UGT1A1*28

One hundred and seven patients received irinotecan treatment and three patients with AA type received paclitaxel treatment. Individual irinotecan treatment shows encouraging survival and tolerability outcomes in patients with GG/GA subtype. Irinotecan may be not suitable for patients with AA subtype.

The precise description of the allelic distribution of the variants of interest in our reference populations is information of great interest for the management of the prescription of these antineoplastic drugs. We characterized the allelic distribution of the UGT1A1*28 variant (rs3064744), as well as the DPYD*2A (rs3918290) variant, c.1679T>G (rs55886062), c.2846A>T (rs67376798) and c.1129-5923C>G (rs75017182; HapB3) in series of 5251 patients who are going to receive treatment with irinotecan and fluoropyrimidines, representative of Valencian, Aragonese and Western Andalusian populations.

All patients received preoperative radiotherapy (50 Gy/25 fractions) with concurrent irinotecan (UGT1A1*1*1: 80 mg/m ; UGT1A1*1*28: 65 mg/m ) and capecitabine (CapIri). We also validated the correlation between UGT1A1*6 polymorphism and SN-38 concentration, along with the clinical efficacy of irinotecan. In conclusion, our study identified the relatively optimal timepoint and concentration range for monitoring SN38 concentrations and revealed the clinical significance of UGT1A1*6 and UGT1A1*28 polymorphisms in guiding irinotecan administration, offering meaningful insights for personalised irinotecan dosing.

P2; N=6; Active, not recruiting; Sponsor:University of Florida

P2, N=45, Active, not recruiting, University of Florida

P2, N=78, Recruiting, Canadian Cancer Trials Group

P1, N=24, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Jul 2024 --> Dec 2023

We showed that the accumulation of UGT1A1 variants or the rarity of the variation is associated with a better prognosis, and the effect magnitude correlates with UGT1A1 deficiency. This study demonstrates the therapeutic potential of host UGT1A1 variations underlying GS against HBV infection outcomes.

P2; Recruiting --> Active, not recruiting | N=78 --> 6

P1, N=24, Not yet recruiting, M.D. Anderson Cancer Center | Initiation date: Jul 2023 --> Jul 2024

P2, N=92, Recruiting, Fudan University

P2, N=45, Active, not recruiting, University of Florida | Trial primary completion date: Jun 2023 --> Sep 2023

P2, N=50, Recruiting, Fudan University

Most recently he received treatment with FOLFIRI and Cetuximab, with a FUDR hepatic arterial infusion pump...Broad spectrum antibiotics, scheduled diphenoxylate and loperamide were initiated with no improvement...Bowel movements improved with intravenous steroids which were transitioned to oral prednisone outpatient...Our case emphasizes standardized pre-therapeutic UGT1A1 testing due to the increased morbidity and mortality associated with IRI toxicity in these patients. It also highlights the need for closer monitoring for adverse drug events to reduce the overall healthcare burden and complications.

Moreover, 5-fluorouracil with leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) therapy has been shown to be effective as a triplet chemotherapy for poor prognostic pancreatic cancer, however, a high frequency of severe neutropenia is known. The combination of biomarker SNPs in the NFTC1 and SLC14A1 genes may be a useful predictor for the toxicity of triplet chemotherapy for pancreatic cancer.

P2, N=240, Recruiting, German Cancer Research Center | Not yet recruiting --> Recruiting

P2, N=240, Not yet recruiting, German Cancer Research Center | Trial completion date: Dec 2029 --> Dec 2030 | Trial primary completion date: Apr 2029 --> Mar 2030

Grades III/IV of nausea were more frequently associated with the ABCC2-1549 AA genotype (83.3% p = 0.004) in patients with colorectal cancer. In pancreatic cancer, a significant absence of diarrhea grades III-IV was noted in patients with the ABCC2 1249 GG genotype compared to the other ABCC2 1249 genotypes.

P2, N=78, Recruiting, Canadian Cancer Trials Group | Not yet recruiting --> Recruiting | Initiation date: Jan 2023 --> Apr 2023

Significance Statement To our knowledge, this is the first study to characterize the enzymes responsible for each step of nintedanib metabolism in the human body. We found that β-glucuronidase may contribute to BIBF1202-G deglucuronidation.

The clinical trial was terminated due to high frequency of unacceptable gastrointestinal toxicities, which precluded dose escalation of veliparib in combination with nal-IRI (ClinicalTrials.gov Identifier: NCT02631733).

Despite the relatively small sample size, 25% of patients had the *28/*28 genotype. We confirmed that *28/*28 is associated with a higher risk for discontinuation of SG for toxicity without an association to disease progression based on mutation status. Early UGT1A1 testing as standard practice may identify patients at risk for excess toxicity, who may undergo early dose reductions to prevent discontinuation of this important advanced breast cancer treatment.

