Assessment of the topoisomerase I gene copy number as a predictive biomarker of objective response to irinotecan in metastatic colorectal cancer

2013 ◽  
Vol 49 (1) ◽  
pp. 84-91 ◽  
Author(s):  
Sune Boris Nygård ◽  
Ib Jarle Christensen ◽  
Signe Lykke Nielsen ◽  
Hans Jørgen Nielsen ◽  
Nils Brünner ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Copy Number ◽  
Topoisomerase I ◽  
Objective Response ◽  
Gene Copy Number ◽  
Predictive Biomarker ◽  
Gene Copy ◽  
I Gene

Increased gene copy number and amplification of FGF2 and FGFR1 in metastatic colorectal cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 402-402 ◽  
Author(s):  
Christopher Hanyoung Lieu ◽  
Marileila Varella-Garcia ◽  
Liang Guo Xu ◽  
Zhi-Qin Jiang ◽  
S. Gail Eckhardt ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Metastatic Colorectal Cancer ◽  
Copy Number ◽  
Resistance Mechanism ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Cell Range ◽  
Previously Treated ◽  
Fgfr1 Gene

402 Background: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play essential roles in tightly regulating cell proliferation, survival, migration, and angiogenesis in cancers. However, gene copy number and amplification of FGF2 and FGFR1 have not been extensively evaluated in patients with metastatic colorectal cancer (CRC). Methods: Two tissue microarrays (TMA) were constructed with resected CRC liver metastases from 120 patients. The TMAs included duplicated intratumoral regions and the invasive margin between tumor and normal hepatic parenchyma. Patients were either untreated, or previously treated with FOLFIRI or FOLFOX +/- bevacizumab. The TMA slides were subjected to a two-color FISH assay using a mixture of FGF2 and FGFR1 in-house developed probes. Results: Results were obtained from 118 patients. The analysis detected an average of 1.90 copies of FGF2 signal per cell (range, 1.10-3.46 copies) and an average of 2.27 copies of FGFR1 signal per cell (range, 1-12-7.14 copies). Three control specimens from each slide were also scored, with an average of 1.74 copies of FGF2 and 1.73 copies of FGFR1. High copy number per cell (mean > 2.5 copies) was detected in 9.3% of specimens for FGF2 and 27.9% for FGFR1, including 2 patients (1.7%) for FGF2 and 5 (4.2%) for FGFR1 with focal amplification, defined by ≥ 10% cells with > 4 copies. Additionally, duplications of gene signals in the same locus were detected in 10 samples (8.5%) for FGF2 and 19 (16.1%) for FGFR1. Intratumoral heterogeneity was rare (detected in 3 patients). There was no statistically significant correlation between FGF2 or FGFR1 gene copy number and prior treatment, pathologic response, relapse free survival, or overall survival, though there was a trend towards higher FGFR1 gene copy number in patients previously receiving bevacizumab (p=0.07). Conclusions: Both FGF2 and FGFR1 display variable copy number among resected CRC liver metastases, with larger variability detected for FGFR1. Gene amplification was rare but detected in several patients for both FGF2 and FGFR1. Follow up studies will investigate higher FGFR1 gene copy number in patients previously treated with bevacizumab, perhaps reflecting a potential escape or resistance mechanism.

KRAS mutation is highly predictive of cetuximab resistance in metastatic colorectal cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10502-10502 ◽  
Author(s):  
F. Di Fiore ◽  
F. Le Pessot ◽  
A. Lamy ◽  
F. Charbonnier ◽  
J. Sabourin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Predictive Factors ◽  
Kras Mutation ◽  
Copy Number ◽  
Gene Copy Number ◽  
Gene Mutations ◽  
Gene Copy ◽  
Kras Gene ◽  
Egfr Gene

