Microsatellite Instability, Tumor Mutational Burden, and Response to Immune Checkpoint Blockade in Patients with Prostate Cancer

Abstract

Purpose: Patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab. We define the genomic features, clinical course, and response to immune checkpoint blockade (ICB) in patients with MSI-H/dMMR and TMB-H prostate cancers without MSI [TMB-H/microsatellite stable (MSS)].

Experimental design: We sequenced 3,244 tumors from 2,257 patients with prostate cancer. MSI-H/dMMR prostate cancer was defined as an MSIsensor score ≥10 or MSIsensor score ≥3 and <10 with a deleterious MMR alteration. TMB-H was defined as ≥10 mutations/megabase. PSA50 and RECIST responses were assigned. Overall survival and radiographic progression-free survival (rPFS) were compared using log-rank test.

Results: Sixty-three (2.8%) men had MSI-H/dMMR, and 33 (1.5%) had TMB-H/MSS prostate cancers. Patients with MSI-H/dMMR and TMB-H/MSS tumors more commonly presented with grade group 5 and metastatic disease at diagnosis. MSI-H/dMMR tumors had higher TMB, indel, and neoantigen burden compared with TMB-H/MSS. Twenty-seven patients with MSI-H/dMMR and 8 patients with TMB-H/MSS tumors received ICB, none of whom harbored polymerase epsilon (polE) catalytic subunit mutations. About 45% of patients with MSI-H/dMMR had a RECIST response, and 65% had a PSA50 response. No patient with TMB-H/MSS had a RECIST response, and 50% had a PSA50 response. rPFS tended to be longer in patients with MSI-H/dMMR than in patients with TMB-H/MSS who received immunotherapy. Pronounced differences in genomics, TMB, or MSIsensor score were not detected between MSI-H/dMMR responders and nonresponders.

Conclusions: MSI-H/dMMR prostate cancers have greater TMB, indel, and neoantigen burden than TMB-H/MSS prostate cancers, and these differences may contribute to profound and durable responses to ICB.

Figure 1.

(A) CONSORT diagram of prostate cancer patients in the MSK-IMPACT genomic cohort, and the MSI-H/dMMR, TMB-H/MSS and MSS/TMB-L subsets in the analysis of OS from metastasis and response to ICB treatment analyses. (B) MSIsensor score and tumor mutational burden calculated from targeted (MSK-IMPACT) sequencing data stratified by MSI-H/dMMR, TMB-H/MSS, and TMB-L/MSS. (C) Overall survival from date of metastasis in patients with metastatic disease at the time of sequencing stratified by MSI-H/dMMR, TMB-H/MSS, and TMB-L/MSS. No significant difference was identified between the 3 groups.

Figure 2.

Clinical outcomes of patients with MSI-H/dMMR and TMB-H/MSS metastatic prostate cancer treated with immune checkpoint blockade (ICB, n=35). (A) Swimmer’s plot showing treatment duration (length of colored bar), progression (red dot), death (black square), censoring (black triangle), PSA at treatment start, and PSA nadir. Patients with PSA inevaluable disease (defined as PSA <2 ng/mL) are identified with hashed treatment duration bars. One patient with an MSI-H/dMMR tumor had an unknown ICB end date and therefore does not have a treatment duration bar (patient in bottom most swimmers lane). (B) Waterfall plot of best PSA response. Associated RECIST responses are superimposed as colored bars. A PSA₅₀ response occurred in 15 of 23 (65%) MSI-H/dMMR patients and in 3 of 6 (50%) TMB-H/MSS patients. (C) RECIST responses. PSA₅₀ responses are superimposed as grey shaded bars. In patients with MSI-H/dMMR tumors, 9 of 20 (45%) had a complete or partial response while no patient with a TMB-H/MSS tumor had a RECIST response. (D) Radiographic PFS (rPFS) from start of ICB for patients with MSI-H/dMMR and TMB-H/MSS metastatic castration-resistant prostate cancer.

Figure 3.

Genomic landscape of MSI-H/dMMR and TMB-H/MSS prostate tumors. (A) Oncoprint of mismatch repair (MMR), other DNA damage repair (DDR) genes, and additional select genes commonly mutated in prostate cancer for all MSI-H/dMMR (N=63) and TMB-H/MSS (N=33) tumors. (B) TMB, neoantigen burden, and indel burden calculated from whole exome recapture of MSK-IMPACT sequencing libraries in the MSI-H/dMMR and TMB-H/MSS cohorts.

Figure 4.

Clonal relatedness of a prostate cancer recurrence from a patient with MSI-H/dMMR prostate cancer who achieved a complete response to anti-PD-L1 therapy. (A) A 46-year-old man diagnosed with high-risk prostate cancer was treated with curative-intent radiation therapy and concurrent ADT. He later developed metastatic disease recurrence which was treated with ADT and later enzalutamide and abiraterone. Biopsy of an adrenal metastasis identified an MSI-H/dMMR phenotype. He was treated with combination ICB and IDO-inhibitor therapy and had a complete and durable response (B), leading to discontinuation of ADT. He later developed a rising PSA without evidence of metastatic recurrence. MRI of the prostate noted a new prostate lesion which on biopsy and targeted MSK-IMPACT tumor sequencing was found to be MSS/TMB-L, with no shared somatic mutations with the patient’s prior metastatic disease. (C–F) WES of the pre- and post-immunotherapy treated tumors confirmed the tumors to be clonally related despite the difference in MSI status. mPCa, metastatic prostate cancer; GG, grade group; RALP, robotic-assisted laparoscopic prostatectomy; IDO, indoleamine 2,3-dioxygenase.