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Genetic Biomarkers Define Subgroup of Likely Prostate Ca ImmunoTx Responders (CME/CE)

Action Points

  • Microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) prostate cancers were found to be rare, accounting for only about 3% of a cohort of 1,346 patients, but about half of these responded to treatment with the checkpoint inhibitor pembrolizumab.
  • Note that for prostate tumors that do respond to immunotherapy, researchers believe that MSI-H/dMMR and other mutations such as CDK12 may be associated with increased neoantigen burden and T-cell infiltration, thereby activating the immune system to fight the cancer.

CME Author: Vicki Brower

Study Authors: Wassim Abida, Michael Cheng, et al.; Zachery R. Reichert, Joshua Urrutia, et al.

Target Audience and Goal Statement:

Oncologists, urologic oncologists, and urologists

The goal was to determine the prevalence of microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) prostate cancer, as well as the clinical benefit of using anti–PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this molecularly defined population.

Questions Addressed

  • What is the prevalence of MSI-H/dMMR in prostate cancer?
  • How do patients with this molecularly defined subtype of prostate cancer respond to immune checkpoint therapy — namely, pembrolizumab (Keytruda), which blocks PD-1?
  • What might be the reasons that patients with this subtype of prostate cancer respond to immunotherapy?

Study Synopsis and Perspective

Wassim Abida, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues conducted next-generation genomic sequencing on the tumors of men with prostate cancer to determine who might respond to the immunotherapy pembrolizumab, an anti-PD1 drug.

As described in the study online in JAMA Oncology, included were patients with the MSI-H/dMMR phenotype, which in other cancers, including colon cancer, is known to respond to immunotherapy. The researchers found that although this is a rare phenotype in prostate cancer — only 3.1% of prostate cancer patients in this study tested positive for these markers — about half of the patients with the marker responded to the immunotherapy, thus rendering the mutation (and biomarker) “therapeutically meaningful.”

This is the largest study to date of MSI-H/dMMR characterization in prostate cancer, the team noted.

Abida and co-authors started with 1,551 tumor samples taken from 1,346 patients with prostate cancer, and found that 32 of the eventual 1,033 patients analyzed had MSI-H/dMMR disease. 11 of these patients had castration-resistant prostate cancer (CRPC), and seven of the 32 (21.9%) carried a germline mutation in a Lynch-syndrome gene — i.e.,an MMR-associated gene. Five of the 11 had a durable clinical benefit from pembrolizumab, and more than half achieved a greater than 50% decline in prostate-specific antigen (PSA) levels.

As of May 2018, 11 of the 32 patients with MSI-H/dMMR disease had undergone treatment with an anti-PD-1 therapy for metastatic CRPC. The duration of therapy ranged from 4.6 to 89 weeks. Six of the patients (54.5%) had a decline in PSA levels >50%, including four patients with declines >99%.

In addition, of eight patients evaluable for radiographic response, four had a radiographic objective response, one had stable disease for about 6 months, and three had radiographic progression. Overall, five or 45.5% of the 11 patients with metastatic disease showed a durable clinical benefit; five (45%) had no benefit; and one patient (9.1%) had stable disease for about 6 months.

Tumors that are MSI-H/dMMR are known to be immunogenic because they harbor many mutations and produce multiple neoantigens, which are recognized by the immune system’s T-cells.

The FDA approved pembrolizumab for the treatment of MSI-H/dMMR solid cancers in May 2017. In addition, the National Comprehensive Cancer Network Guidelines were recently amended to include consideration of MSI-H/dMMR testing, and treatment with pembrolizumab for this phenotype in metastatic CRPC in the second-line setting, or beyond.

“Detection of MSI thus represents the first clinical indication for prospective tumor profiling in patients with prostate cancer,” the authors wrote, adding, however, that the best method for determining a patient’s status, and the clinical implications for broad screening for this phenotype remain unknown.

