Identification of Blood-Based Biomarkers for the Prediction of the Response to Neoadjuvant Chemoradiation in Rectal Cancer

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...

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Veröffentlicht in:Cancers 2021-07, Vol.13 (14), p.3642
Hauptverfasser: Dayde, Delphine, Gunther, Jillian, Hirayama, Yutaka, Weksberg, David C., Boutin, Adam, Parhy, Gargy, Aguilar-Bonavides, Clemente, Wang, Hong, Katayama, Hiroyuki, Abe, Yuichi, Do, Kim-Anh, Hara, Kazuo, Kinoshita, Takashi, Komori, Koji, Shimizu, Yasuhiro, Tajika, Masahiro, Niwa, Yasumasa, Wang, Y. Alan, DePinho, Ronald, Hanash, Samir, Krishnan, Sunil, Taguchi, Ayumu
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container_issue 14
container_start_page 3642
container_title Cancers
container_volume 13
creator Dayde, Delphine
Gunther, Jillian
Hirayama, Yutaka
Weksberg, David C.
Boutin, Adam
Parhy, Gargy
Aguilar-Bonavides, Clemente
Wang, Hong
Katayama, Hiroyuki
Abe, Yuichi
Do, Kim-Anh
Hara, Kazuo
Kinoshita, Takashi
Komori, Koji
Shimizu, Yasuhiro
Tajika, Masahiro
Niwa, Yasumasa
Wang, Y. Alan
DePinho, Ronald
Hanash, Samir
Krishnan, Sunil
Taguchi, Ayumu
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.
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Alan ; DePinho, Ronald ; Hanash, Samir ; Krishnan, Sunil ; Taguchi, Ayumu</creator><creatorcontrib>Dayde, Delphine ; Gunther, Jillian ; Hirayama, Yutaka ; Weksberg, David C. ; Boutin, Adam ; Parhy, Gargy ; Aguilar-Bonavides, Clemente ; Wang, Hong ; Katayama, Hiroyuki ; Abe, Yuichi ; Do, Kim-Anh ; Hara, Kazuo ; Kinoshita, Takashi ; Komori, Koji ; Shimizu, Yasuhiro ; Tajika, Masahiro ; Niwa, Yasumasa ; Wang, Y. Alan ; DePinho, Ronald ; Hanash, Samir ; Krishnan, Sunil ; Taguchi, Ayumu</creatorcontrib><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. 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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). 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These findings suggest that circulating VEGFR3 can contribute to the prediction of the nCRT response in LARC patients together with circulating EGFR and COX2.</description><subject>Antigens</subject><subject>Biomarkers</subject><subject>Blood</subject><subject>Cancer</subject><subject>Carcinoembryonic antigen</subject><subject>Cathepsin B</subject><subject>Colorectal cancer</subject><subject>Cyclooxygenase-2</subject><subject>DNA methylation</subject><subject>E-cadherin</subject><subject>Epidermal growth factor</subject><subject>Epidermal growth factor receptors</subject><subject>Growth factors</subject><subject>Insulin</subject><subject>Insulin-like growth factor-binding protein 4</subject><subject>Mass spectrometry</subject><subject>Patients</subject><subject>Plasma</subject><subject>Plasma levels</subject><subject>Plasma proteins</subject><subject>Predictions</subject><subject>Proteins</subject><subject>Proteomes</subject><subject>Rectum</subject><subject>Scientific imaging</subject><subject>Surgery</subject><subject>Tumors</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular endothelial growth factor receptors</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkU1vFDEMhiMEolXbM9dIXLhMm8STzOSCxK74qFRRhOAc5cPDZplNlmSmEv31zLIFQX2xZT967Vcm5AVnlwCaXXmbPJbKgbegWvGEnArWiUYp3T79pz4hF7Vu2RIAvFPdc3ICrdB9L-GU3F8HTFMcordTzInmga7GnEOzshUDXcW8s-X7soUOudBpg_RTwRD9H_jQ-Yx1n1NFOmX6EbMN2_nOpomuN7jLxYZ4lI5pIf1kR7r-ffg5eTbYseLFQz4jX9-9_bL-0Nzcvr9ev7lpfKvaqQEnrQctBuYQmA7BSce8RC16xySgAy6gCxqC9YOTuuPMdaicZNJ7UB2ckddH3f3sdhj84rfY0exLXKz9NNlG8_8kxY35lu9MD0zpHhaBVw8CJf-YsU5mF6vHcbQJ81yNkFJyBoqrBX35CN3muaTF3oFqW8UF4wt1daR8ybUWHP4ew5k5vNY8ei38AiJkmKI</recordid><startdate>20210720</startdate><enddate>20210720</enddate><creator>Dayde, Delphine</creator><creator>Gunther, Jillian</creator><creator>Hirayama, Yutaka</creator><creator>Weksberg, David C.</creator><creator>Boutin, Adam</creator><creator>Parhy, Gargy</creator><creator>Aguilar-Bonavides, Clemente</creator><creator>Wang, Hong</creator><creator>Katayama, Hiroyuki</creator><creator>Abe, Yuichi</creator><creator>Do, Kim-Anh</creator><creator>Hara, Kazuo</creator><creator>Kinoshita, Takashi</creator><creator>Komori, Koji</creator><creator>Shimizu, Yasuhiro</creator><creator>Tajika, Masahiro</creator><creator>Niwa, Yasumasa</creator><creator>Wang, Y. 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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. 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source Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central
subjects Antigens
Biomarkers
Blood
Cancer
Carcinoembryonic antigen
Cathepsin B
Colorectal cancer
Cyclooxygenase-2
DNA methylation
E-cadherin
Epidermal growth factor
Epidermal growth factor receptors
Growth factors
Insulin
Insulin-like growth factor-binding protein 4
Mass spectrometry
Patients
Plasma
Plasma levels
Plasma proteins
Predictions
Proteins
Proteomes
Rectum
Scientific imaging
Surgery
Tumors
Vascular endothelial growth factor
Vascular endothelial growth factor receptors
title Identification of Blood-Based Biomarkers for the Prediction of the Response to Neoadjuvant Chemoradiation in Rectal Cancer
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