Pharmacogenetic study in metastatic colorectal cancer (CRC) patients receiving third-line panitumumab-irinotecan: A GERCOR ancillary study.

Abstract

2537^ Background: Test the predictive value of gene polymorphisms potentially linked to panitumumab and irinotecan pharmacodynamics. Methods: 45 patients with metastatic CRC refractory to standard therapy were enrolled in this ancillary pharmacogenetic study as part of a phase II trial that included 63 patients. Inclusion required wild-type KRAS tumor status (codons 12-13, analyses performed in each center). After inclusion, central KRAS re-assessment was performed (codons 12-13-59-61) and 9 patients over 45 were found to carry a KRAS mutation. Patients received panitumumab (6 mg/kg, day 1) associated with irinotecan (180 mg/m2, day 1), Q2W until disease progression or unacceptable toxicity. Analyzed polymorphisms on blood DNA were : EGFR (CA repeats in intron 1, -216G>T, -191C>A), EGF (61A>G), CCND1 (870A>G), UGT1A1 (*28). Results: Cutaneous toxicity imputable to panitumumab i.e. folliculitis and paronychia was not linked to EGFR, EGF or CCND1 polymorphisms. Diarrhea (12 grade 1, 13 grade 2, 8 grade 3) was linked to CCND1 polymorphism: 22% grade 2-3 in AA patients vs 63% in AG+GG patients (p = 0.007). As expected, neutropenia (6 grade 1, 4 grade 2, 5 grade 3) was more frequent in patients bearing the *28 allele of UGT1A1 gene (33% grade 2-3 vs 5% in *1/*1, p = 0.020). In these 45 patients, response rate, progression-free survival and overall survival (OS) were only significantly related to re-assessed KRAS status. Of note, a tendency for a longer OS was observed in patients bearing the *28 allele of UGT1A1 gene (p = 0.091, analysis adjusted for KRAS). Interestingly, the frequency of KRAS mutation was higher in patients with long CA repeats in EGFR gene intron 1: 54.5% i.e. 6 mutated patients among the 11 patients with both alleles ≥17 vs 10.5% i.e. 2 mutated patients among the 19 patients with intermediary alleles vs. 6.7% i.e. 1 mutated patient among the 15 patients with both alleles <17 (p = 0.004). Conclusions: Present data indicate that A870 allele of CCND1 gene (40% AA patients) may protect from diarrhea induced by panitumumab-irinotecan. Also, these results report an original relationship between EGFR polymorphism in intron 1 and KRAS mutation status that merits further confirmation.