UGT1A1 Polymorphism for Irinotecan Dose Escalation in Patients with BRAF-Mutated Metastatic Colorectal Cancer Treated with First-Line Bevacizumab and FOLFIRI

Background. Patients with metastatic colorectal cancer (mCRC) and BRAF V600E mutation have a poor prognosis, with a median progression-free survival (PFS) of only 5–7 months after initial therapy. The current standard first-line chemotherapy for these patients includes FOLFOX or FOLFIRI plus bevacizumab. In this study, we explored the effects and oncological outcomes of UGT1A1 polymorphism for irinotecan escalation in patients with BRAF-mutated mCRC. Patients and Methods. This retrospective study included 17 patients with BRAF-mutated mCRC between April 2016 and December 2019. UGT1A1 genotyping was performed on all patients prior to initiating bevacizumab plus FOLFIRI chemotherapy. The primary endpoint was PFS, and the secondary endpoints were toxicity, response rate, disease control rate, and overall survival (OS). Results. Fifteen and two patients had UGT1A1 1∗/1∗ and 1∗/28∗, respectively. Eight underwent irinotecan dose escalation with tolerable adverse effects (AEs), and nine maintained an irinotecan dose of 180 mg/m2 or required deescalation to 150 mg/m2 due to intolerable AEs. After a median follow-up period of 15.7 (range, 3–54) months, the median PFS and OS were 9.4 and 15.7 months, respectively. Grade 3/4 AEs were observed in three (6%) patients. The disease control and partial response rates were 64.7% and 11.8%, respectively, indicating that most patients (14, 82.3%) could maintain this as a first-line line therapy with stable disease or proceed to second-line therapy if disease progression occurred, thereby maintaining acceptable performance status. Conclusions. The oncological outcomes of patients with BRAF-mutated mCRC treated using FOLFIRI plus bevacizumab with irinotecan dose escalation as a first-line therapy are acceptable with tolerable AEs; this may be a feasible treatment option in such patients. Pretherapeutic UGT1A1 genotyping-guided dose adjustment can achieve favorable outcomes.

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

Background : Uridine diphosphate glucuronosyltransferase 1 family polypeptide A1 (UGT1A1 ) is a predictive biomarker for the side-effects of irinotecan; irinotecan chemotherapy reduces the volume of tumors harboring UGT1A1 polymorphisms. We aimed to determine whether UGT1A1 polymorphisms can predict progression-free survival in patients with local cervical cancer treated with irinotecan. Methods : We retrospectively analyzed the data of 51 patients with cervical cancer treated at a single institution between 2010 and 2015. All patients were diagnosed with the 2009 International Federation of Gynecology and Obstetrics (FIGO) stage IB1, IB2, IIA, or IIB squamous cell carcinoma, underwent radical hysterectomy, and received irinotecan chemotherapy as neoadjuvant and/or adjuvant treatment. All patients were examined for irinotecan side effects using UGT1A1 tests. Conditional inference tree and survival analyses were performed considering stage, age, UGT1A1 status, and the number of metastatic lymph nodes to determine primary factors associated with progression-free survival. Results : The tree-structured survival model determined high recurrence-risk factors related to progression-free survival. The most relevant factor was ≥2 metastatic lymph nodes (p = 0.004). The second most relevant was UGT1A1 genotype (p = 0.024). Among patients with ≤1 metastatic lymph node, those with UGT1A1 polymorphisms benefited from irinotecan chemotherapy and demonstrated significantly longer progression-free survival (p = 0.020) than those with wild-type UGT1A1 . Conclusion : Irinotecan chemotherapy has the potential to benefit patients with cervical cancer, UGT1A1 polymorphism, and ≤1 metastatic lymph nodes.

Impact of UGT1A1 gene polymorphism on survival in metastatic colorectal cancer patients treated with irinotecan-containing therapy.

813 Background: UGT1A1 polymorphisms have been reported to be associated with increased irinotecan (IRI)-induced toxicity. However, influence of the polymorphisms on survival in metastatic colorectal cancer (mCRC) patients (pts) treated with IRI-containing therapy remains controversial. Methods: We retrospectively reviewed data of consecutive mCRC pts who received FOLFIRI/IRI with or without an anti-VEGF agent as 2nd line therapy at the Shizuoka Cancer Center between April 2008 and December 2015. The primary selection criteria were histologically confirmed adenocarcinoma, prior history of oxaliplatin-containing therapy, and adequate organ function. UGT1A1 polymorphisms were screened and pts with homozygous (*6/*6, *28/*28) or compound heterozygous (*6/*28) were excluded. Results: Among 103 pts found eligible for this analysis, 63 were wild type (W) (−/−) for UGT1A1, and 40 were heterozygous type (H) (-/*6, -/*28), with the following characteristics: median age (range), 60 (30–77) vs 67 (37–84); male/female, 41/22 vs 18/22; PS 0/1/2, 40/21/2 vs 21/18/1; tumor location right/left, 16/47 vs 9/31; peritoneal metastasis −/+, 49/14 vs 33/7; disease status metastasis/recurrence, 49/14 vs 23/17; RAS wild type/mutant, 25/37 vs 18/21; IRI regimen doublet/mono, 51/12 vs 33/7; anti-VEGF agent use −/+, 16/47 vs 12/28; and median IRI dose intensity, 63.7 vs 60 mg/m2/week. Incidences of grade 3/4 neutropenia, febrile neutropenia, and diarrhea in W/H pts were 36%/48%, 5%/9%, 5%/13% (initial IRI dose 180 mg/m2). Median PFS was 6.2 M in W, and 3.9 M in H (p = 0.36). Median OS was 12.1 M in W and 10.9 M in H (p = 0.86). RR was 13% in W, and 10% in H (p = 0.68). DCR was 81% in W, and 58% in H (p = 0.012). Multivariate analysis identified no liver-limited disease, disease status (metastatic), UGT1A1 H type, IRI monotherapy, and no anti-VEGF as independent predictors of poorer PFS (HR 1.76, 2.01, 1.67, 2.17, 2.58), and initial dose of CPT < 180mg/m2 and no anti-VEGF as independent predictors of poorer OS (HR 1.85 and 1.85). UGT1A1 polymorphism was not detected as an independent predictor of RR or DCR. Conclusions: UGT1A1 polymorphism may be useful in predicting PFS in mCRC pts treated with IRI-containing therapy.