Dataset Information

Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer.

ABSTRACT: The standard of care in locally advanced rectal cancer is neoadjuvant chemoradiation (nCRT) followed by radical surgery. Response to nCRT varies among patients and pathological complete response is associated with better outcome. However, there is a lack of effective methods to select rectal cancer patients who would or would not have a benefit from nCRT. The utility of clinicopathological and radiological features are limited due to lack of adequate sensitivity and specificity. Molecular biomarkers have the potential to predict response to nCRT at an early time point, but none have currently reached the clinic. Integration of diverse types of biomarkers including clinicopathological and imaging features, identification of mechanistic link to tumor biology, and rigorous validation using samples which represent disease heterogeneity, will allow to develop a sensitive and cost-effective molecular biomarker panel for precision medicine in rectal cancer. Here, we aim to review the recent advance in tissue- and blood-based molecular biomarker research and illustrate their potential in predicting nCRT response in rectal cancer.

SUBMITTER: Dayde D

PROVIDER: S-EPMC5372589 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer.

Dayde Delphine D Tanaka Ichidai I Jain Rekha R Tai Mei Chee MC Taguchi Ayumu A

International journal of molecular sciences 20170307 3

The standard of care in locally advanced rectal cancer is neoadjuvant chemoradiation (nCRT) followed by radical surgery. Response to nCRT varies among patients and pathological complete response is associated with better outcome. However, there is a lack of effective methods to select rectal cancer patients who would or would not have a benefit from nCRT. The utility of clinicopathological and radiological features are limited due to lack of adequate sensitivity and specificity. Molecular biomar ...[more]

PMID: 28272347

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Project description:PurposeTo evaluate the role of diffusion kurtosis and diffusivity as potential imaging biomarkers to predict response to neoadjuvant chemoradiation therapy (CRT) from baseline staging magnetic resonance imaging (MRI) in locally advanced rectal cancer (LARC).Materials and methodsThis retrospective study included 45 consecutive patients (31 male/14 female) who underwent baseline MRI with high b-value sequences (up to 1500 mm/s2) for LARC followed by neoadjuvant chemoradiation and surgical resection. The mean age was 57.4 years (range 34.2-72.9). An abdominal radiologist using open source software manually segmented T2-weighted images. Segmentations were used to derive diffusion kurtosis and diffusivity from diffusion-weighted images as well as volumetric data. These data were analyzed with regard to tumor regression grade (TRG) using the four-tier American Joint Committee on Cancer (AJCC) classification, TRG 0-3. Proportional odds regression was used to analyze the four-level ordinal outcome. A sensitivity analysis was performed using univariable logistic regression for binary TRG groups, TRG 0/1 (> 90% response), or TRG 2/3 (< 90% response). p < 0.05 was considered significant throughout.ResultsIn the univariable proportional odds regression analysis, higher diffusivity summary (Dsum) values were observed to be significantly associated with higher odds of being in one or more favorable TRG group (TRG 0 or 1). In other words, on average, patients with higher Dsum values were more likely to be in a more favorable TRG group. These results are mostly consistent with the sensitivity analysis, in which higher values for most Dsum values [all but region of interest (ROI)-max D median (p = 0.08)] were observed to be significantly associated with higher odds of being TRG 0 or 1. Tumor volume of interest (VOI) and ROI volume, ROI kurtosis mean and median, and VOI kurtosis mean and median were not significantly associated with TRG.ConclusionDiffusivity derived from the baseline staging MRI, but not diffusion kurtosis or volumetric data, is associated with TRG and therefore shows promise as a potential imaging biomarker to predict the response to neoadjuvant chemotherapy in LARC.Clinical relevance statementDiffusivity shows promise as a potential imaging biomarker to predict AJCC TRG following neoadjuvant CRT, which has implications for risk stratification. Patients with TRG 0/1 have 5-year disease-free survival (DFS) of 90-98%, as opposed to those who are TRG 2/3 with 5-year DFS of 68-73%.

Project description:The current standard of care for patients with locally advanced rectal cancer (LARC) is neoadjuvant chemoradiation (nCRT) followed by total mesorectal excision surgery. However, the response to nCRT varies among patients and only about 20% of LARC patients achieve a pathologic complete response (pCR) at the time of surgery. Therefore, there is an unmet need for biomarkers that could predict the response to nCRT at an early time point, allowing for the selection of LARC patients who would or would not benefit from nCRT. To identify blood-based biomarkers for prediction of nCRT response, we performed in-depth quantitative proteomic analysis of pretreatment plasma from mice bearing rectal tumors treated with concurrent chemoradiation, resulting in the quantification of 567 proteins. Among the plasma proteins that increased in mice with residual rectal tumor after chemoradiation compared to mice that achieved regression, we selected three proteins (Vascular endothelial growth factor receptor 3 [VEGFR3], Insulin like growth factor binding protein 4 [IGFBP4], and Cathepsin B [CTSB]) for validation in human plasma samples. In addition, we explored whether four tissue protein biomarkers previously shown to predict response to nCRT (Epidermal growth factor receptor [EGFR], Ki-67, E-cadherin, and Prostaglandin G/H synthase 2 [COX2]) also act as potential blood biomarkers. Using immunoassays for these seven biomarker candidates as well as Carcinoembryonic antigen [CEA] levels on plasma collected before nCRT from 34 patients with LARC (6 pCR and 28 non-pCR), we observed that levels of VEGFR3 (p = 0.0451, AUC = 0.720), EGFR (p = 0.0128, AUC = 0.679), and COX2 (p = 0.0397, AUC = 0.679) were significantly increased in the plasma of non-pCR LARC patients compared to those of pCR LARC patients. The performance of the logistic regression model combining VEGFR3, EGFR, and COX2 was significantly improved compared with the performance of each biomarker, yielding an AUC of 0.869 (sensitivity 43% at 95% specificity). Levels of VEGFR3 and EGFR were significantly decreased 5 to 7 months after tumor resection in plasma from 18 surgically resected rectal cancer patients, suggesting that VEGFR3 and EGFR may emanate from tumors. These findings suggest that circulating VEGFR3 can contribute to the prediction of the nCRT response in LARC patients together with circulating EGFR and COX2.

Dataset Information

Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer.

Publications

Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer.

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