Oral Presentation Australian Society for Medical Research Annual Scientific Meeting 2016

Interleukin 1 Beta Variance is Predictive of Chemotherapy-induced Gastrointestinal Toxicity (CIGT) Risk in Patients Receiving 5-fluorouracil. (#10)

Samantha K Korver 1 , Imogen A Ball 1 , Rachel J Gibson 1 2 , Richard M Logan 1 , Jonathan Tuke 1 , Alison Richards 3 , Kelly Mead 3 , Chris S Karapetis 3 , Dorothy M Keefe 4 , Joanne M Bowen 1 , Janet K Coller 1
  1. University of Adelaide, Adelaide, SA, Australia
  2. University of South Australia, Adelaide, SA, Australia
  3. Flinders Medical Centre, Adelaide, SA, Australia
  4. Royal Adelaide Hopsital, Adelaide, SA, Australia

Introduction: Severe chemotherapy-induced gastrointestinal toxicities (CIGT) following 5-fluorouracil (5-FU) treatment are highly prevalent and negatively affect therapy. Currently, there are no diagnostic markers which predict a patient’s risk of severe CIGT prior to treatment. A small pilot study investigated the relationship between genetic variants in the interleukin-1 beta (IL-1β) - toll-like receptor (TLR) signalling pathway with the incidence of severe CIGT in 34 patients receiving 5-FU-based treatment. This study reported severe CIGT risk was associated with TLR2 and TNF genetic variability and cancer type (receiver operator characteristic (ROC) area under the curve (AUC) of 87.3%).

Objective: To validate this pilot study in a new, larger and independent cohort of patients.

Methods: Sixty-five patients (49 female) who completed 5-FU treatment at the Royal Adelaide Hospital and Flinders Medical Centre were recruited. CIGT data (toxicity: symptoms of Grade ≥ 3 NCI’s CTCAE v4, early treatment cessation or reduction), demographics and treatment parameters were collected from clinical case notes. Genetic variability in the following genes was determined using a customised Sequenom MassArray: IL1B, IL2, IL6, IL6R, IL10, TNF, TGFB, TLR2, TLR4, MD2, MYD88, BDNF, CRP, ICE and OPRM1. Multivariate logistic regression created a prediction model of severe CIGT risk and ROC curves assessed the model performance.

Results: Thirteen (20%) patients experienced severe CIGT. Colorectal and gastric cancer as well as genetic variants in interleukin-1 beta (IL1B, rs16944 and rs1143634) were significantly associated with severe CIGT risk (P=3.4x10-5), with a ROC AUC of 91.9%.

Conclusions: This study identified different genetic loci associated with severe CIGT risk (IL1B compared to TLR2 and TNF). Although different genetic loci were identified as predictive, these results still suggest genetic variance in the TLR4/IL-1β signalling pathway is predictive of severe CIGT risk. Further patients are being recruited to expand the study cohort to 150.