Of note, two patients in the study acquired the MSI-H phenotype somatically, later in the course of their disease, after their cancers had metastasized. “Although MSI may have been subclonal in the earlier samples and thus missed owing to tumor heterogeneity, this result indicates that it was not a truncal event and would have been missed if only an older archival sample had been profiled,” the authors explained. “These data suggest that metastatic tissue may represent the optimal material for assessment of MSI status.”

About half of the patients with the markers did not respond to immunotherapy, which may be due to drug resistance, which should be investigated, the researchers said.

Source References:

JAMA Oncology, online Dec. 27, 2018; DOI: 10.1001/jamaoncol.2018.5801

JAMA Oncology, online Dec. 27, 2018; DOI: 10.1001/jamaoncol.2018.5789

Study Highlights: Explanation of Findings

The study included tumor samples taken from patients undergoing treatment for prostate cancer at Memorial Sloan Kettering Cancer Center from 2015 to 2018. Samples were analyzed using a targeted sequencing assay, and patients were assigned MSIsensor scores of high, indeterminate, or low.

There were 1,033 patients with adequate tumor quality to undergo analysis for MSI status. Analyses revealed that 3.1% of patients had MSI-H/dMMR prostate cancer with 2.2% having high MSIsensor scores. Nine patients had indeterminate scores with evidence of dMMR.

About one in five (21.9%) patients with MSI-H/dMMR disease had a pathogenic germline mutation in a Lynch syndrome-associated gene. These included five patients with mutations in MSH2, one with a mutation in MSH6, and one with a mutation in PMS2.

“Next-generation sequencing-based tumor genomic profiling may therefore represent a robust and efficient strategy to identify the subset of patients with prostate cancer who may benefit from anti-PD/PD-L1 therapy,” Abida and co-authors wrote.

They noted that the results confirm those in a previous study that established pembrolizumab as a pan-solid tumor treatment in patients with various cancers with the MSI-H/dMMR phenotype.

Writing in an accompanying editorial, Zachery R. Reichert, MD, PhD, of the University of Michigan Rogel Cancer Center in Ann Arbor, and colleagues noted that because half of patients with MSI-positive tumors did not respond to the immunotherapy in the new trial, this would indicate that the presence of MSI alone is not sufficient for treatment response. “The exact molecular features that contribute to response are currently unknown,” the editorialists stated.

Reichert and co-authors also pointed out that not all patients with prostate cancer who respond to anti-PD-1 therapy have the MSI-H/dMMR phenotype, demonstrating that its presence is not necessary for response. In addition, about 7% of patients with CRPC in this study had another mutation, CDK12, which is also known to be immunogenic and has been linked to increased neoantigen burden and T-cell infiltration — i.e., markers of immunogenicity.

“Prospective clinical trials will be necessary to determine whether patients whose tumors harbor CDK12 mutations — such as those whose tumors harbor MSI — are significantly more likely to respond to checkpoint inhibitor therapy,” Reichert and co-authors wrote, adding that these trials have already begun.

Another issue in determining which prostate cancer subgroups are most likely to respond to immunotherapy is that that there is no one standard method used to test for the MSI-H phenotype: polymerase chain reaction, immunohistochemistry, and next-generation sequencing, as used by Abida’s team, may be used, but the FDA has not weighed in on which method is best to use, and on whether standardization of this research is important. “It remains unclear which test’s positive result is most associated with a response,” the editorial noted.

“The new study demonstrated the importance of testing for MSI in metastatic samples, because testing in archived prostate tissue failed to detect MSI in two of six patients whose metastatic CRPC tumors harbored MSI,” Reichert and co-authors continued. They acknowledged, however, that obtaining prostate metastases for analysis is technically challenging, because they are usually located in the bone. And while in the future, cell-free DNA sequencing to detect MSI could be possible, metastatic biopsies for now should be performed in centers with expertise in doing this procedure, the editorialists said.

Leah Lawrence wrote the original story for MedPage Today.


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