Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Eur Urol. 2019 Mar;75(3):378-382. doi: 10.1016/j.eururo.2018.10.009. Epub 2018 Oct 15.
Mismatch repair (MMR) gene mutations are rare in prostate cancer, and their histological and clinical characteristics are largely unknown. We conducted a retrospective study to explore disease characteristics and treatment outcomes of men with metastatic prostate cancer harboring germline and/or somatic MMR mutations detected using clinical-grade genomic assays. Thirteen patients with a deleterious MMR gene mutation were identified. Median age was 64 yr, 75% had grade group 5 (Gleason sum 9 or 10), 23% had intraductal histology, 46% had metastatic disease at initial diagnosis, and 31% had visceral metastases. Most patients (46%) had MSH6 mutations, 73% demonstrated microsatellite instability, and median tumor mutational load was 18/Mb (range, 3-165 mutations/Mb). Surprisingly, responses to standard hormonal therapies were very durable (median progression-free survival [PFS] of 67 mo to initial androgen deprivation and median PFS of 26 mo to abiraterone/enzalutamide). Two of four men receiving PD-1 inhibitors achieved a ≥50% prostate-specific antigen response at 12 wk, with a median PFS duration in these four men of 9 mo. Despite aggressive clinical and pathological features, patients with MMR-mutated advanced prostate cancer appear to have particular sensitivity to hormonal therapies, as well as anecdotal responses to PD-1 inhibitors. Certain histological features (grade group 5, intraductal carcinoma) should prompt evaluation for MMR deficiency. These data are only hypothesis generating. PATIENT SUMMARY: Prostate cancers with mismatch repair gene mutations have aggressive clinical and pathological features; however, these are very sensitive to standard and novel hormonal therapies, and also demonstrate anecdotal sensitivity to PD-1 inhibitors such as pembrolizumab.
错配修复（MMR）基因突变在前列腺癌中较为罕见，其组织学和临床特征在很大程度上尚不清楚。我们进行了一项回顾性研究，旨在探讨使用临床级基因组检测发现的携带有胚系和/或体细胞 MMR 基因突变的转移性前列腺癌患者的疾病特征和治疗结局。鉴定出 13 名具有有害 MMR 基因突变的患者。中位年龄为 64 岁，75%的患者为分级组 5（Gleason 总和 9 或 10），23%的患者有导管内组织学，46%的患者在初始诊断时即发生转移性疾病，31%的患者有内脏转移。大多数患者（46%）存在 MSH6 基因突变，73%存在微卫星不稳定，肿瘤突变负荷中位数为 18/Mb（范围 3-165 个突变/Mb）。令人惊讶的是，标准激素治疗的反应非常持久（初始去势治疗的无进展生存期[PFS]中位数为 67 个月，阿比特龙/恩杂鲁胺的 PFS 中位数为 26 个月）。接受 PD-1 抑制剂治疗的 4 名男性中有 2 名在 12 周时达到了前列腺特异性抗原应答≥50%，这 4 名男性的 PFS 持续时间中位数为 9 个月。尽管存在侵袭性的临床和病理特征，但 MMR 突变的晚期前列腺癌患者似乎对激素治疗具有特殊的敏感性，并且对 PD-1 抑制剂也有偶发的反应。某些组织学特征（分级组 5、导管内癌）应提示评估 MMR 缺陷。这些数据仅具有生成假说的作用。患者总结：具有错配修复基因突变的前列腺癌具有侵袭性的临床和病理特征；然而，这些对标准和新型激素治疗非常敏感，并且也表现出对 PD-1 抑制剂如 pembrolizumab 的偶发敏感性。
