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Three in a hundred prostate cancers have a broken proofreading system, and in the men who did, immunotherapy worked and kept working.
In a case series, 1,551 tumours from 1,346 men with prostate cancer were prospectively analysed with a targeted sequencing assay between January 2015 and January 2018, with tumour mutation burden and MSIsensor score calculated and mutational signature analysis and mismatch repair immunohistochemistry performed in selected cases. Among the 1,033 men whose tumours were of adequate quality for MSIsensor analysis, 32, 3.1%, had microsatellite instability-high or mismatch repair-deficient prostate cancer: 23 with high MSIsensor scores and a further 9 with indeterminate scores but other evidence of deficient repair. Seven of the 32, 21.9%, had a pathogenic germline mutation in a Lynch syndrome-associated gene. Of the 6 men with more than one tumour analysed, 2 displayed an acquired microsatellite instability-high phenotype later in the disease course. Eleven men with microsatellite instability-high or mismatch repair-deficient castration-resistant disease received anti-PD-1 or anti-PD-L1 therapy: 6, 54.5%, had a PSA decline of more than half, 4 of them with radiographic responses, and 5 of the 6 responders were still on therapy at up to 89 weeks.
It is the argument for sequencing every man with advanced prostate cancer rather than only the ones who look high risk: the phenotype is uncommon, it is invisible clinically, it opens the only durable immunotherapy route in this disease, and in one man in five it also identifies Lynch syndrome in the family.
Shares MSH2, dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing), Lynch syndrome.
Shares MSH6, MSH2, MSI-high (microsatellite instability by PCR or sequencing), Lynch syndrome.
Shares dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing), Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability.
Shares MSH2, MLH1, Lynch syndrome, JAMA Oncology.
Shares dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing), Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability.