翻译：李静玉
沈阳军区总医院肿瘤科住院医师，肿瘤学硕士，第一作者发表核心期刊论文2篇，参与国家自然科学基金和辽宁省自然基金项目3项。目前主要从事肿瘤内科诊疗。
背景
ICI能够克服免疫抑制，激活对肿瘤细胞的有效免疫应答。ICIS治疗使多种实体瘤患者总生存率得到临床意义上的延长，部分应答患者(PTS)疾病控制率得到提高。然而，在ICI治疗期间，大约9%-29%的患者肿瘤生长速率(TGR)加快，通常称之为疾病超进展（Hyperprogression），疾病超进展的发生机制尚不清楚，其中有一些患者出现MDM2家族基因扩增。
方法
我们回顾性分析了334例采用抗PD1/PD-L1(单抗或联合)治疗晚期实体肿瘤的患者。纳入标准包括3个时间点的影像学评估：参考期（ICI治疗基线检查之前的3个月至2周)、ICI治疗前（基线检查，28天内完成)和ICI治疗期间。如果患者根据RECIST 1.1影像学疗效评价提示疾病进展且ICI治疗中TGR较参考期增加2倍，则认为是疾病超进展。对超进展患者的石蜡包埋肿瘤组织进行FISH分析，以评价MDM 2家族基因的扩增。
结果
在ICI期间，由于缺乏肿瘤评估，73例患者最初被排除分析之外。在剩余患者中，有109例在首次评估时确定疾病进展，其中只有45例具有研究所要求的全部影像学检查，符合分析标准。7例符合超进展标准，占应可评估患者的3.5% (7/197)，占所有疾病进展患者的6.4%（7/109）。超进展与与组织学、年龄、血清标志物及免疫检查点抑制剂种类无相关性。对3例MDM 2家族基因进行FISH检测：1例 MDM4基因扩增(信号均值>8)，其他病例仅显示MDM 4比值增加，意义不明。
结论
尽管是回顾性分析且样本数量较少，本研究结果提示超进展是一个少见的临床相关事件。MDM2家族基因改变作为预测超进展的生物标志物具有良好前景，但有必要进行前瞻性的基因组学和生物学分析。
专家点评
沈阳军区总医院肿瘤科主任，中国医科大学、大连医科大学、沈阳药科大学、锦州医科大学硕士研究生导师。从事恶性肿瘤综合治疗的临床及科研工作近20年，擅长乳腺、呼吸系统、消化系统、泌尿生殖系统等部位常见及各种罕见恶性肿瘤的科普宣教、预防、诊断及综合治疗。常年致力于各种实体肿瘤的精准诊疗和临床转化研究，擅长乳腺、呼吸道、胃肠道等恶性肿瘤的预防、诊断及治疗。主持科研立项9项，共计70余万元；获得省部级以上科研奖励10项，发表中文核心期刊近50篇，SCI收录 20篇，总影响因子42.79分；担任辽宁省细胞生物学学会肿瘤精准治疗与大数据管理分会主任委员、辽宁省抗癌协会肿瘤标志专业委员会副主任委员、辽宁省自然科学基金项目评审专家等40余项学术兼职。
随着抗PD（L）1癌症免疫治疗的普及，人们发现其中一部分患者在治疗初期会发生疾病快速进展，称之为“超进展”。2016年ESMO大会上J.Lahmar等人首次提出超进展，此后有多篇报道相继发表。这是本届ESMO大会上唯一一篇关于肿瘤免疫治疗超进展的研究，提醒我们要持续关注这一话题。关于超进展的判定对RECIST标准提出了挑战，因该标准未能在疾病早期评估治疗前和治疗后的肿瘤生长动力学。有学者提出诸如TGR（肿瘤生长速率）、TGK（肿瘤生长动力学）和TTF（治疗失败时间）等参数，具体标准包括：(1) 在免疫检查点抑制剂治疗后第一次评价时进展，或至治疗失败时间（TTF）<2月；（2）肿瘤体积增加>50%；(3)肿瘤增长速度（TGR)增加>2倍。目前超进展的发生机制尚不清楚，与假性进展不同，出现超进展的患者生存率极低。研究表明，超进展现象与老年、较高的转移负荷和既往放疗独立相关，但与治疗前肿瘤负荷高或生长迅速无相关性。另有研究提示，超进展可能与肿瘤MDM2家族基因扩增和EGFR突变有关。此外，肿瘤突变负荷和循环DNA可能对此也有一定预测价值。彻底揭示超进展的谜团，还需要更多病例的积累和更深入的研究。患者和临床医生应该意识到要正确选择最佳治疗并仔细监测疾病的演变。
1、Fuentes-Antrás J, Provencio M, Díaz-Rubio E, et al. Hyperprogression as a distinct outcome after immunotherapy.Cancer Treat Rev. 2018;70:16-21.
2、Stephane Champiat, Laurent Dercle, Samy Ammari, et al. Hyperprogressive disease is a new pattern of progression in cancer patients treated by Anti-PD-1/PD-L1. Clin Cancer Res. 2017;23(8):1920-1928.
3、Kato S, Goodman A, Walavalkar V, et al. Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate. Clin Cancer Res. 2017;23(15):4242-4250
4、Saâda-Bouzid E, Defaucheux C, Karabajakian A, et al. Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol. 2017;28(7):1605-1611.
5、E. Fare`1, S. Sdao2, S. Damian1, S. ESMO Congress 2018 (Abstract 1211P).
附原文：
Hyperprogression during immuno-checkpoint inhibitors (ICIs): A clinically significant problem? (Abstract 1211P)
Background: ICIs can overcome immune-suppression and activate effective immune responses against cancer cells. Therapy with ICIs have led to a clinically-meaningful extension in overall survival across several solid tumors, being endowed with long term disease control-rate in a part of responding patients (pts). However, an acceleration of the tumor growth rate (TGR) during ICI, defined as hyperprogressive disease (HPD), has been reported in 9-29% of pts. Mechanisms underlying HPD are unknown, yet murine double minute 2 (MDM2) family amplification was found in some of these pts.
Methods: We retrospectively identified a series of 334 pts with miscellaneous advanced solid tumors treated with anti-PD1/PD-L1-containing ICI (mono or combo therapy) at our Institution. Inclusion criteria included imaging assessment at 3 timepoints: during reference period (from 3 months to 2 weeks before ICI baseline scan), before ICI therapy start (baseline scan, performed within 28 days) and during ICI treatment. Patients were considered HPD if they showed progressive disease (PD) by RECIST 1.1 at first radiological evaluation and a≥2-fold increase of the TGR during ICI therapy compared to reference period. FISH analysis to evaluate MDM2 family genes amplification was performed in HPD cases whose paraffin embedded tumor material was available.
Results: 73 cases were initially excluded from our analysis due to lack of tumor assessment during ICI. Of the remaining pts, 109 reported PD at first evaluation. Of them, only 45 were suitable for the analyses, having all requested radiological examinations available. Seven cases met HPD criteria: 3,5% of evaluable pts (7/197) and 6.4% of all the PD. No correlation with histology, age, serum biomarkers and type of ICI was found. FISH test for MDM2 family has been performed on 3 cases: one case showed amplification MDM4 gene (mean of signals > 8); other cases showed only increased MDM4 ratio score of unknown significance.
Conclusions: Despite the limits of a retrospective analysis and small numbers, in our series HPD is a rare but clinically relevant event. The role of MDM2 family alteration as predictive biomarker is promising and deserves more investigations. Prospective studies including genomic and biological analysis are warranted.
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