INTRODUCTION: A subset of prostate cancers (PCs) has a hypermutated phenotype. We hypothesized that lethal PCs with a high mutational load (ML) have DNA repair defects including mismatch-repair (MMR) aberrations and that such aberrations may impact outcome. METHODS: Diagnostic and metastatic castration resistant prostate cancer (mCRPC) tissues were tested by A) immunohistochemistry (IHC) for MSH2, MSH6, MLH1, and PMS2; B) microsatellite instability (MSI) (Promega v1.2 assay); C) targeted next generation sequencing (NGS) of the coding regions of 113 genes, a panel enriched for DNA-repair genes that includes MMR genes. Utilizing NGS data we also evaluated ML and MSI by NGS (MSINGS; Pritchard et al, 2014). IHC was used as reference for sensitivity (SE) and specificity (SP) of methods B) and C).Youden’s index was used to determine the optimal cut off for the ROC for IHC in relation to MSINGS and ML. Demographics and clinical data were retrospectively collected from electronic records. Relationship between ML in diagnostic and mCRPC samples was evaluated by paired t-test. The relationship between ML and MMR deficient tumors on IHC (MMRd) and/or MSI tumors by PCR (MMRd/MSI) was analyzed by negative binomial regression model. The relationship between MMRd/MSI tumors and overall survival (OS) was analyzed using univariate and multivariate Cox regression, adjusting for radical treatment (prostatectomy or radiotherapy), Gleason score, age, PSA and stage and presence of metastatic disease at diagnosis.
RESULTS: We analyzed 306 PC biopsies (180 hormone-sensitive [HS] and 126 castration resistant [CR]) from 208 patients. Overall 16 patients (7.7%) had either MMRd or MSI. Matched, same-patient, HSPC and mCRPC tumor biopsies were available for 82 patients. Only one case with MMRd status in HS was not confirmed in matched mCRPC. This patient was considered MMR proficient for the survival analysis. MSI had a SE of 80% and a SP of 97%. An MSI by NGS cut-off of 0.096 had SE of 60% and SP of 99%, with an area under ROC curve of 0.83. A ML cut-off of 11 mutations per panel had SE of 60% and SP of 99%, with an area under ROC curve of 0.79. Although ML in diagnostic samples correlates with ML in mCRPC, ML was significantly higher in mCRPC MMRd/MSI cases (p <0.001; predicted ML of 14 versus 4 mutations per panel). MMRd/MSI and MMR proficient patients were balanced for type of radical treatments, Gleason score, presence of metastatic disease, PSA, age and stage at diagnosis. Despite this, median OS from start of LHRH for the MMRd/MSI group was significantly shorter than in the MMR proficient group in univariable and multivariable analysis (3.84 vs 6.81 years; aHR: 2.44; 95% CI 1.27 -4.70; p = 0.008).
CONCLUSION: We provide evidence that MMRd/MSI status represents a negative prognostic factor for survival for metastatic CRPC. MMRd/MSI status in diagnostic biopsies accurately identifies MMRd/MSI in mCRPC. MSINGS and ML can detect MMRd/MSI tumors.
Citation Format: Pasquale Rescigno, Daniel Nava Rodrigues, Wei Yuan, Suzanne Carreira, Maryou Lambros, George Seed, Ruth Riisnaes, Susana Miranda, David Dolling, Matthew Clarke, Mateus Crespo, Claudia Bertan, Gunther Boysen, Joaquin Mateo, Ana Ferreira, Adam Sharp, Ines Figueiredo, Semini Sumanasuriya, Mariane Sousa Fontes, Diletta Bianchini, Zafeiris Zafeiriou, Johann Sebastian de Bono. Mismatch repair defects in lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4679. doi:10.1158/1538-7445.AM2017-4679