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

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 813-813
Author(s):  
Hiromichi Shirasu ◽  
Kentaro Yamazaki ◽  
Mitsuhiro Furuta ◽  
Masahiro Kawahira ◽  
Takeshi Kawakami ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Intensity ◽  
Disease Status ◽  
Cancer Center ◽  
Prior History ◽  
Compound Heterozygous ◽  
Wild Type ◽  
Ugt1a1 Polymorphism ◽  
Anti Vegf

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.

The efficacy of antiepidermal growth factor receptor monoclonal antibodies for patients with KRAS G13D mutations and chemorefractory metastatic colorectal cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 527-527
Author(s):  
Kohei Akiyoshi ◽  
Yasuhide Yamada ◽  
Naoki Takahashi ◽  
Yoshitaka Honma ◽  
Satoru Iwasa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Cancer Center ◽  
Wild Type ◽  
Duration Of Treatment ◽  
Kras Mutations

527 Background: The treatment benefits of epidermal growth factor receptor (EGFR) monoclonal antibodies for patients with KRAS mutations have not been demonstrated. However, some studies have suggested that all KRAS mutations are not equivalent, and that KRAS G13D mutations might have some survival benefit. Methods: We retrospectively analyzed the efficacy and toxicity of treatment with EGFR monoclonal antibody in 8 patients with KRAS G13D mutations and 5-FU/oxaliplatin/irinotecan (CPT) refractory metastatic colorectal cancer compared with 94 KRAS wild type patients at the National Cancer Center Hospital. Results: Eight patients with KRAS G13D mutations were treated with anti-EGFR monoclonal antibodies between July, 2009 and July, 2011. The median age was 66 (42-70); male/female 6/2; PS was 0/1/2, 2/5/1; treatment regimen was cetuximab/ cetuximab+CPT/ panitumumab+CPT, 2/5/1. Response rate (RR) was 12.5% and disease control rate (DCR) was 50.0% with 1 PR, 3 SD, and 4 PD. The PR case treated with cetuximab+CPT showed marked regression of tumor and long duration of treatment (9 months). The progression free survival (PFS) of 2 SD cases was 4.2 and 3.9 months. The other SD case is now on treatment. The median PFS of the 8 patients was 2.1 months (95% confidence interval [CI]: 0.0-5.2). The median overall survival (OS) has not been reached. Grade 3/4 toxicities included 1 hypomagnesemia G4 and 1 rash acneiform G3. Meanwhile, 94 KRAS wild type patients treated with anti EGFR monoclonal antibodies had an RR of 22.3% and DCR was 66.0% with 21 PR, 41 SD, 30 PD, and 2 NE. PFS was 5.6 months (95% CI: 4.9-6.3) and OS was 8.6 months (95% CI: 6.5-10.7). Conclusions: In this analysis, we identified one PR to anti-EGFR monoclonal antibody in a patient with KRAS G13D mutation and chemo-refractory metastatic colorectal cancer. However, we were unable to demonstrate equivalent efficacy in patients with KRAS G13D mutations and KRAS wild type patients. Further studies are needed to evaluate the efficacy and prognosis for this treatment.

Toxicity and tolerance profile of ANTI-EGFRS in metastatic colorectal cancer RAS wild type from the east of Algeria.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16032-e16032
Author(s):  
Ammari Abdelaziz ◽  
Linda Djebnoune ◽  
Besma Khater ◽  
Aicha Benmansour ◽  
Assia Bensalem
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Medical Oncology ◽  
Onset Time ◽  
Progression Free Survival ◽  
Cancer Center ◽  
Healthcare Team ◽  
Wild Type ◽  
Free Survival ◽  
Median Progression Free Survival

