might benefit from PD-1 inhibitors, which are already approved for melanoma, lung cancer, and other malignancies, Chinnaiyan says. “I think it's building upon the idea of identifying various subclasses of metastatic prostate cancer that would preferentially respond to specific treatments—so moving towards precision medicine.”
Researchers will soon launch a clinical trial to investigate how well patients with CDK12 mutations respond to checkpoint inhibitors.
Adam Dicker, MD, PhD, of the Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University in Philadelphia, PA, who was not involved in the study, considers it a “major contribution” that provides new genomic insight into prostate cancer, and could help researchers determine who may benefit from immunotherapy and why.
“I think there's a lot more we need to figure out in the realm of prostate cancer, “Dicker says,” but it's the beginning of a road map for precision oncology, and before we didn't have a road map.” –Catherine Caruso
For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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