Do irinotecan (IRI) dose reductions driven by UGT1A1*28 genotyping prevent IRI-related severe neutropenia? A real-world study.

Abstract

e16116 Background: IRI is widely used in the treatment of gastrointestinal cancers. Consistent with current guidelines, UGT1A1 genotyping may drive IRI dose reductions, but the usefulness of this approach is still unclear. We assessed potential clinical variables that may predict grade ≥3 neutropenia and more specifically the upfront genotyping of UGT1A1 polymorphisms associated with IRI toxicity, according to predefined IRI dose reductions. Methods: We genotyped UGT1A1*28 polymorphisms in 247 patients with metastic colorectal, gastric and pancreatic cancers who received second or third-line IRI-based chemotherapy in clinical practice at a single academic center. Concomitant DPYD sequencing was undertaken in 179 patients receiving also fluoropyrimidines. We compared the incidence of severe neutropenia with full-dose IRI in UGT1A1 6/6 and 6/7 carriers, and in UGT1A1 7/7 carriers who underwent initial IRI dose reductions by at least 30%. Results: The incidence of UGT1A1 7/7, 6/7, 6/6 genotypes was 11.3%, 51.4%, and 37.2%, respectively. IRI dose reductions were significantly more frequent with UGT1A 7/7 and 6/7 genotypes (odds ratio [OR] = 9.5; 95% confidence interval [CI]: 4.3-21.7), and combination chemotherapy (OR = 3.8; 95%CI: 1.3 – 11.1). Other clinical parameters, including sex, cancer type, baseline neutrophils levels, performance status were not significantly associated with IRI dose reductions. Despite initial IRI reductions driven by the UGT1A1 panel, patients with UGT1A1 7/7 genotype had an increased, albeit non-significant, risk of grade ≥3 neutropenia, compared to patients with UGT1A1 6/6 and 6/7 genotypes who received full dose IRI (incidence: 39% versus 21%; OR = 2.4; 95%CI: 0.85 – 7.03). Conclusions: UGT1A1 testing is a determinant of IRI dose reductions, however this strategy does not reduce the burden of grade ≥3 neutropenia in UGT1A1 7/7 carriers. Further studies beyond the UGT1A1*28 genotype are needed to fully understand the increased risk of neutropenia in patients candidate to IRI-based chemotherapy.