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/MSS). Methods: We sequenced 3,244 tumors from 2,257 prostate cancer patients. MSI-H/dMMR prostate cancer was defined as 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 (OS) and radiographic progression-free survival (rPFS) were compared using log rank test. Results: 63 (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. 27 patients with MSI-H/dMMR and 8 patients with TMB-H/MSS tumors received ICB, none of whom harbored POLE mutations. 45% of MSI-H/dMMR patients had a RECIST response and 65% had a PSA50 response. No TMB-H/MSS patient had a RECIST response and 50% had a PSA50 response. rPFS tended to be longer in MSI-H/dMMR patients than in TMB-H/MSS patients who received immunotherapy. Pronounced differences in genomics, TMB or MSIsensor score were not detected between MSI-H/dMMR responders and non-responders. Conclusions: MSI-H/dMMR prostate cancers have greater TMB, indel and neoantigen burden compared with TMB-H/MSS prostate cancers, and these differences may contribute to more profound and durable responses to ICB.

中文翻译：

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前列腺癌患者的微卫星不稳定性、肿瘤突变负担以及对免疫检查点阻断的反应


目的：微卫星不稳定性高/错配修复缺陷 (MSI-H/dMMR) 和高肿瘤突变负荷 (TMB-H) 前列腺癌患者是派姆单抗的候选者。我们定义了 MSI-H/dMMR 和无 MSI 的 TMB-H 前列腺癌 (TMB-H/MSS) 患者的基因组特征、临床病程以及对免疫检查点阻断 (ICB) 的反应。方法：我们对 2,257 名前列腺癌患者的 3,244 个肿瘤进行了测序。 MSI-H/dMMR前列腺癌被定义为MSIsensor评分≥10或MSIsensor评分≥3且<10且存在有害的MMR改变。 TMB-H 定义为≥10 个突变/兆碱基。分配 PSA50 和 RECIST 反应。使用对数秩检验比较总生存期（OS）和放射学无进展生存期（rPFS）。结果：63 名 (2.8%) 男性患有 MSI-H/dMMR，33 名 (1.5%) 男性患有 TMB-H/MSS 前列腺癌。 MSI-H/dMMR 和 TMB-H/MSS 肿瘤患者在诊断时更常见表现为 5 级和转移性疾病。与 TMB-H/MSS 相比，MSI-H/dMMR 肿瘤具有更高的 TMB、插入缺失和新抗原负荷。 27 名 MSI-H/dMMR 患者和 8 名 TMB-H/MSS 肿瘤患者接受了 ICB，其中没有一人携带 POLE 突变。 45% 的 MSI-H/dMMR 患者有 RECIST 缓解，65% 有 PSA50 缓解。没有 TMB-H/MSS 患者有 RECIST 反应，50% 的患者有 PSA50 反应。 MSI-H/dMMR 患者的 rPFS 往往比接受免疫治疗的 TMB-H/MSS 患者更长。 MSI-H/dMMR 应答者和无应答者之间未检测到基因组学、TMB 或 MSIsensor 评分的显着差异。结论：与 TMB-H/MSS 前列腺癌相比，MSI-H/dMMR 前列腺癌具有更大的 TMB、插入缺失和新抗原负担，这些差异可能有助于对 ICB 产生更深刻和持久的反应。