e16032 Background: The results of the different studies showed that the use of anti-EGFRs (Epidermal Growth Factor Receptor) in the management of mCRCs, confront the healthcare team to a new toxicity which until then, were unknown before the era of anti EGFRs. knowing that there were no Algerian patients in these studies, reason for us to do this work. Methods: Between October 2015 and October 2018, our work consists of an epidemiological, observational, descriptive, longitudinal prospective study, including all patients with metastatic colorectal cancer RAS wild type, receiving specific medical treatment with anti EGFR (Panitumumab or Cetuximab) from Medical Oncology Department of Didouche Mourad Hospital of Constantine and the Medical Oncology Department of Batna’s Anti Cancer Center, performance status 0-2, and age 18-75 years. We have completed this work whose main objective is to evaluate the toxicity of anti EGFRs in patients with mCRC RAS wild-type from the east of Algeria. Results: 60 patients received an anti EGFR (Panitumumab or Cetuximab), in our study the most common toxicity was folliculitis with an average onset time of 3.36 weeks and a frequency of 83% of grade 2 and 3. Xerosis was observed in 71% of patients. Paronychia was observed in 50% of patients, in addition to the classical toxicities observed with the different chemotherapy regimens used in mCRCs. For secondary objectives, the median progression free survival in our study was 12 months, with a 95% confidence interval [10,787-13,213]. This median progression-free survival is comparable to those reported in the major anti-EGFR trials. Conclusions: Our results suggest that the Algerian patients with metastatic colorectal cancer RAS wild-type have the same profile of toxicity comparing to the results from different international trials studying anti EGFRs.

scholarly journals Intensive first-line FIr-C/FOx-C association of triplet chemotherapy plus cetuximab in RAS wild-type metastatic colorectal cancer patients: preliminary phase II data and prediction of individual limiting toxicity syndromes by pharmacogenomic biomarkers

2019 ◽  
Vol 11 ◽  
pp. 175883591984642 ◽  
Author(s):  
Gemma Bruera ◽  
Silvia Massacese ◽  
Francesco Pepe ◽  
Umberto Malapelle ◽  
Antonella Dal Mas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Rating Scale ◽  
Objective Response ◽  
Dose Intensity ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
First Line ◽  
Triplet Chemotherapy

Background: Intensive triplet chemotherapy/bevacizumab significantly increased metastatic colorectal cancer (MCRC) outcome. This phase II study investigated the safety/activity of FIr-C/FOx-C triplet/cetuximab (CET) in first-line RAS wild-type and the prediction of individual limiting toxicity syndromes (LTS) by pharmacogenomic biomarkers. Methods: A Simon two-step design was used: p0 70%, p1 85%, power 80%, α5%, β20%; projected objective response rate (ORR) I step 14/19. FIr-C/FOx-C: 5-fluorouracil (5-FU) 12h-timed flat infusion 900 mg/m2 d1–2, 8–9, 15–16, 22–23; irinotecan (CPT-11) 160 mg/m2 d1 and 15, oxaliplatin 80 mg/m2 d8 and 22; CET 400mg/m2 then 250 mg/m2 d1, 8, 15, 22; every 28 days. Toxicity, and individual LTS were evaluated, compared by a Chi-square test; and activity/efficacy by log-rank. 5-FU/CPT-11 pharmacogenomic biomarkers, 5-FU degradation rate (5-FUDR), single nucleotide polymorphisms (SNPs) ABCB1, CYP3A4, DYPD, UGT1A1 were evaluated in patients with LTS and at a recommended dose. Results: A total of 29 patients <75 years, with a primary/intermediate Cumulative Index Rating Scale were enrolled; the median age was 59 years; there were 7 young-elderly (yE; 24%). Recommended CPT-11/5-FU doses were 120/750 mg/m2. In the intent-to-treat analysis, the ORR was 58.6%. The primary endpoint was met in patients who received the planned three treatment cycles: the objective response (OR) was 14/18 (78%). At a median follow up of 18 months, progression-free survival (PFS) was 12, and overall survival (OS) was 23 months. At the recommended doses (received dose intensity >80%), grade 3–4 toxicities were: diarrhea 23%, asthenia 15%, vomiting 8%, hypertransaminasemy 8%; LTS 19 (65.5%), with 83% in yE patients. LTS prevalently multiple (ms) versus single site were 59% versus 7% ( p = 0.006). The prevalence of reduced FUDR was 56%, SNPs CYP3A4 22%, UGT1A1 71%, and of >2 positive pharmacogenomics biomarkers was 78%, prevalently reported in patients who developed gastrointestinal LTS. Conclusions: FIr-C/FOx-C is highly active and tolerable at recommended doses in non-elderly RAS wild-type MCRC patients. LTS provided an evaluation of the toxicity burden in individual patients. Reduced FUDR, CYP3A4, and UGT1A1 SNPs may predict individual LTS-ms in patients at risk of limiting gastrointestinal toxicity. Trial registration: The trial was registered at Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2009-016793-32.

