Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

Abstract

BackgroundTo evaluate a new UGT1A and DPYD polymorphism panel to better predict irinotecan-induced toxicity and the clinical response in Chinese patients with metastatic colorectal cancer (mCRC).MethodsThe genotypes of UGT1A (UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A7*4 and UGT1A9*22) and DPYD (DPYD*5, DPYD c.1896 T > C, and DPYD*2A) were examined by direct sequencing in 661 mCRC patients receiving irinotecan-based chemotherapy. The influences of UGT1A and DPYD polymorphisms on severe irinotecan-induced toxicities and clinical outcomes were assessed.ResultsIn the cohort studied here, the incidence of UGT1A1*6, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A9*22, DPYD*5, and DPYD c.1896 T > C variants were 34.8%, 24.2%, 34.3%, 39.4%, 81.8%, 48.4% and 20.4%, respectively. UGT1A1*27 and DPYD*2A had low frequencies and UGT1A7*4 was not found. A total of 59 patients (8.9%) suffered severe diarrhea and 136 patients (20.6%) suffered severe neutropenia. UGT1A1*28 heterozygotes (OR = 2.263, 95%CI 1.395–3.670), UGT1A1*28 homozygotes (OR = 5.910, 95%CI 1.138–30.672) and UGT1A1*6 homozygotes (OR = 4.737, 95%CI 1.946–11.533) were independent risk factors for severe neutropenia. UGT1A polymorphisms were not found to relate to severe diarrhea. DPYD*5 was determined to be an independent risk factor for severe diarrhea (OR = 2.143, 95%CI 1.136–4.041). Neither DPYD*5 nor DPYD c.1896 T > C was found to relate to severe neutropenia. In the first-line irinotecan-based treatment, UGT1A1*28 and DPYD*5 contributed to higher response rates (P = 0.043 and P = 0.019, respectively), while DPYD*5 was found to associate with better progression-free survival (P = 0.015). UGT1A1*27 contributed to worse overall survival (P < 0.001).ConclusionResults still showed UGT1A1*6 and UGT1A1*28 to be partially associated with irinotecan-induced toxicity and clinical response. An examination of more UGT1A loci, except for UGT1A1*6 and UGT1A1*28, was not helpful to improve the predictive value of irinotecan-based toxicity and efficacy. An examination of DPYD*5 assisted in the prediction of severe diarrhea.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3406-2) contains supplementary material, which is available to authorized users.

<p>Hyaluronic Acid Capped, Irinotecan and Gene Co-Loaded Lipid-Polymer Hybrid Nanocarrier-Based Combination Therapy Platform for Colorectal Cancer</p>

“…6 Clinical trials have shown that irinotecan has a survival advantage in patients with metastatic colorectal cancer, making irinotecan one of the most important drugs in the management of metastatic CRC. 7 Unfortunately, chemotherapy using irinotecan may be limited by multidrug resistance, inability to have a selective distribution, or other adverse effects. 8 The application of nano-systems offers new prospects for the effective therapy of CRC.…”

Correlation between UGT1A1 gene polymorphism and irinotecan chemotherapy in metastatic colorectal cancer: a study from Guangxi Zhuang

“…A combination of irinotecan and fluorouracil is a standard first-line regimen for advanced CRC, especially advanced CRC with rapid progression, with an efficacy rate of up to 40% [10][11][12]. However, this regimen has two major adverse reactions of delayed-onset diarrhea and neutropenia, where the incidences of grade 3~4 neutropenia and severe diarrhea are 45% and 20~40% [13], respectively, which limits its clinical application and exhibits inter-individual variations. Irinotecan is hydrolyzed in vivo by carboxylesterase (CE) into an active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38).…”

UGT1A1 polymorphism has a prognostic effect in patients with stage IB or II uterine cervical cancer and one or no metastatic pelvic nodes receiving irinotecan chemotherapy

“…The UGT1A1 genotype has previously been implicated as a prognostic marker for CPT-11 therapy in colorectal cancer [25]. Some controversial studies have suggested a limited survival bene t in patients who were UGT1A1-poor metabolizers due to UGT1A1 polymorphisms [26,27], although this association has been inconsistently reported [28].…”