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 |
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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. |
doi_str_mv | 10.3390/cancers13143642 |
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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. 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><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers13143642</identifier><identifier>PMID: 34298853</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>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</subject><ispartof>Cancers, 2021-07, Vol.13 (14), p.3642</ispartof><rights>2021 by the authors. 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/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c464t-3b5ac392f0be309ddb5b0c5e928b053eb31237d93dacfb59710b7e6b505cc3673</citedby><cites>FETCH-LOGICAL-c464t-3b5ac392f0be309ddb5b0c5e928b053eb31237d93dacfb59710b7e6b505cc3673</cites><orcidid>0000-0001-8543-2352 ; 0000-0003-3117-1390 ; 0000-0002-2760-7836</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306983/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306983/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids></links><search><creatorcontrib>Dayde, Delphine</creatorcontrib><creatorcontrib>Gunther, Jillian</creatorcontrib><creatorcontrib>Hirayama, Yutaka</creatorcontrib><creatorcontrib>Weksberg, David C.</creatorcontrib><creatorcontrib>Boutin, Adam</creatorcontrib><creatorcontrib>Parhy, Gargy</creatorcontrib><creatorcontrib>Aguilar-Bonavides, Clemente</creatorcontrib><creatorcontrib>Wang, Hong</creatorcontrib><creatorcontrib>Katayama, Hiroyuki</creatorcontrib><creatorcontrib>Abe, Yuichi</creatorcontrib><creatorcontrib>Do, Kim-Anh</creatorcontrib><creatorcontrib>Hara, Kazuo</creatorcontrib><creatorcontrib>Kinoshita, Takashi</creatorcontrib><creatorcontrib>Komori, Koji</creatorcontrib><creatorcontrib>Shimizu, Yasuhiro</creatorcontrib><creatorcontrib>Tajika, Masahiro</creatorcontrib><creatorcontrib>Niwa, Yasumasa</creatorcontrib><creatorcontrib>Wang, Y. Alan</creatorcontrib><creatorcontrib>DePinho, Ronald</creatorcontrib><creatorcontrib>Hanash, Samir</creatorcontrib><creatorcontrib>Krishnan, Sunil</creatorcontrib><creatorcontrib>Taguchi, Ayumu</creatorcontrib><title>Identification of Blood-Based Biomarkers for the Prediction of the Response to Neoadjuvant Chemoradiation in Rectal Cancer</title><title>Cancers</title><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.</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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Alan</au><au>DePinho, Ronald</au><au>Hanash, Samir</au><au>Krishnan, Sunil</au><au>Taguchi, Ayumu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of Blood-Based Biomarkers for the Prediction of the Response to Neoadjuvant Chemoradiation in Rectal Cancer</atitle><jtitle>Cancers</jtitle><date>2021-07-20</date><risdate>2021</risdate><volume>13</volume><issue>14</issue><spage>3642</spage><pages>3642-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>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.</abstract><cop>Basel</cop><pub>MDPI AG</pub><pmid>34298853</pmid><doi>10.3390/cancers13143642</doi><orcidid>https://orcid.org/0000-0001-8543-2352</orcidid><orcidid>https://orcid.org/0000-0003-3117-1390</orcidid><orcidid>https://orcid.org/0000-0002-2760-7836</orcidid><oa>free_for_read</oa></addata></record> |
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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 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-05T01%3A48%3A26IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Identification%20of%20Blood-Based%20Biomarkers%20for%20the%20Prediction%20of%20the%20Response%20to%20Neoadjuvant%20Chemoradiation%20in%20Rectal%20Cancer&rft.jtitle=Cancers&rft.au=Dayde,%20Delphine&rft.date=2021-07-20&rft.volume=13&rft.issue=14&rft.spage=3642&rft.pages=3642-&rft.issn=2072-6694&rft.eissn=2072-6694&rft_id=info:doi/10.3390/cancers13143642&rft_dat=%3Cproquest_pubme%3E2554461201%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2554461201&rft_id=info:pmid/34298853&rfr_iscdi=true |