Sequencing of different targeted therapies in management of KRAS wild-type metastatic colorectal cancer: A meta-analysis.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 679-679
Author(s):  
Jin Li ◽  
Gong Chen ◽  
Weijia Fang ◽  
Yongsong Tang
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Targeted Therapies ◽  
Meta Analysis ◽  
Objective Response ◽  
Indirect Comparison ◽  
Cochrane Library ◽  
Wild Type ◽  
Anti Vegf ◽  
Significant Difference

679 Background: First-line (1L) antiendothelial growth factor receptor (anti-EGFR) is considered suitable in metastatic colorectal cancer (mCRC) patients. As no treatment guidelines recommend target therapy sequence in mCRC, this meta-analysis determined the optimal sequence of targeted therapies in patients with KRAS wild type (WT) mCRC. Methods: PICO framework was used to retrieve relevant studies from PubMed, Embase, Cochrane Library and Google Scholar. mCRC patients treated with 1L anti-EGFR and second-line (2L) anti -VEGF were compared with 1L anti-VEGF and 2L anti-EGFR treatment (gp. A). Patients treated with 1L anti-VEGF and 2L anti-EGFR treatment were compared with anti-VEGF in 1L and 2L (gp. B). We also compared 2L and 3L anti-EGFR therapies (gp. C). Primary and secondary outcomes of overall survival (OS) and progression free survival (PFS) were presented as hazard ratio (HR) and 95% confidence intervals (95% CIs). Objective response rate (ORR) was evaluated in terms of relative risk (RR) and 95% CI. P < 0.05 was considered statistically significant. Results: We identified nine studies for this analysis including 1478 KRAS WT mCRC patients. In gp. p A (three studies; two retrospective and one post-hoc analysis; 450 patients), 1L anti-EGFR and 2L anti-VEGF treatment had a significantly higher OS (HR 0.83, 95% CI 0.53-1.32; p = 0.0022) and PFS (HR 0.85, 95% CI 0.76- 0.96; p = 0.0081) than 1L anti-VEGF and 2L anti-EGFR. Comparison in gp. B (n = 3 RCTs involving 431 mCRC KRAS WT patients) showed no significant difference in OS (HR 0.95, 95% CI 0.70- 1.29; p = 0.6897; I2 = 42.69%) and PFS (HR 1.43, 95% CI 0.83- 2.47; p = 0.1962; I2 = 81.55%) between the two lines of treatment. ORR was higher with anti-VEGF in both 1L and 2L in gp. B (RR 3.58, 95% CI 0.72- 17.85; p = 0.1191). In gp. C, indirect comparison showed similar OS with 3L and 2L anti-EGFR therapies ((3L and 2L: n = 2 studies each; HR 0.86. 95% CI 0.71-1.04; HR 0.78, 95% CI 0.51-1.20; 2L vs. 3L; p = 0.06). Conclusions: Patients with KRAS WT mCRC achieved maximum benefit with 1L anti-EGFR and 2L anti-VEGF than with 1L anti-VEGF and 2L anti-EGFR or 1L and 2L anti-VEGF. Hence, it is suggested to initiate the therapy with 1L anti-EGFR to derive the maximum clinical benefit.

Anti-VEGF versus Anti-EGFR in the real world in metastatic colorectal cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16040-e16040
Author(s):  
Fernando Namuche ◽  
Claudio J. Flores
Keyword(s):  
Colorectal Cancer ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Rank Test ◽  
Cancer Center ◽  
Wild Type ◽  
Cox Regression Analysis ◽  
Anti Vegf ◽  
Kaplan Meier ◽  
Qualitative Variables

