Abstract
Hyperprogressive disease (HPD), an unexpected acceleration of tumor growth kinetics, is described in cancer patients treated with anti-PD-1/anti-PD-L1 agents. Here, our aim was to take into consideration the host and explore whether single nucleotide polymorphisms (SNPs) in key genes involved in immune response might predispose to HPD. DNA was extracted from blood-samples from 98 patients treated under CPI monotherapy. Four candidate genes (PD-1, PD-L1, IDO1 and VEGFR2) and 15 potential SNPs were selected. The TGKR (ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. Hyperprogression was defined as a TGKR≥2. TGKR calculation was feasible for 80 patients (82%). HPD was observed for 11 patients (14%) and was associated with shorter overall survival (P = 0.003). In univariate analysis, HPD was significantly associated with age ≥70 y (P = 0.025), immune-related toxicity (P = 0.016), VEGFR2 rs1870377 A/T or A/A (P = 0.005), PD-L1 rs2282055 G/T or G/G (P = 0.024) and PD-L1 rs2227981 G/A or A/A (P = 0.024). Multivariate analysis confirmed the correlation between HPD and age ≥70 y (P = 0.006), VEGFR2 rs1870377 A/T or A/A (P = 0.007) and PD-L1 rs2282055 G/T or G/G (P = 0.018). Immunogenetics could become integral predictive factors for CPI-based immunotherapy.
Highlights
Hyperprogressive disease (HPD), an unexpected acceleration of tumor growth kinetics, is described in cancer patients treated with anti-PD-1/anti-PD-L1 agents
To better elucidate the potential relationship between host immunogenetics and Checkpoint inhibitors (CPIs) treatment outcome and hyperprogressive disease (HPD), we correlated the outcome of patients treated with CPI and selected polymorphisms described in four key genes: PD-1 (Programmed Cell Death 1 gene, 2q37.3), PD-L1 (Programmed Death Ligand 1 gene, 9p24.1), IDO1 (Indoleamine 2,3-Dioxygenase 1 gene, 8p11.21) and VEGFR2 (Vascular Endothelial Growth Factor Receptor 2 gene, 4q12)
All patients were treated by CPI monotherapy alone, with a majority of anti-PD1 (87%)
Summary
Hyperprogressive disease (HPD), an unexpected acceleration of tumor growth kinetics, is described in cancer patients treated with anti-PD-1/anti-PD-L1 agents. A single response profile, such as pseudo-progression, is observed under CPIs7 Among these typically-related response profiles under CPIs is hyperprogressive disease (HPD) which was defined as an unanticipated and paradoxical acceleration of the tumor growth[7,8]. Among these typically-related response prfiles under CPIs is hyperprogressive disease (HPD), which has been defined as an unanticipated and paradoxical acceleration of tumor growth[7,8]. To better elucidate the potential relationship between host immunogenetics and CPI treatment outcome and HPD, we correlated the outcome of patients treated with CPI and selected polymorphisms described in four key genes: PD-1 (Programmed Cell Death 1 gene, 2q37.3), PD-L1 (Programmed Death Ligand 1 gene, 9p24.1), IDO1 (Indoleamine 2,3-Dioxygenase 1 gene, 8p11.21) and VEGFR2 (Vascular Endothelial Growth Factor Receptor 2 gene, 4q12)
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