10502 Background: In metastatic colorectal cancer (MCRC), no molecular predictive markers to cetuximab response have been yet established. The aim was to evaluate whether KRAS gene mutations, EGFR immunochemistery (IHC) and EGFR gene copy number correlate with response to cetuximab. Methods: 59 patients with MCRC treated by cetuximab between July 2004 and December 2005 were retrospectively included. Clinical data were collected and tumour response was evaluated according to RECIST criteria. EGFR IHC was performed using the Dako kit. The EGFR gene copy number was determined by FISH (Fluorescence in-Situ Hybridization). Detection of KRAS gene mutations on exon 2 was performed by sequencing of extracted paraffin-embedded DNA and then by 2 methods, SNaPshot and PCR-LCR, specifically developed to detect small fractions of mutated tumor cells. Response to cetuximab was studied according to clinical data, IHC, FISH and KRAS mutation analysis using the Fischer exact test. Predictive factors of response were determined by logistic regression. Skin reactions were collected but not considered for this analysis as regards the lack of accurate grading in a retrospective study. Times to progression (TTP) were calculated using the Kaplan-Meier method and compared with log-rank test. Results: 12 patients (20.3%) responded to cetuximab (2 patients with complete response and 10 patients with partial response), 19 (32.2%) had stable disease and 28 (47.5%) were in disease progression. A KRAS mutation was detected in 22/59 tumours and, in 6 cases, was missed by sequencing analysis but detected using the SNaPshot and PCR-LCR assays. No KRAS mutation was found in responders patients. KRAS mutation was associated with disease progression (p = 0.0005) and TTP was significantly decreased in mutated KRAS patients (3 vs 5.5 months, p = 0.015). There was no correlation between EGFR IHC and cetuximab response. No EGFR gene copy number increase was detected in responders patients. Predictive factors of cetuximab resistance were KRAS mutation (p=0.003; OR:0.10; 95IC:0.22–0.40) and age<60 (p=0.024; OR:0.13; 95IC:0.02–0.77). Conclusions: KRAS mutation is highly predictive of cetuximab resistance in MCRC. Our study also highlights the need of sensitive methods to ensure an efficient mutation detection. No significant financial relationships to disclose.

EGFR gene copy number to predict response to anti-EGFR treatment and survival in RAS wild type and RAS/BRAF/PIK3CA wild type metastatic colorectal cancer.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e15108-e15108
Author(s):  
Olli Carpen ◽  
Annika Ålgars ◽  
Jari Sundström ◽  
Soili Kytölä ◽  
Pia Österlund ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Copy Number ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Wild Type ◽  
Egfr Gene

scholarly journals Mechanisms of Topoisomerase I (TOP1) Gene Copy Number Increase in a Stage III Colorectal Cancer Patient Cohort

PLoS ONE ◽  
2013 ◽  
Vol 8 (4) ◽  
pp. e60613 ◽  
Author(s):  
David Hersi Smith ◽  
Ib Jarle Christensen ◽  
Niels Frank Jensen ◽  
Bo Markussen ◽  
Maria Unni Rømer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patient ◽  
Copy Number ◽  
Topoisomerase I ◽  
Colorectal Cancer Patient ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Patient Cohort ◽  
Number Increase ◽  
Copy Number Increase

scholarly journals DNA Topoisomerase I Gene Copy Number and mRNA Expression Assessed as Predictive Biomarkers for Adjuvant Irinotecan in Stage II/III Colon Cancer

2015 ◽  
Vol 22 (7) ◽  
pp. 1621-1631 ◽  
Author(s):  
Sune Boris Nygård ◽  
Ben Vainer ◽  
Signe Lykke Nielsen ◽  
Fred Bosman ◽  
Sabine Tejpar ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Mrna Expression ◽  
Copy Number ◽  
Topoisomerase I ◽  
Gene Copy Number ◽  
Predictive Biomarkers ◽  
Gene Copy ◽  
Dna Topoisomerase I ◽  
Dna Topoisomerase ◽  
I Gene
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