Division of Oncology, Department of Medicine, University of Washington, Seattle, WA, United States of America.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
PLoS One. 2020 May 26;15(5):e0233260. doi: 10.1371/journal.pone.0233260. eCollection 2020.
While response rates to anti-PD1 therapy are low in unselected metastatic castration resistant prostate cancer (mCRPC) patients, those with inactivating mutations in mismatch repair (MMR) genes (i.e. MMR deficiency; MMRd) or microsatellite instability (MSI) are thought likely to respond favorably. To date, there is limited published data on this biologically distinct and clinically relevant subgroup's natural history and response to treatment.
We retrospectively identified patients at two academic institutions who had MMRd/MSI-high metastatic prostate cancer (PC). Clinical and pathologic characteristics at the time of diagnosis as well as response to standard therapies and immune checkpoint therapy were abstracted. Descriptive statistics, including PSA50 response (≥50% decline in PSA from baseline) and clinical/radiographic progression free survival (PFS), are reported.
27 men with MMRd and/or MSI-high metastatic PC were identified. 13 (48%) men had M1 disease at diagnosis and 19 of 24 (79%) men that underwent prostate biopsy had a Gleason score ≥8. Median overall survival from time of metastasis was not reached (95% CI: 33.6-NR mos) after a median follow up of 33.6 mos (95% CI: 23.8-50.5 mos). Seventeen men received pembrolizumab, of which 15 had PSA response data available. PSA50 responses to pembrolizumab occurred in 8 (53%) men. Median PFS was not reached (95% CI: 1.87-NR mos) and the estimated PFS at 6 months was 64.1% (95% CI: 33.7%-83.4%). Of those who achieved a PSA50 response, 7 (87.5%) remain on treatment without evidence of progression at a median follow up of 12 months (range 3-20 months).
MMRd PC is associated with high Gleason score and advanced disease at presentation. Response rates to standard therapies are comparable to those reported in unselected patients and response rate to checkpoint blockade is high. Our study is limited by small sample size, and more research is needed to identify additional factors that may predict response to immunotherapy.
尽管抗 PD-1 治疗在未经选择的转移性去势抵抗性前列腺癌（mCRPC）患者中的反应率较低，但那些具有错配修复（MMR）基因失活突变（即 MMR 缺陷；MMRd）或微卫星不稳定性（MSI）的患者可能反应良好。迄今为止，关于这一生物学上不同且临床上相关的亚组的自然史和对治疗的反应，已有有限的已发表数据。
我们回顾性地确定了在两个学术机构的 MMRd/MSI-高转移性前列腺癌（PC）患者。在诊断时的临床和病理特征，以及对标准治疗和免疫检查点治疗的反应都被提取出来。报告了描述性统计数据，包括 PSA50 反应（PSA 从基线下降≥50%）和临床/放射学无进展生存期（PFS）。
确定了 27 名 MMRd 和/或 MSI-高转移性 PC 患者。13 名（48%）男性在诊断时患有 M1 疾病，24 名接受前列腺活检的男性中有 19 名（79%）的 Gleason 评分≥8。在中位随访 33.6 个月（95%CI：23.8-50.5 个月）后，中位总生存期从转移时未达到（95%CI：33.6-NR mos）。17 名男性接受了 pembrolizumab 治疗，其中 15 名有 PSA 反应数据。pembrolizumab 的 PSA50 反应发生在 15 名（53%）男性中。中位 PFS 未达到（95%CI：1.87-NR mos），估计 6 个月的 PFS 为 64.1%（95%CI：33.7%-83.4%）。在 PSA50 反应的患者中，7 名（87.5%）在中位随访 12 个月（范围 3-20 个月）时仍在接受治疗，且没有进展的证据。
MMRd PC 与高 Gleason 评分和疾病晚期表现相关。对标准治疗的反应率与未选择的患者报告的反应率相当，对检查点阻断的反应率较高。我们的研究受到样本量小的限制，需要更多的研究来确定可能预测免疫治疗反应的其他因素。
