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The effect of 5-fluorouracil/leucovorin chemotherapy on CpG methylation, or the confounding role of leukocyte heterogeneity: An illustration.

ABSTRACT: Blood-based epigenome-wide association studies that aim at comparing CpG methylation between colorectal cancer (CRC) patients and controls can lead to the discovery of diagnostic or prognostic biomarkers. Numerous confounders can lead to spurious associations. We aimed to see if 5-fluorouracil (5-FU)/leucovorin chemotherapy administered to cases prior to the collection of their blood has an effect on methylation. 304 patients who received treatment and 273 who did not were profiled on the HumanMethylation450 array. Association tests were adjusted for confounders, including proxies for leukocyte cell counts. There were substantial methylation differences between these two groups that vanished once the leukocyte heterogeneity was accounted for. We observed a significant decrease of T cells in the treatment group (CD4+: p=10(-6); CD8+: p=0.036) and significant increase of NK cells (p=0.05) and monocytes (p=0.0006). 5-FU/leucovorin has no effect on global and local blood-based methylation profiles, other than through differences in the leukocyte compositions that the treatment induced.

SUBMITTER: Lemire M

PROVIDER: S-EPMC4722538 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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The effect of 5-fluorouracil/leucovorin chemotherapy on CpG methylation, or the confounding role of leukocyte heterogeneity: An illustration.

Lemire Mathieu M Zaidi Syed H E SH Zanke Brent W BW Gallinger Steven S Hudson Thomas J TJ Cleary Sean P SP

Genomics 20150911 6

Blood-based epigenome-wide association studies that aim at comparing CpG methylation between colorectal cancer (CRC) patients and controls can lead to the discovery of diagnostic or prognostic biomarkers. Numerous confounders can lead to spurious associations. We aimed to see if 5-fluorouracil (5-FU)/leucovorin chemotherapy administered to cases prior to the collection of their blood has an effect on methylation. 304 patients who received treatment and 273 who did not were profiled on the HumanM ...[more]

PMID: 26368860

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Project description:IntroductionLiposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has shown clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPAC) who progressed on gemcitabine-based chemotherapy. However, its role in patients with mPAC previously treated with conventional irinotecan-containing chemotherapy has not been appropriately investigated.MethodsIn this retrospective analysis, patients with mPAC who received nal-IRI plus 5-FU/LV after conventional irinotecan-containing regimen between January 2017 and March 2020, were identified from two referral cancer centers in South Korea. The ratio of time to progression (TTP) with nal-IRI plus 5-FU/LV to TTP with conventional irinotecan (TTPr) was analyzed with respect to the duration and cumulative dose of conventional irinotecan treatment.ResultsIn total, 35 patients treated with nal-IRI plus 5-FU/LV after the irinotecan-containing regimen were analyzed. The median age was 58 years and 16 (46%) patients were male. The median duration of conventional irinotecan therapy was 4.6 months at a median cumulative dose of 1230 mg. The objective response rate of nal-IRI plus 5-FU/LV was 2.9%, and stable disease was achieved in 11 (31.4%) patients. During the median follow-up of 9.2 [95% confidence interval (CI): 7.8-10.5] months, the median progression-free survival (PFS) and overall survival (OS) were 2.0 (95% CI: 1.4-2.6) months and 4.4 (95% CI: 3.6-5.7) months, respectively. The 6-month PFS and OS rates were 16.3% and 37.5%, respectively. The median TTPr was 0.41 (range, 0.07-2.07), showing a negative correlation with the cumulative dose of prior irinotecan therapy (R = -0.37, p = 0.041). A tentative negative correlation between TTPr and duration of prior irinotecan therapy was observed (R = -0.35, p = 0.062). The most common grade 3-4 toxicities were neutropenia (20%) and fatigue (8.6%).ConclusionNal-IRI plus 5-FU/LV showed modest effectiveness and manageable toxicities for patients with mPAC previously treated with conventional irinotecan-containing chemotherapy. The cumulative dose of prior conventional irinotecan therapy may be inversely correlated with the effectiveness of nal-IRI plus 5-FU/LV.

Project description:Importance:Dysregulation of the mesenchymal-epithelial transition (MET) signaling pathway is associated with poor prognosis in gastroesophageal adenocarcinoma (GEC). We report results of METGastric, a phase 3 trial of the MET inhibitor onartuzumab plus standard first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, MET-positive, advanced GEC. Objective:To determine whether the addition of onartuzumab to first-line fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) improves efficacy compared with mFOLFOX6 plus placebo in HER2-negative, MET-positive GEC. Design, Setting, and Participants:Randomized, double-blind, multicenter trial conducted from November 2012 to March 2014. Patients were 18 years or older with an adenocarcinoma of the stomach or gastroesophageal junction with metastatic disease not amenable for curative therapy. Tumor samples were centrally tested for MET expression using Ventana anti-Total c-MET (SP44) rabbit monoclonal antibody, HER2 status, and Lauren histologic subtype. MET-positive tumors were defined as at least 50% of tumor cells showing weak, moderate, and/or strong staining intensity (MET 1+/2+/3+, respectively) by immunohistochemistry. Interventions:Patients with HER2-negative, MET-positive GEC were enrolled and randomized 1:1 to receive mFOLFOX6 with or without onartuzumab (10 mg/kg). Main Outcomes and Measures:Co-primary end points: overall survival in the intent-to-treat (ITT) population and in patients with MET 2+/3+ GEC. Secondary end points: progression-free survival (PFS), overall response rate (ORR), and safety. Results:Enrollment was stopped early due to sponsor decision, which was agreed with an independent data monitoring committee. At the data cutoff (April 25, 2014) there were 562 patients in the ITT population (n?=?283 placebo plus mFOLFOX6 [median age, 58 y; 65% male]; n?=?279 onartuzumab plus mFOLFOX6 [median age, 60 y; 67% male]); 109 (38.5%) and 105 (37.6%) of the ITT population were MET 2+/3+, respectively. Addition of onartuzumab to mFOLFOX6 did not significantly improve OS, PFS, or ORR vs placebo plus mFOLFOX6 in the ITT (OS hazard ratio [HR], 0.82; 95% CI, 0.59-1.15; P?=?.24; PFS HR, 0.90; 95% CI, 0.71-1.16; P?=?.43; ORR, 46.1% vs 40.6%) or MET 2+/3+ populations (OS HR, 0.64; 95% CI, 0.40-1.03; P?=?.06; PFS HR, 0.79; 95% CI, 0.54-1.15; P?=?.22; ORR, 53.8% vs 44.6%). Safety was as expected for onartuzumab. Conclusions and Relevance:Addition of onartuzumab to first-line mFOLFOX6 did not significantly improve clinical benefits in the ITT or MET 2+/3+ populations. Trial Registration:clinicaltrials.gov Identifier: NCT01662869.

Dataset Information

The effect of 5-fluorouracil/leucovorin chemotherapy on CpG methylation, or the confounding role of leukocyte heterogeneity: An illustration.

Publications

The effect of 5-fluorouracil/leucovorin chemotherapy on CpG methylation, or the confounding role of leukocyte heterogeneity: An illustration.

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