Relationships Between SMAD3 Expression and Preoperative Fluoropyrimidine‐Based Chemoradiotherapy Response in Locally Advanced Rectal Cancer Patients

Lin, Chih-Hung; Huang, Chun‐Ming; Tsai, Hsiang-Lin; Huang, Ching‐Wen; Yeh, Yung‐Sung; Chai, Chee‐Yin; Wang, Jaw‐Yuan

doi:10.1007/s00268-014-2917-0

Cited by 9 publications

(11 citation statements)

References 59 publications

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“…The finding of 3 independent SNPs predictive of pCR in SMAD3 provides a strong rational to an involvement of this gene in the response to CRT. Consistently with our data, the overexpression of phosphorylated SMAD3 in pre-CRT cancer tissues, was a marker of poor pathological response to fluoropyrimidines-based neoadjuvant CRT in 86 LARC patients [ 28 ].…”

Section: Discussionsupporting

confidence: 89%

Predictive role of microRNA-related genetic polymorphisms in the pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients

et al. 2016

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In rectal cancer, a pathologic complete response (pCR) to pre-operative treatment is a favourable prognostic marker, but is reported in a minority of the patients. We aimed at identifying microRNA-related host genetic polymorphisms predictive of pCR.A panel of 114 microRNA-related tagging polymorphisms was selected and analyzed on 265 locally advanced rectal cancer patients treated with neoadjuvant chemo-radiotherapy. Patients were stratified in two subgroups according to the radiotherapy dose (50.4Gy for 202 patients, 55.0Gy for 78 patients). Interactions among genetic and clinical-pathological variants were investigated by recursive partitioning analysis.Only polymorphisms with a consistent significant effect in the two subgroups of patients were selected as predictive markers of pCR. The results were validated by bootstrap analysis. SMAD3-rs744910, SMAD3-rs745103, and TRBP-rs6088619 were associated to an increased chance of pCR (p=0.0153, p=0.0471, p=0.0125). DROSHA-rs10719 and SMAD3-rs17228212 had an opposite detrimental effect on pathological tumour response (p=0.0274, p=0.0049). Recursive partitioning analysis highlighted that a longer interval time between the end of radiotherapy and surgery increases the chance of pCR in patients with a specific combination of SMAD3-rs744910 and TRBP-rs6088619 genotypes.This study demonstrated that microRNA-related host genetic polymorphisms can predict pCR to neo-adjuvant chemo-radiotherapy, and could be used to personalize the interval time between the end of radiotherapy and surgery.

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Section: Discussionsupporting

confidence: 89%

Predictive role of microRNA-related genetic polymorphisms in the pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients

et al. 2016

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“…1 E, F). Treatment response to neoadjuvant CCRT is an early indicator of the long-term prognosis in LARC patients [ 23 , 24 ]. In the CAO/ARO/AIO-94 trial, patients with complete (TRG 4) or intermediate pathologic responses (TRG 2 and 3) had improved DFS after preoperative CCRT than those with poor responses [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

A retrospective comparison of outcome and toxicity of preoperative image-guided intensity-modulated radiotherapy versus conventional pelvic radiotherapy for locally advanced rectal carcinoma

Huang

Tsai

et al. 2016

Journal of Radiation Research

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The aim of the study was to compare clinical outcomes and toxicity between 3D conformal radiotherapy (3DCRT) and image-guided intensity-modulated radiotherapy (IG-IMRT) administered through helical tomotherapy in locally advanced rectal cancer (LARC) patients receiving preoperative chemoradiotherapy. We reviewed 144 patients with Stage II–III rectal cancer receiving preoperative fluoropyrimidine-based chemoradiotherapy followed by radical resection. Tumor responses following chemoradiotherapy were evaluated using the Dworak tumor regression grade (TRG). Of the 144 patients, 45 received IG-IMRT and 99 received 3DCRT. A significant reduction in Grade 3 or 4 acute gastrointestinal toxicity (IG-IMRT, 6.7%; 3DCRT, 15.1%; P = 0.039) was observed by IG-IMRT. The pathologic complete response (pCR) rate did not differ between the IG-IMRT and the 3DCRT group (17.8% vs 15.1%, P = 0.52). Patients in the IG-IMRT group had the trend of favorable tumor regressions (TRG 3 or 4) compared with those in the 3DCRT group (66.7% vs 43.5%, P = 0.071). The median follow-up was 53 months (range, 18–95 months) in the 3DCRT group and 43 months (range, 17–69 months) in the IG-IMRT group. Four-year overall, disease-free, and local failure–free survival rates of the IG-IMRT and 3DCRT groups were 81.6% and 67.9% (P = 0.12), 53.8% and 51.8% (P = 0.51), and 88% and 75.1% (P = 0.031), respectively. LARC patients treated with preoperative IG-IMRT achieved lower acute gastrointestinal adverse effects and a higher local control rate than those treated with 3DCRT, but there was no prominent difference in distant metastasis rate and overall survival between two treatment modalities.