e16040 Background: The incidence of colorectal cancer (CRC) in Peru has increased in the last decades. But the use of monoclonal antibodies is restricted in our population because of insureance issues. Approximately 20% of patients with CRC already have metastases at diagnosis. There is a lack of data in the benefits of our population with the use of anti-VEGF and anti-EGFR that this study intents to fill. Methods: We retrospectively reviewed the electronic medical records of 58 patients with metastatic CRC, KRAS, NRAS and BRAF wild type from one specialized Peruvian cancer center between 2006 and 2017 Descriptive results for numeric variables were presented as means with standard deviation (SD) or medians with interquartile range (IQR), depending on their distributions; otherwise, we expressed the qualitative variables as numbers with percentages. The survival analysis was performed with Kaplan Meier method for PFS and OS, comparing the curves with Log Rank test. A multivariate analysis was performed using the Cox regression model with the statistically significant variables found in the univariate analysis. Results: There was 29 patients in the anti-EGFR arm, and 29 patients in the anti-VEGF arm. Patients that received first anti-EGFR and then anti-VEGF had better OS [HR, 0.87; 95% CI,0.019-0.811; p < 0.001] than patients that received first anti-VEGF and then anti-EGFR. Multpile Cox regressión analysis demonstrated that metastasectomy, debut with less thant 2 metastasis site, left side tumor, and histologic grade were associated with better OS. Conclusions: Patients with mCRC RAS and BRAF wild type that received anti-EGFR and then anti-VEGF had better OS than patients that received anti-VEGF and then anti-EGFR.

Real-world treatment outcomes from nationwide ONCO-colon Turkey registry in RAS wi̇ld-type patients treated with biologics first-line metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15561-e15561
Author(s):  
Umut Kefeli ◽  
Cagatay Arslan ◽  
Mahmut Emre Yildirim ◽  
Abdurrahman Isikdogan ◽  
Nuri Karadurmus ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Real World ◽  
Response Rate ◽  
Wild Type ◽  
First Line ◽  
Real World Data ◽  
Mutant Type ◽  
Anti Vegf

e15561 Background: Efficacy of anti-angiogenic and anti-EGFR agents has been demonstrated metastatic colorectal cancer (mCRC). Real-world evidence is especially important to detect the findings of patients outside of clinical trials. It complements together with clinical trials. However, there are a few studies that evaluated these treatments with biologics in the real-world setting. Recognizing the change that has occurred over the years will also shed light on future approaches. Therefore, we aimed to investigate the real-world data of patients with RAS-wild type mCRC. Methods: Medical records from 28 centers were collected for patients diagnosed with RAS wild-type mCRC between January 2016 and April 2019 and were included into the study. Histopathological, molecular and clinical characteristics of the patients were recorded. The treatment duration, response rate, progression-free survival and safety results were determined. Also, changes over the years were compared. Patients were compared according to the first-line biological treatments as anti-EGFR group (Group A and B) (panitumumab and cetuximab) and anti-VEGF group (group C). Results: Patients with KRAS mutant type were 43,6% and 6.1% patients were NRAS mutant type. A total of 1064 patients with documented RAS wild-type status were evaluated. 33%, 37% and 30% of all first line patients were treated with regimen including panitumumab, cetuximab and anti-VEGF, respectively. The median follow-up time was 24 (1-59) months. Median age was 61 (17-88) years. Thirty-five percent of the patients were female. Twenty percent of the patients had a right-sided colon tumor. Patients received median 6 cycles of treatment. Also, responded patients received median 6 cycles of treatment as maintenance treatment with biologics plus fluoropyrimidine. Overall response rate was 46,4%, 41,9% and 41,5% in A, B and C group respectively (p = 0,170). The median OS was 26, 27, and 23 months in A, B and C group respectively (p = 0.044). The median PFS of the patients in first-line setting that received panitumumab, cetuximab and bevacizumab were 11.6 (SE:0,6; 95% CI: 10.4-12.7), 11.0 (SE:0,5; 95% CI: 9.9-12.0), and 9.6 (SE:0,4; 95% CI: 8.8-10.4) months respectively (p = 0.012). In univariate analysis, female gender (p = 0.030), left sided tumors(p = 0.001), ECOG performance status (PS) 0-1 (p = 0.001), normal CEA level at initial diagnosis(p = 0.001) and treatment with anti-EGFR agents(p = 0.016) were found as favorable factors. PS 0-1 and normal CEA level at initial diagnosis were found as independent prognostic factors in multivariate analysis (p = 0.049, p = 0.031 respectively). Conclusions: This analysis of real-world data confirms the comparable efficacy of anti-EGFR agents in RAS-wild type mCRC. However, anti-EGFR treatment provides PFS and OS advantage when compared with anti-VEGF treatment in these patients.

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