A predictive biomarker for altered 5-fluorouracil pharmacokinetics following repeated administration in a rat model of colorectal cancer

The Eph receptors represent the largest group among Receptor Tyrosine kinase (RTK) families. The Eph/ephrin signaling axis plays center stage during development, and the deep perturbation of signaling consequent to its dysregulation in cancer reveals the multiplicity and complexity underlying its function. In the last decades, they have emerged as key players in solid tumors, including colorectal cancer (CRC); however, what causes EphA2 to switch between tumor-suppressive and tumor-promoting function is still an active theater of investigation. This review summarizes the recent advances in understanding EphA2 function in cancer, with detail on the molecular determinants of the oncogene-tumor suppressor switch function of EphA2. We describe tumor context-specific examples of EphA2 signaling and the emerging role EphA2 plays in supporting cancer—stem—cell-like populations and overcoming therapy-induced stress. In such a frame, we detail the interaction of the EphA2 and EGFR pathway in solid tumors, including colorectal cancer. We discuss the contribution of the EphA2 oncogenic signaling to the resistance to EGFR blocking agents, including cetuximab and TKIs.

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Circulating tumor cell-related transcripts in blood as prognostic biomarkers of early recurrence after liver resection for colorectal metastases

The International Journal of Biological Markers ◽

10.1177/1724600819849438 ◽

2019 ◽

Vol 34 (3) ◽

pp. 269-275

Author(s):

Felice Giuliante ◽

Elena Panettieri ◽

Francesco Ardito ◽

Agostino De Rose ◽

Krizia Pocino ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Resection ◽

Tumor Cell ◽

Carcinoembryonic Antigen ◽

Growth Factor Receptor ◽

Predictive Biomarker ◽

Circulating Tumor Cell ◽

Early Recurrence ◽

Colorectal Metastases

Background: Several prognostic factors were proposed to improve early detection of recurrence after liver resection of metastases of colorectal cancer. Circulating tumor cell-related transcripts were evaluated in colorectal cancer patients with conflicting results. The aim of this study was to investigate usefulness of carcinoembryonic antigen CAM5, epidermal growth factor receptor, and ERCC1 transcripts in the bloodstream as predictive factors of recurrence in patients who underwent liver resection for metastases of colorectal cancer. Methods: Peripheral blood was collected from 29 patients at the time of the colorectal cancer liver metastasis resection, and from 25 normal controls. Follow-up draws (FUDs) were also performed at 30 days, and 3 and 12 months since surgery. On each sample, carcinoembryonic antigen CAM5, ERCC1, and GAPDH mRNAs were examined by quantitative reverse transcription (qRT). Results: Carcinoembryonic antigen transcript levels were linearly correlated to the number of spiked cells (qRT analytical limit = five cells). Among 29 patients (20 M/9 F; mean age 63 years (range 32–79), highly significant levels of carcinoembryonic antigen, if compared to the baseline, were detected in those relapsing after surgery ( P <0.05). The main differences were between the 1st- and 12th-month FUDs. Significantly higher levels of carcinoembryonic antigen were also detected in patients who died from disease progression during the follow-up (as evaluated at 30 days and 90 days FUDs). Conclusions: Blood carcinoembryonic antigen-mRNA absolute copy number overtime variation can represent a valid early predictor of relapse after liver resection in colorectal liver metastases patients. Prospective studies, in the context of large clinical trials, will provide further data to also qualify ERCC1 as a predictive biomarker for decisions on therapeutic strategies.

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The Clinical Significance of MiR-148a as a Predictive Biomarker in Patients with Advanced Colorectal Cancer

PLoS ONE ◽

10.1371/journal.pone.0046684 ◽

2012 ◽

Vol 7 (10) ◽

pp. e46684 ◽

Cited By ~ 94

Author(s):

Masanobu Takahashi ◽

Miriam Cuatrecasas ◽

Francesc Balaguer ◽

Keun Hur ◽

Yuji Toiyama ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Significance ◽

Advanced Colorectal Cancer ◽

Predictive Biomarker

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Tumor bulk as a prognostic biomarker and predictor of benefit from anti-EGFR therapy in patients with metastatic colorectal cancer: Analysis of 476 patients from the ARCAD Clinical Trials Program.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.108 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 108-108

Author(s):

Benjamin Adam Weinberg ◽

Manel Rakez ◽

Benoist Chibaudel ◽

Tim Maughan ◽

Richard Adams ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Primary Tumor ◽

