Relationship between UGT1A1*6/*28 polymorphisms and severe toxicities in Chinese patients with pancreatic or biliary tract cancer treated with irinotecan-containing regimens

Abstract

PurposeThe aim of this retrospective study was to investigate the relationship between UGT1A1 polymorphisms and toxicities in Chinese patients with pancreatic or biliary tract cancer receiving irinotecan-containing regimens as the second- or third-line chemotherapy.Patients and methodsA total of 36 patients with unresectable pancreatic cancer and 12 patients with unresectable biliary tract cancer were included. Approximately 33 patients were treated with FOLFIRI regimen, a chemotherapy regimen, where FOL stands for folinic acid, F for fluorouracil, and IRI for irinotecan (irinotecan 180 mg/m2 at day 1, CF 200 mg/m2 at day 1–2, 5-FU 400 mg/m2 at day 1–2, followed by continuous infusion of 5-FU 600 mg/m2 for 22 hours at day 1–2, every 2 weeks). The other 15 patients were treated with irinotecan monotherapy (180 mg/m2, every 2 weeks). UGT1A1*6/*28 polymorphisms were detected by direct sequencing.ResultsThe frequencies of GG, GA, AA genotypes for UGT1A1*6 were 70.8% (n=34), 25.0% (n=12), and 4.2% (n=2), respectively. And those of TA6/TA6, TA6/TA7, TA7/TA7 for UGT1A1*28 were 79.2% (n=38), 18.8% (n=9), and 2.0% (n=1), respectively. A total of 22 patients (45.8%) had grade III–IV neutropenia, and six patients (12.5%) experienced grade III–IV diarrhea. The incidence of grade III–IV neutropenia in patients with UGT1A1*6 GA or AA genotype was 71.4%, which was significantly higher than that with GG genotype (35.3%, P=0.022). No relationship was found between grade III–IV neutropenia and UGT1A1*28 polymorphism. The statistical analysis between grade III–IV diarrhea and UGT1A1*6/*28 polymorphisms was not conducted in view of the limited number of patients.ConclusionIn Chinese patients with pancreatic or biliary tract cancer administered irinotecan-containing regimens, those with UGT1A1*6 variant may have a high risk of severe neutropenia.

Effect of drug metabolizing enzymes and transporters in Thai colorectal cancer patients treated with irinotecan-based chemotherapy

“…However, UGT1A1 genotype was associated with an increased risk of grade 1-4 and severe neutropenia at the first and second cycle. Similar to the study by Yang et al 29 , UGT1A1*28 and *6 were significantly associated with higher incidence of grade 3-4 neutropenia. www.nature.com/scientificreports/ A meta-analysis by Han et al 30 found that Asian cancer patients with UGT1A1*28 and *6 are at increased risk of irinotecan-induced neutropenia.…”

Association of UGT1A1*6, UGT1A1*28, or ABCC2 c.3972C>T genetic polymorphisms with irinotecan‐induced toxicity in Asian cancer patients: Meta‐analysis

“…Applying the exclusion criteria, 195 articles were removed and the remaining 105 full‐text articles were assessed in depth in line with the predetermined eligibility criteria. Finally, 42 articles were included in the meta‐analysis for assessing the associations of UGT1A1*6/UGT1A1*28 or ABCC2 c.3972C>T with irinotecan‐induced severe toxicities 12,14,21–24,26–31,34,35,48–75 . The complete selection process for the articles following PRISMA guidelines is shown in Figure 1.…”

“…[19][20][21][22][23][24][25] However, some studies did not find any significant association of UGT1A1*6 genetic polymorphism and irinotecan-driven toxicities. 18,26 When patients inherit both of these polymorphisms (UGT1A1*6 and UGT1A1*28), irinotecan toxicity may be exacerbated profoundly due to combined genetic effects as evidenced in some studies, 14,[26][27][28] although the results from other studies are again inconclusive and inconsistent. 18,[29][30][31] In these controversial clinical situations, it is also important to note that in addition to the UGT1A1 enzyme, irinotecan, SN-38, and SN-38G are transported out of the cell into bile by members of the ATP-binding cassette (ABC) transporter family, especially ABCC2 encoded by the ABCC2 gene.…”

Association of UGT1A1*6,*28 or ABCC2 c.3972C>T genetic polymorphisms with irinotecan induced toxicity in Asian cancer patients: Meta-analysis

“…Following exclusion criteria, 195 articles were removed, and the rest 106 full-texts articles were assessed in depth following eligibility criteria. Finally, 42 articles were included in this meta-analysis for assessing the associations ofUGT1A1*6/*28 or ABCC2 c.3972C>T with irinotecan induced severe toxicities [12,14,21,[22][23][24][26][27][28][29][30][31]34,35,]. The complete selection process of articles following PRISMA guidelines is shown in Figure 1.…”

“…When patients inheriting both of these polymorphisms (UGT1A1*6 and UGT1A1*28), the toxicities of irinotecan may be exacerbated profoundly due to combined genetic effects as evidenced in some studies [14,[26][27][28] although the results are again inconclusive and inconsistent as found in other studies [18,[29][30][31]. In these controversial clinical situations, it is also important to noted that in addition to the UGT1A1 enzyme, irinotecan, SN-38 and SN-38G are transported out of the cell into bile by members of the ATP-binding cassette (ABC) transporter family especially ABCC2 encoded by theABCC2 gene [32,33].…”