Wang Zhenghang, Liu Chang, Bai Yuezong, Zhao Xiaochen, Cui Longgang, Peng Zhi, Zhang Xiaotian, Wang Xicheng, Zhao Zhengyi, Li Jian, Shen Lin
Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
Medical Affairs, 3D Medicines Inc., Shanghai, China.
Front Oncol. 2021 Nov 9;11:761110. doi: 10.3389/fonc.2021.761110. eCollection 2021.
Emerging evidence showed that immune checkpoint inhibitors (ICIs) lead to hyperprogressive disease (HPD) in a small proportion of patients. There is no well-recognized standard for the evaluation of HPD. Comprehensive exploration of HPD definition system in gastrointestinal cancer treated with ICI is lacking to date.
A total of 126 patients with advanced or metastatic gastrointestinal cancer treated with ICI monotherapy were analyzed. Seven definitions of HPD were defined with tumor growth kinetics (TGK) or tumor growth rate (TGR) by including new lesions or not, and with different cutoffs. Incidence and performance of different criteria were compared. Clinicopathologic characteristics and baseline genomic variations associated with HPD were also explored.
Tumor growth kinetics ratio of more than two fold that incorporated new lesions into calculation of HPD outperformed other definitions by successfully stratifying 14 patients (11.1%) with both accelerated disease progression (median PFS, 1.62 1.93 months; hazard ratio, 1.85; 95% CI, 0.98 to 3.48; P = 0.059) and worse overall survival (median OS, 3.97 10.23 months; hazard ratio, 2.30; 95% CI, 1.11 to 4.78; P = 0.021). Baseline genomic alterations in circulating tumor DNA, including SMARCA2, MSH6, APC signaling pathway, and Wnt signaling pathway, might be associated with the risk of HPD.
Incorporating new lesions emerging during the treatment was shown to be reliable for the assessment of TGK. TGK serves as a more convenient way to reflect tumor growth acceleration compared with TGR. Genomic alterations were suggested to be associated with the occurrence of HPD.
新出现的证据表明，免疫检查点抑制剂（ICI）在一小部分患者中会导致超进展性疾病（HPD）。目前尚无公认的HPD评估标准。迄今为止，缺乏对接受ICI治疗的胃肠道癌中HPD定义系统的全面探索。
分析了126例接受ICI单药治疗的晚期或转移性胃肠道癌患者。通过纳入或不纳入新病灶，采用肿瘤生长动力学（TGK）或肿瘤生长率（TGR），并设置不同的临界值，定义了7种HPD定义。比较了不同标准的发生率和性能。还探讨了与HPD相关的临床病理特征和基线基因组变异。
将新病灶纳入HPD计算的肿瘤生长动力学比值超过两倍，通过成功分层14例（11.1%）疾病进展加速（中位无进展生存期，1.62±1.93个月；风险比，1.85；95%置信区间，0.98至3.48；P = 0.059）且总生存期较差（中位总生存期，3.97±10.23个月；风险比，2.30；95%置信区间，1.11至4.78；P = 0.021）的患者，其表现优于其他定义。循环肿瘤DNA中的基线基因组改变，包括SMARCA2、MSH6、APC信号通路和Wnt信号通路，可能与HPD风险相关。
纳入治疗期间出现的新病灶被证明对TGK评估是可靠的。与TGR相比，TGK是反映肿瘤生长加速的更便捷方式。提示基因组改变与HPD的发生有关。
