Toxicity related to immunotherapy in urothelial cancer: Tumour genetic risk variants

The treatment of urothelial cancer (UC) has been revolutionized by the introduction of immune checkpoint inhibitors (ICIs). However, while ICIs have achieved better therapeutic results than traditional chemotherapeutic agents, immune-related adverse events (irAEs) can lead to poor treatment outcomes. This exploratory study was designed to seek tumour single-nucleotide polymorphisms (SNPs) related to irAEs in patients with UC treated with ICIs. Tumour specimens were collected at several hospitals in Madrid (Spain) from 102 patients treated with nivolumab, atezolizumab, avelumab or pembrolizumab. DNA was extracted from formalin-fixed paraffin-embedded tumour biopsies, and 49 SNPs genotyped using a MassARRAY platform. Among the 49 SNPs analyzed, rs1738074 was associated both with overall toxicity (p<0.001), and with the appearance of specific toxicities such as dermatitis and pneumonitis (p=0.005 and p=0.036, respectively). In effect, 100% of patients with pneumonitis were homozygous for the variant allele (p=0.020). Other SNPs were also linked to a higher risk of irAEs: rs2301756 to pneumonitis (p=0.005), rs55733913 and rs2117997 to dermatitis (p=0.026, p=0.021, respectively) and rs4988956 to hepatitis (p=0.027). Contrarily, two SNPs, rs11571302 and rs66502444, showed a possible protective role against asthenia (p=0.012, p=0.030, respectively). This exploratory study highlights the possible useful role of tumour SNPs as biomarkers to predict the risk of UC patients developing irAEs. Further studies are needed to validate the utility of SNPs as biomarkers of ICI-induced toxicity.