Lung Metastases ◽

Performance Status ◽

Progression Free Survival ◽

Predictive Biomarker ◽

Wild Type ◽

Cox Models ◽

Study Results

108 Background: Primary tumor sidedness has emerged as a prognostic and predictive biomarker for patients (pts) with metastatic colorectal cancer (mCRC). Tumor bulk has also been postulated to predict response to anti-EGFR therapy. We sought to evaluate the role of tumor bulk as a predictive biomarker to anti-EGFR therapy in pts with left- (LS) and right-sided (RS) mCRC. Methods: Data from 476 pts with mCRC enrolled across 2 first-line trials of anti-EGFR plus chemotherapy versus chemotherapy were pooled. Pts were included if there was available information on tumor sidedness and tumor bulk. All were KRAS wild-type and BRAF wild-type or unknown BRAF status. The right colon was defined as the cecum through the transverse colon, and the left colon as the splenic flexure through the rectum. Tumor bulk was the mean tumor size of target lesions at baseline, bulky defined as > 3.5 cm. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for performance status (PS), platelet count, primary tumor (PT) resection, number of metastatic sites, and stratified by study. Results: Pts with bulky tumors (211, 44%) had higher PS, white blood cell and platelet counts, higher CEA, fewer sites of metastatic disease, more liver than lung metastases, and fewer had PT resection. OS and PFS medians in months (mos) are presented in the table with 95% confidence intervals (95%CIs). Bulky tumors had inferior median OS compared with non-bulky (mOS, 17.9 vs. 21.3 mos, HRadj 1.33, 95% CI 1.05-1.69, P = 0.016) although median PFS was similar (mPFS, 8.6 vs. 8.7 mos, HRadj 1.15, 95% CI 0.92-1.42, P = 0.21). Conclusions: Tumor bulk is an independent prognostic factor for OS in KRAS wild-type and BRAF wild-type or unknown BRAF status pts. Pts with non-bulky RS tumors have survival outcomes similar to pts with bulky LS tumors. Although the mPFS for pts with RS tumors treated with anti-EGFR therapy was the lowest across subgroups, this finding was not statistically significant. Further research is warranted into whether pts with bulky RS tumors benefit from anti-EGFR therapy. Clinical trial information: NCT00182715, NCT00640081. [Table: see text]

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In vivo Recombinant Adenovirus-mediated p53 Gene Therapy in a Syngeneic Rat Model for Colorectal Cancer

Journal of Korean Medical Science ◽

10.3346/jkms.2004.19.6.834 ◽

2004 ◽

Vol 19 (6) ◽

pp. 834 ◽

Cited By ~ 8

Author(s):

Jeong-Heum Baek ◽

Munna L Agarwal ◽

Raymond R Tubbs ◽

Alex Vladisavljevic ◽

Hiroshi Tomita ◽

...

Keyword(s):

Colorectal Cancer ◽

Gene Therapy ◽

Rat Model ◽

Recombinant Adenovirus ◽

P53 Gene

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Excision Repair Cross-Complementation Group 1 (ERCC1): A Prognostic and Predictive Biomarker in Patients with Colorectal Cancer Receiving Adjuvant Oxaliplatin Based Chemotherapy

Journal of Cancer Therapy ◽

10.4236/jct.2016.79065 ◽

2016 ◽

Vol 07 (09) ◽

pp. 622-634 ◽

Cited By ~ 1

Author(s):

Adel Gabr ◽

T. M. Elsaba ◽

Khalid Razek ◽

Shaima Tamam ◽

Haisam Atta

Keyword(s):

Colorectal Cancer ◽

Excision Repair ◽

Predictive Biomarker ◽

Complementation Group ◽

Group 1

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Urinary 8-iso PGF2α and 2,3-dinor-8-iso PGF2α can be indexes of colitis-associated colorectal cancer in mice

PLoS ONE ◽

10.1371/journal.pone.0245292 ◽

2021 ◽

Vol 16 (1) ◽

pp. e0245292

Author(s):

Yusuke Miyazaki ◽

Tatsuro Nakamura ◽

Shinya Takenouchi ◽

Akane Hayashi ◽

Keisuke Omori ◽

...