P2, N=45, Active, not recruiting, University of Florida | Recruiting --> Active, not recruiting

P=N/A, N=100, Not yet recruiting, National Taiwan University Hospital

P2, N=240, Not yet recruiting, German Cancer Research Center | Initiation date: Dec 2022 --> May 2023

P1, N=24, Not yet recruiting, M.D. Anderson Cancer Center

Chemotherapy-related hyperbilirubinemia is a prognostic factor for treatment outcome in pediatric ALL and genetic variation in UGT1A aids in predicting the clinical impact of hyperbilirubinemia.

P2, N=53, Recruiting, University of Florida | Trial primary completion date: Dec 2022 --> Jun 2023

In a sensitivity analysis, adjusted for UGT1A1 status and for possible demographic and clinical confounders, adjusted OR was 0.56 [0.33, 0.94] for the association between rs2231142 (ABCG2) and the composite outcome. In conclusion, we describe novel association between the minor allele of rs2231142 in the efflux transporter gene ABCG2 and protection against severe side effects in CRC patients treating with irinotecan.

The prevalence of heterozygous and homozygous of UGT1A1*28 polymorphism in GI cancer patients in the Appalachian region is 51.5%, consistent with the reported literature. Homozygous and heterozygous UGT1A1 *28 alterations constituted 13.2 and 38.3% respectively. Data collection for pre-emptive chemotherapy dosage adjustments and adverse events is ongoing to integrate testing for UGT1A1 polymorphism routinely for all GI malignancies cancer patients starting irinotecan chemotherapy.

P2; Suspended --> Recruiting

P2, N=78, Not yet recruiting, Canadian Cancer Trials Group

Thus, an SNP in the R3HCC1 gene may be a useful biomarker for the toxicity of irinotecan-containing chemotherapy for mCRC and pancreatic cancer.

P2; Recruiting --> Suspended

The mini-PDX model confirmed that the patient's tumor was sensitive to a combination regimen of irinotecan and tegafur-gimeracil-oteracil (S-1)...After six courses of treatment with a regimen comprising 300 mg irinotecan on day 1 + 40 mg S-1 twice daily on days 2-15 + 350 mg trastuzumab once-every 3 weeks, the patient continued with S-1 treatment for 4 courses and trastuzumab for 1 year...Thus, the mini-PDX model combined with the NGS rapidly assessed drug sensitivity in a patient with GC and revealed key genetic mutations. However, the proposed technique requires further research to confirm its potential in the individualized treatment of patients with refractory malignancies.

By genotyping UGT1A9*22 polymorphisms, we could identify high-risk gastric cancer patients receiving irinotecan-containing chemotherapy, who would experience severe toxicity. When treating high-risk patients with the UGT1A9*22 polymorphism, clinicians should closely monitor them for signs of severe toxicity such as intense diarrhea or neutropenia.

This review aimed to summarize the pharmacogenetic studies of the most commonly used drugs in the chemotherapy of gastrointestinal (GI) tumors: oxaliplatin, irinotecan, and fluoropyrimidines. More and more evidence is emerging in favor of the fact that the choice of a dose of fluorouracil based on pharmacogenetic testing according to DPYD*2A, can be not only effective but also cost-effective. Additional, well-planned trials of the UGT1A1 genotype-based approach to irinotecan therapy are predicted to reduce adverse drug events in people with the UGT1A1*28/*28 genotypes and improve treatment efficacy in the rest of the patients, which might be cost-effective.

Although FOLFIRINOX (L-Leucovorin/5-FU/Irinotecan/Oxaliplatin) is established as one of the standard therapies for patients with metastatic pancreatic cancer, the modified FOLFIRINOX (mFOLFIRINOX) is often used in clinical practice to reduce the incidence of toxicities...The incidences of severe neutropenia and FN in patients receiving mFOLFIRINOX in our clinical practice were comparable to previous reports. The risk factors for severe neutropenia in patients receiving mFOLFIRINOX were a low baseline white blood cell count and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism.

P2, N=240, Not yet recruiting, German Cancer Research Center | Initiation date: Jul 2022 --> Dec 2022

Based on our findings, the safety and efficacy of mFOLFIRINOX (irinotecan 80 mg/m) in DV patients were comparable with the standard mFOLFIRINOX (irinotecan 150 mg/m) in non-DV patients.

mCRC patients homozygous for the UGT1A1*28 allele can tolerate irinotecan at an initial dose of 120 mg/m with favorable oncological outcomes and toxicity profiles. Further prospective studies are warranted to optimize irinotecan-based chemotherapy in these patients.

P2, N=53, Recruiting, University of Florida | Trial completion date: Dec 2022 --> Dec 2024 | Trial primary completion date: Sep 2022 --> Dec 2022