Abstract 1838P
Background
IRI is widely used in the treatment of advanced gastrointestinal cancers. Consistent with current guidelines, UGT1A1 genotyping may drive IRI dose reductions, but the usefulness of this approach, performed in a prospective manner, is still unclear. We assessed the incidence of grade ≥3 neutropenia in patients who undergo IRI-based chemotherapies after upfront genotyping of UGT1A1 polymorphisms.
Methods
We genotyped UGT1A1*28 polymorphisms in 247 patients receiving second or third line IRI-based chemotherapy in clinical practice at a single academic center. Concomitant DPYD sequencing was performed in 179 patients receiving also fluoropyrimidines. Based on the results of the UGT1A1 genotyping, in UGT1A1 6/6 and 6/7 carriers full-dose IRI was delivered, whereas in UGT1A1 7/7 carriers initial IRI dose reductions by at least 30% were done. We compared the incidence of grade ≥3 neutropenia occurring in UGT1A1 6/6 and 6/7 carriers, and in UGT1A1 7/7 carriers.
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, baseline bilirubin levels, performance status were not significantly associated with dose reductions. Despite initial IRI reductions, UGT1A1 7/7 genotype was associated to 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 determinants of severe neutropenia in these patients.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
N. Personeni: Advisory/Consultancy: Amgen, ArQule, Merck Serono, Servier, AbbVie, Gilead, Lilly; Travel/Accommodation/Expenses: Amgen, ArQule. A. Santoro: Advisory/Consultancy: BMS (Bristol-Myers-Squibb), Servier, Gilead, Pfizer, Eisai, Bayer, MSD, ArQule, Sanofi; Speaker Bureau/Expert testimony: Takeda, BMS, Roche, AbbVie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, ArQule, Lilly, Sandoz, Eisai, Novartis, Bayer, MSD. L. Rimassa: Advisory/Consultancy: Amgen, ArQule, Basilea, Bayer, Celgene, Eisai, Exelixis, Hengrui, Incyte, Ipsen, Lilly, MSD, Roche, Sanofi; Speaker Bureau/Expert testimony: AbbVie, Amgen, Eisai, Gilead, Ipsen, Lilly, Roche, Sanofi; Research grant/Funding (institution): Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Incyte, Ipsen, Lilly, MSD. All other authors have declared no conflicts of interest.