Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17

Brule, Stephanie Yasmin; Jonker, Derek J.; Karapetis, Christos S.; O’Callaghan, Chris; Moore, Malcolm J.; Wong, Ralph; Tebbutt, Niall C.; Underhill, C.R.; Yip, Desmond; Zalcberg, John; Tu, Dongsheng; Goodwin, Rachel

doi:10.1016/j.ejca.2015.03.015

Cited by 296 publications

(275 citation statements)

References 28 publications

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“…In the present study, the frequency of KRAS mutations was found to be significantly higher in RC than in LC. Although previous reports are consistent with our data,28, 29 the finding that KRAS mutations preferentially occur in RC with the MSS phenotype has not been previously demonstrated. In addition, this finding also suggested that patients having LC with the MSS phenotype may benefit from EGFR antibody therapy, whereas those having RC with the MSS phenotype may not benefit.…”

Section: Discussionsupporting

confidence: 85%

Molecular differences in the microsatellite stable phenotype between left‐sided and right‐sided colorectal cancer

Takahashi

Sugai

Habano

et al. 2016

Intl Journal of Cancer

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Differences in the pathogenesis of microsatellite stable (MSS) sporadic colorectal cancers (CRCs) between left‐sided CRC (LC) and right‐sided CRC (RC) have not been clarified. To identify pathogenesis‐related genomic differences between MSS CRCs within the two locations, we performed a comprehensive molecular analysis using crypt isolation with samples from 92 sporadic CRCs. Microsatellite instability (MSI; high and low/negative) and DNA methylation status (low methylation epigenome; intermediate methylation epigenome [IME] or high methylation epigenome [HME]) were determined using polymerase chain reaction (PCR) microsatellite analysis and PCR‐bisulfite pyrosequencing, respectively. Additionally, mutations in the TP53, KRAS, BRAF and PIK3CA genes were examined using PCR‐bisulfite pyrosequencing (for KRAS and BRAF mutations) or PCR‐single conformation polymorphism (for TP53 and PIK3CA mutations), followed by sequencing of aberrant bands. Finally, a genome‐wide study using a copy number alteration (CNA)‐targeted single nucleotide polymorphism array was performed. Ninety‐two CRCs were classified into 71 MSS and 21 MSI phenotypes. We examined 71 CRCs with the MSS phenotype (LC, 56; RC, 15). Mutations in KRAS were associated with RC with the MSS phenotype, whereas mutations in TP53 were more frequently found in LC with the MSS phenotype. There were significant differences in the frequencies of KRAS and TP53 mutations in the IME between LC and RC with the MSS phenotype. Although CNA gains were associated with LC with the MSS phenotype, CNA losses were not major alterations associated with the MSS phenotype. These findings suggested that the molecular pathogenesis of the MSS phenotype in LC was different from that in RC.

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Section: Discussionsupporting

confidence: 85%

Molecular differences in the microsatellite stable phenotype between left‐sided and right‐sided colorectal cancer

Takahashi

Sugai

Habano

et al. 2016

Intl Journal of Cancer

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“…Our data only highlight statistical difference between of right-and left-sided origin of the primary tumor. Although differences varied with stages, metaanalysis on early-stage colon cancer reported a worse prognosis for right-sided tumors (41,42). More investigation is needed to better decipher the molecular differences such as RAS or BRAF mutational status between right-and left-sided colon cancers and their association with prognosis, prediction of PFS benefit, and interaction with anti-EGFR therapy.…”

Section: Discussionmentioning

confidence: 99%

Circulating DNA as a Strong Multimarker Prognostic Tool for Metastatic Colorectal Cancer Patient Management Care

Messaoudi

Moulière

Manoir

et al. 2016

Clinical Cancer Research

147

108

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Purpose: Circulating cell-free DNA (ccfDNA) is a valuable source of tumor material obtained from a simple blood sampling that enables noninvasive analysis of the tumor genome. Our goal was to carry out a multiparametric analysis of ccfDNA and evaluate its prognostic value by investigating the overall survival (OS) of 97 metastatic colorectal cancer patients (mCRC).Experimental Design: Qualitative parameters (determination of the main KRAS exon2 and BRAF V600E mutations) and quantitative parameters (total ccfDNA concentration, mutant ccfDNA concentration, the proportion of mutant ccfDNA, and ccfDNA integrity index) were determined simultaneously in a single run using a unique Q-PCR multimarker approach (100% success rate).Results: The median follow-up time was 36 months and median OS was 22 months. Patients showing high ccfDNA levels had significantly shorter OS (18.07 months vs. 28.5 months, P ¼ 0.0087). Moreover, multivariate analysis revealed that a high ccfDNA level is an independent prognostic factor (P ¼ 0.034). All ccfDNA parameters were of prognostic interest: patients with higher levels of mutant ccfDNA and higher mutation loads for the detected mutations had shorter OS (P ¼ 0.0089 and P ¼ 0.05, respectively). In addition, the level of ccfDNA fragmentation correlated positively with decreased OS in the exclusive KRAS/ BRAF-mutant cohort of patients (P ¼ 0.0052) and appeared as a strong independent prognostic factor (P ¼ 0.0072), whereas it was not significant in the exclusive KRAS/BRAF WT cohort of patients (P ¼ 0.67).Conclusions: Our data provide for the first time qualitative and quantitative evidence in favor of multiparametric ccfDNA analysis in mCRC patients for prognostic assessment.

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“…The embryological definition of the border between midgut and hindgut is at two thirds of the transverse colon. Tumor location is a source of biological heterogeneity potentially with prognostic and predictive implications [18][19][20].…”

Section: Discussionmentioning

confidence: 99%

HER3 expression is correlated to distally located and low-grade colon cancer

et al. 2016

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Background HER3 is a member of the human epidermal growth factor receptor complex (EGFR, HER2, HER3 and HER4). It has been investigated as a prognostic biomarker in colorectal cancer but is sparingly studied in colon cancer. HER3 can affect cellular proliferation, differentiation and migration in oncogenesis through ligand binding and activation of intracellular signal pathways. Recently, we found that expression of cell surface HER3 can be detected at a high extent in primary colorectal tumors, lymph node and liver metastases and that it correlated with poor prognosis. This large, explorative, retrospective study evaluates the prognostic value of HER3 in colon cancer and the association of HER3 to tumor location. Material and methods. Immunohistochemical detection with a monoclonal HER3 antibody in primary colon tumors of stage II and III, from 521 patients, was performed. Results HER3 was expressed at high levels in 67% of the colon tumors. High HER3 expression was associated with distal tumor location (p50.0001) and low-grade tumor (p50.0001). In the group of patients with distal colon cancer (230/521), HER3 expression correlated to shorter disease-free survival (DFS) (p ¼ 0.03) in the univariate analysis and in the multivariate analysis, a hazard ratio of 0.56 (95% CI 0.31-0.99) (p ¼ 0.047) was observed. Conclusion In this explorative, retrospective study, high HER3 expression in colon cancer was associated to distal colon location and low-grade tumor. High HER3 expression was of prognostic value according to DFS in distal colon cancer in univariate and multivariate analysis. We could not find a significant value of HER3 expression with respect to overall survival (OS).

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Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17

Cited by 296 publications

References 28 publications

Molecular differences in the microsatellite stable phenotype between left‐sided and right‐sided colorectal cancer

Molecular differences in the microsatellite stable phenotype between left‐sided and right‐sided colorectal cancer

Circulating DNA as a Strong Multimarker Prognostic Tool for Metastatic Colorectal Cancer Patient Management Care

HER3 expression is correlated to distally located and low-grade colon cancer

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