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Mismatch Repair Mutations and Immunotherapy in Prostate Cancer

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Key Points

  • A total of 8.1% of men with advanced prostate cancer had evidence of mismatch repair mutations in their tumors. These men survived 3.8 years after beginning prostate cancer treatment, compared with 7.0 years for men with advanced disease with no detectable mismatch repair defects.
  • Half of tumors with mismatch repair mutations had high levels of PD-L1, compared with 9.8% without these mutations.
  • Over half of tumors with mismatch repair mutations had been invaded by T cells from the patient’s immune system.

A group of men with especially aggressive prostate cancer may respond unusually well to immunotherapy, according to a study published by Rodrigues et al in the Journal of Clinical Investigation. The research offers the possibility of effective treatment, with clinical trials already underway.

An international team led by scientists at The Institute of Cancer Research, London, and Dana-Farber Cancer Institute looked at 127 tumor biopsies from 124 patients and genomic information from a further 254 patients acquired by the Prostate Cancer Foundation/Stand Up to Cancer International Prostate Cancer Dream Team.

Study Findings

The team found that 8.1% of men with advanced prostate cancer had evidence of mismatch repair mutations in their tumors. These men survived 3.8 years after beginning prostate cancer treatment, compared with 7.0 years for men with advanced disease with no detectable mismatch repair defects.

Cancers with ‘mismatch repair’ gene mutations cannot correct single-letter mistakes in their DNA code properly and so are genetically unstable. They acquire more and more mutations as they grow and rapidly evolve drug resistance. The researchers suspected these ultramutant cancer cells might be particularly easy for the immune system to recognize, since they will look different from healthy cells.

Researchers looked at the levels of the protein programmed cell death ligand 1 (PD-L1) on the surface of cancer cells as a way of indicating the likely response to checkpoint inhibitor immunotherapy. They found that half of tumors with mismatch repair mutations had high levels of PD-L1, compared with 9.8% without these mutations—making men with these tumors much more likely to benefit from a checkpoint inhibitor. They also found that over half of tumors with mismatch repair mutations had been invaded by T cells from the patient’s immune system—another indicator that immunotherapy may well be effective.

The researchers are now developing tests to identify men with mismatch repair mutations in their tumors. Based on these results, new clinical trials led by The Institute of Cancer Research and The Royal Marsden are testing the effectiveness of checkpoint inhibitors in this group of patients.

Study leader Johann de Bono, MD, FRCP, MSc, PhD, Regius Professor of Cancer Research at The Institute of Cancer Research, London, and consultant oncologist at The Royal Marsden NHS Foundation Trust, said, “Our study found that some men with advanced prostate cancers have genomic mutations in their tumors that make the disease unstable, aggressive, and resistant to standard therapies. These men with ‘mismatch’ repair mutations only live about half as long as others who also have advanced prostate cancer but whose tumors don’t carry such mutations.”

“We made an exciting step forward in working out how to treat men with such aggressive, unstable tumors. We discovered that tumors with mismatch repair mutations have key hallmarks which make them particularly likely to respond to checkpoint inhibitor immunotherapy. We are now developing tests that could pick out patients with these mutations, and we’re running new clinical trials to see if immunotherapy can offer new hope for these men.”

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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