PROSTATE CANCER GENETICS

For men with advanced prostate cancer who have certain genomic mutations, overall survival (OS) is roughly half that of patients who do not have the genetic anomalies, according to a new study that aims to refine the ways in which such mutations are identified.

The study was published online September 4 in the Journal of Clinical Investigation.

In the analysis, 8.1% of a cohort of 124 men with advanced disease had defective mismatch repair (dMMR) cancers, which means they may have benefited from immune checkpoint–inhibiting therapies, report Daniel Nava Rodrigues, MD, of the Institute of Cancer Research, London, United Kingdom, and international colleagues.

In the United States, the checkpoint inhibitor pembrolizumab (Keytruda, Merck) was approved in 2017 for use in all dMMR tumors and all tumors with a high degree of microsatellite instability (MSI-H). This approval was hailed as a milestone, as it was the first time that a drug was approved for use in a specific genetic mutation regardless of the site of the cancer. Such drugs are termed tissue-agnostic antitumor agents.

The dMMR amd MSI-H defects are found most commonly in colorectal, endometrial, and gastrointestinal cancers; they appear less commonly in other cancers, including those of the prostate.

In the new study, Rodrigues and colleagues sought to further characterize differences in clinical behavior between dMMR and non-dMMR prostate cancers (the latter are known as MMR-proficient [pMMR] cancers).

The team studied 127 biopsy specimens from 124 patients with advanced prostate cancer who underwent treatment at the Royal Marsden Hospital in London, United Kingdom. They determined dMMR status on the basis of either loss of mismatch repair protein expression or MSI, using polymerase chain reaction assay.

Ten men had dMMR cancers; the other 114 had pMMR cancers.

Advanced prostate cancer was defined as metastatic castration-resistant disease, meaning that the disease had progressed despite hormone therapy.

From time of diagnosis, the median OS was 8.5 years in the pMMR group vs 4.1 years in the dMMR group, per Kaplan-Meier survival analysis (log-rank test, P = .07). From the time of hormone therapy initiation, median OS was 7.0 years for the pMMR group vs 3.8 years for the dMMR group (log-rank test, P = .003).

The findings indicate that dMMR is a "clinically aggressive phenotype" and that such tumors "constitute a discrete subtype with decreased survival time," write the authors.

Furthermore, half of all men with dMMR cancers had high PD-L1 levels; by contrast, fewer than 10% of the men with pMMR cancers had high PD-L1 levels. Such high levels are a hallmark of tumors that are more likely to respond to immunotherapy with programmed cell death checkpoint inhibitors.