Clinical Characterization of Mismatch Repair Gene-Deficient Metastatic Castration-Resistant Prostate Cancer

Abstract

Mismatch repair-deficient (dMMR) prostate cancer is rare and has not been well studied. We aimed to evaluate the clinical characterization of dMMR metastatic castrationresistant prostate cancer (mCRPC) patients. The MMR genes include MLH1, MLH3, MSH2, MSH6, PMS1, PMS2, and EPCAM, and were analyzed by targeted sequencing of plasma cell-free DNA samples. A total of 109 mCRPC patients were identified, including 50 patients with MMR alterations (pathogenic alterations, n = 7; alterations of unknown significance, n = 43) and 59 patients with wild-type MMR. For the seven patients with pathogenic MMR alterations, the median age at diagnosis was 63.5 years, and 42.9% had a Gleason score ≥8. The median time from androgen deprivation therapy (ADT) initiation to CRPC was 24 months. Compared with the wild-type MMR subgroup, patients with MMR alterations, pathogenic MMR alterations, or MMR alterations of unknown significance showed higher rates of hotspot missense mutations or copy number amplifications in the AR gene (24/50 vs. 10/59, P = 7.8 × 10 −4 ; 7/7 vs. 10/59, P = 2.5 × 10 −5 ; 17/43 vs. 10/59, P = 0.013). The presence of any MMR alterations was associated with an inferior response to abiraterone [median progression-free survival (PFS): 5.0 vs. 10.9 months, P = 0.022]. Shorter PFS times were observed in both the pathogenic MMR alteration subgroup (median PFS: 5 months) and the MMR alterations of unknown significance subgroup (median PFS: 5.3 months), compared with the PFS of those with wild-type MMR genes (median PFS: 10.9 months, P = 0.052). There was no statistically significant difference in response to docetaxel chemotherapy between the MMR alterations of unknown significance and the wild-type MMR subgroups (median PFS: 8.2 vs. 8.1 months, P = 0.23). Our results demonstrate that dMMR mCRPC patients have an equivalent response to standard ADT and taxanebased chemotherapy treatments compared with wild-type MMR patients. Patients with both pathogenic and unknown significance alterations of MMR genes had poorer responses to abiraterone therapy.

Histopathological and genetic features of mismatch repair‐deficient high‐grade prostate cancer

“…In prior series, MMR-deficient prostate cancer has been associated with high-grade histology (grade groups 4-5) and advanced pathological stage, consistent with the aggressive clinical behaviour and short progression-free survival periods observed in these patients. 15,30,31 Ductal histology, 17 tumourinfiltrating lymphocytes 16 and pleomorphic giant tumour cells 27 have also been reported in MMRdeficient prostate cancer. In the present study, MMRdeficient prostate cancers without prior systemic treatment were invariably high-grade.…”

“…This study has limitations that need to be highlighted. First, the number of cases is relatively small, albeit comparable to prior series of MMR‐deficient prostate cancer 9,15,30,31 . Secondly, because most cases were identified in a sequencing database, a selection bias resulting in enrichment for high‐grade tumours is likely.…”

“…First, the number of cases is relatively small, albeit comparable to prior series of MMR-deficient prostate cancer. 9,15,30,31 Secondly, because most cases were identified in a sequencing database, a selection bias resulting in enrichment for high-grade tumours is likely. However, prior molecular studies have invariably found a similar association between MMRdeficiency and high-grade histology, suggesting that the present series is not different from others.…”

Exploiting the DNA Damage Response for Prostate Cancer Therapy

“…While only a single hypermutagenic polymerase mutation has been reported in CRPC to our knowledge, both dMMR and APOBEC signatures appear in CRPC, but occur infrequently compared to some other cancer types [ 71 , 72 , 73 ]. MSI-high/dMMR tumors were identified in some CRPC cohorts, constituting up to 5% of analyzed patients depending on the cohort analyzed [ 74 , 75 ]. Numerous prostate cancer samples exhibit APOBEC signature mutations that increase along the spectrum of disease progression from localized to mCRPC, although the overall frequency is low compared to several other tumor types [ 71 , 76 ].…”

Mutational spectrum of DNA damage and mismatch repair genes in prostate cancer

“…The risk of PCa in men with MMR gene mutations has been demonstrated to be significantly enhanced ( Rantapero et al, 2020 ). Individuals that have MMR mutations are typically predicted to account for 2%–5% of PCa cases ( Ritch et al, 2020 ; Ye et al, 2020 ), and they are generally identified by their Gleason score 8 and de novo metastases ( Dominguez-Valentin et al, 2016 ; Ye et al, 2020 ; Jiang et al, 2021 ; Graham and Schweizer, 2022 ). The genetic mutations in MMR genes in the prostate may aid in understanding PCa carcinogenesis, which may have additional repercussions for ICBs and other types of treatment.…”