Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate.
Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate.
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DOI：
10.1158/1078-0432.ccr-16-3133
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发表时间：
2017-08-01
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影响因子：
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通讯作者：
Kurzrock R
中科院分区：
文献类型：
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作者：
Kato S;Goodman A;Walavalkar V;Barkauskas DA;Sharabi A;Kurzrock R
检查点抑制剂显示出有益的抗癌效果，包括长期缓解。PD-L1表达/扩增、高突变负担和错配修复缺陷与反应相关。然而，我们观察到一部分患者似乎是“超进展者”，与治疗前相比，肿瘤生长和临床恶化的速度大大加快，Gustave Roussy研究所最近也报道了这一点。目前的研究调查了免疫治疗后与“超进展”相关的潜在基因组标记。连续接受免疫治疗（CTLA-4， PD-1/PD-L1抑制剂或其他[研究]药物）并通过下一代测序评估其肿瘤的IV期癌症患者进行分析（N=155）。我们将超进展定义为治疗失败时间(TTF) <2个月，与免疫治疗前成像相比，肿瘤负担增加50%，进展速度增加2倍。在155例患者中，所有6例MDM2/MDM4扩增患者中TTF <2个月。在抗pd1 /PDL1单药治疗后，这些患者中的4例显示现有肿瘤大小显着增加（55%至258%），新的大肿块，并且进展速度显着加快（与免疫治疗前两个月相比，2.3倍，7.1倍，7.2倍和42.3倍）。在多变量分析中，MDM2/MDM4和EGFR改变与TTF<2个月相关。10例EGFR改变的患者中有2例也是超进展者（肿瘤大小增加53.6%和125%；增加35.7倍和41.7倍）。一些MDM2家族扩增或EGFR异常的患者在使用单药检查点（PD-1/PD-L1）抑制剂后，临床结果较差，肿瘤生长速度显著增加。基因组谱可能有助于识别有免疫治疗进展风险的患者。迫切需要进一步调查。
Checkpoint inhibitors demonstrate salutary anti-cancer effects including long-term remissions. PD-L1 expression/amplification, high mutational burden and mismatch repair-deficiency correlate with response. We have, however, observed a subset of patients who appear to be “hyper-progressors,” with a greatly accelerated rate of tumor growth and clinical deterioration compared to pre-therapy, which was also recently reported by Institut Gustave Roussy. The current study investigated potential genomic markers associated with “hyper-progression” after immunotherapy. Consecutive stage IV cancer patients who received immunotherapies (CTLA-4, PD-1/PD-L1 inhibitors or other [investigational] agents) and had their tumor evaluated by next-generation sequencing were analyzed (N=155). We defined hyper-progression as time-to-treatment failure (TTF) <2 months, >50% increase in tumor burden compared to pre-immunotherapy imaging, and >2-fold increase in progression pace. Amongst 155 patients, TTF <2 months was seen in all six individuals with MDM2/MDM4 amplification. After anti-PD1/PDL1 monotherapy, four of these patients showed remarkable increases in existing tumor size (55% to 258%), new large masses, and significantly accelerated progression pace (2.3-, 7.1-, 7.2- and 42.3-fold compared to the two months before immunotherapy). In multivariate analysis, MDM2/MDM4 and EGFR alterations correlated with TTF<2 months. Two of 10 patients with EGFR alterations were also hyper-progressors (53.6% and 125% increase in tumor size; 35.7- and 41.7-fold increase). Some patients with MDM2 family amplification or EGFR aberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent checkpoint (PD-1/PD-L1) inhibitors. Genomic profiles may help to identify patients at risk for progression on immunotherapy. Further investigation is urgently needed.