Keyword(s):

Colorectal Cancer ◽

Mass Spectrometry ◽

Liquid Chromatography ◽

Morphological Study ◽

Critical Role ◽

Repeated Administration ◽

Tumor Formation ◽

Liquid Chromatography Mass Spectrometry ◽

Chromatography Mass Spectrometry ◽

Lipid Metabolites

Early diagnosis of colorectal cancer is needed to reduce the mortal consequence by cancer. Lipid mediators play critical role in progression of colitis and colitis-associated colon cancer (CAC) and some of their metabolites are excreted in urine. Here, we attempted to find novel biomarkers in urinary lipid metabolite of a murine model of CAC. Mice were received single administration of azoxymethane (AOM) and repeated administration of dextran sulfate sodium (DSS). Lipid metabolites in their urine was measured by liquid chromatography mass spectrometry and their colon was collected to perform morphological study. AOM and DSS caused inflammation and tumor formation in mouse colon. Liquid chromatography mass spectrometry-based comprehensive analysis of lipid metabolites showed that cyclooxygenase-mediated arachidonic acid (AA) metabolites, prostaglandins, and reactive oxygen species (ROS)-mediated AA metabolites, isoprostanes, were predominantly increased in the urine of tumor-bearing mice. Among that, urinary prostaglandin (PG)E2 metabolite tetranor-PGEM and PGD2 metabolite tetranor-PGDM were significantly increased in both of urine collected at the acute phase of colitis and the carcinogenesis phase. On the other hand, two F2 isoprostanes (F2-IsoPs), 8-iso PGF2α and 2,3-dinor-8-iso PGF2α, were significantly increased only in the carcinogenesis phase. Morphological study showed that infiltrated monocytes into tumor mass strongly expressed ROS generator NADPH (p22phox). These observations suggest that urinary 8-iso PGF2α and 2,3-dinor-8-iso PGF2α can be indexes of CAC.

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Effect of Deoxycholic Acid on the Tumour Incidence, Distribution, and Receptor Status of Colorectal Cancer in the Rat Model

Digestion ◽

10.1159/000199183 ◽

1985 ◽

Vol 31 (2-3) ◽

pp. 77-81 ◽

Cited By ~ 22

Author(s):

J. Summerton ◽

Nicola Goeting ◽

G.A. Trotter ◽

I. Taylor

Keyword(s):

Colorectal Cancer ◽

Rat Model ◽

Deoxycholic Acid ◽

Tumour Incidence ◽

Receptor Status

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KRASandBRAFMutations in Advanced Colorectal Cancer Are Associated With Poor Prognosis but Do Not Preclude Benefit From Oxaliplatin or Irinotecan: Results From the MRC FOCUS Trial

Journal of Clinical Oncology ◽

10.1200/jco.2009.22.4295 ◽

2009 ◽

Vol 27 (35) ◽

pp. 5931-5937 ◽

Cited By ~ 377

Author(s):

Susan D. Richman ◽

Matthew T. Seymour ◽

Philip Chambers ◽

Faye Elliott ◽

Catherine L. Daly ◽

...

Keyword(s):

Colorectal Cancer ◽

Prognostic Factor ◽

Braf Mutation ◽

Poor Prognosis ◽

Advanced Colorectal Cancer ◽

Progression Free Survival ◽

Predictive Biomarker ◽

Poor Prognostic Factor ◽

Minimal Impact ◽

The Impact

PurposeActivating mutation of the KRAS oncogene is an established predictive biomarker for resistance to anti–epidermal growth factor receptor (anti-EGFR) therapies in advanced colorectal cancer (aCRC). We wanted to determine whether KRAS and/or BRAF mutation is also a predictive biomarker for other aCRC therapies.Patients and MethodsThe Medical Research Council Fluorouracil, Oxaliplatin and Irinotecan: Use and Sequencing (MRC FOCUS) trial compared treatment sequences including first-line fluorouracil (FU), FU/irinotecan or FU/oxaliplatin in aCRC. Tumor blocks were obtained from 711 consenting patients. DNA was extracted and KRAS codons 12, 13, and 61 and BRAF codon 600 were assessed by pyrosequencing. Mutation (mut) status was assessed first as a prognostic factor and then as a predictive biomarker for the benefit of adding irinotecan or oxaliplatin to FU. The association of BRAF-mut with loss of MLH1 was assessed by immunohistochemistry.ResultsThree hundred eight (43.3%) of 711 patients had KRAS-mut and 56 (7.9%) of 711 had BRAF-mut. Mutation of KRAS, BRAF, or both was present in 360 (50.6%) of 711 patients. Mutation in either KRAS or BRAF was a poor prognostic factor for overall survival (OS; hazard ratio [HR], 1.40; 95% CI, 1.20 to 1.65; P < .0001) but had minimal impact on progression-free survival (PFS; HR, 1.16; 95% CI, 1.00 to 1.36; P = .05). Mutation status did not affect the impact of irinotecan or oxaliplatin on PFS or OS. BRAF-mut was weakly associated with loss of MLH1 staining (P = .012).ConclusionKRAS/BRAF mutation is associated with poor prognosis but is not a predictive biomarker for irinotecan or oxaliplatin. There is no evidence that patients with KRAS/BRAF mutated tumors are less likely to benefit from these standard chemotherapy agents.

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