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“…88 The phosphorylated isoform of SMAD3 is considered as a hallmark for SMAD3 activation, increased expression of which has been shown to be associated with a poor TRG. 60 b-Catenin can be detected at the membranous, cytoplasmic, and nuclear levels, representing its function within the Wnt cascade, and counts activation of genes linked to the APC gene among its downstream effects. A shift in treatment response has been demonstrated that is dependent on nuclear versus cytoplasmic expression of b-catenin, with increased nuclear expression being association with radioresistance.…”

Section: Cell Signalingmentioning

confidence: 99%

“…Nucleic acid metabolism p-SMAD3, 60 found that the greatest numbers of significant biomarkers lie in the domains of "response to stimulus" and the interplay of this domain with "cell death." In addition, while a relatively small number of biomarkers responsible for cellular metabolism have been evaluated to date, many of these demonstrate a high level of correlation with TRG.…”

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confidence: 99%

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Network Mapping of Molecular Biomarkers Influencing Radiation Response in Rectal Cancer

Poynter

Galea

Veselkov

et al. 2019

Clinical Colorectal Cancer

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Preoperative radiotherapy (RT) plays an important role in the management of locally advanced rectal cancer (RC). Tumor regression after RT shows marked variability, and robust molecular methods are needed to help predict likely response. The aim of this study was to review the current published literature and use Gene Ontology (GO) analysis to define key molecular biomarkers governing radiation response in RC. A systematic review of electronic bibliographic databases (Medline, Embase) was performed for original articles published between 2000 and 2015. Biomarkers were then classified according to biological function and incorporated into a hierarchical GO tree. Both significant and nonsignificant results were included in the analysis. Significance was binarized on the basis of univariate and multivariate statistics. Significance scores were calculated for each biological domain (or node), and a direct acyclic graph was generated for intuitive mapping of biological pathways and markers involved in RC radiation response. Seventytwo individual biomarkers across 74 studies were identified. On highest-order classification, molecular biomarkers falling within the domains of response to stress, cellular metabolism, and pathways inhibiting apoptosis were found to be the most influential in predicting radiosensitivity. Homogenizing biomarker data from original articles using controlled GO terminology demonstrated that cellular mechanisms of response to RT in RC-in particular the metabolic response to RT-may hold promise in developing radiotherapeutic biomarkers to help predict, and in the future modulate, radiation response.

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Relationships Between SMAD3 Expression and Preoperative Fluoropyrimidine‐Based Chemoradiotherapy Response in Locally Advanced Rectal Cancer Patients

Abstract: Our data suggested that analyzing pre-chemoradiotherapy tumors for phosphorylated SMAD3 overexpression would assist physicians in identifying locally advanced rectal cancer patients who may have a poor response risk to preoperative fluoropyrimidine-based chemoradiotherapy.

Cited by 9 publications

References 59 publications

Predictive role of microRNA-related genetic polymorphisms in the pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients

Predictive role of microRNA-related genetic polymorphisms in the pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients

A retrospective comparison of outcome and toxicity of preoperative image-guided intensity-modulated radiotherapy versus conventional pelvic radiotherapy for locally advanced rectal carcinoma

Network Mapping of Molecular Biomarkers Influencing Radiation Response in Rectal Cancer

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