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Gene Expression Levels as Predictive Markers of Outcome in Pancreatic Cancer after Gemcitabine-Based Adjuvant Chemotherapy

BACKGROUND AND AIMS: The standard palliative chemotherapy for pancreatic ductal adenocarcinoma (PDAC) is gemcitabine-based chemotherapy; however, PDAC still presents a major therapeutic challenge. The aims of this study were to investigate the expression pattern of genes involved in gemcitabine sens...

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Published in:Neoplasia (New York, N.Y.) N.Y.), 2010-10, Vol.12 (10), p.807,IN7-817,IN8
Main Authors: Fujita, Hayato, Ohuchida, Kenoki, Mizumoto, Kazuhiro, Itaba, Soichi, Ito, Tetsuhide, Nakata, Kohei, Yu, Jun, Kayashima, Tadashi, Souzaki, Ryota, Tajiri, Tatsuro, Manabe, Tatsuya, Ohtsuka, Takao, Tanaka, Masao
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container_title Neoplasia (New York, N.Y.)
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creator Fujita, Hayato
Ohuchida, Kenoki
Mizumoto, Kazuhiro
Itaba, Soichi
Ito, Tetsuhide
Nakata, Kohei
Yu, Jun
Kayashima, Tadashi
Souzaki, Ryota
Tajiri, Tatsuro
Manabe, Tatsuya
Ohtsuka, Takao
Tanaka, Masao
description BACKGROUND AND AIMS: The standard palliative chemotherapy for pancreatic ductal adenocarcinoma (PDAC) is gemcitabine-based chemotherapy; however, PDAC still presents a major therapeutic challenge. The aims of this study were to investigate the expression pattern of genes involved in gemcitabine sensitivity in resected PDAC tissues and to determine correlations of gene expression with treatment outcome. MATERIALS AND METHODS: We obtained formalin-fixed paraffin-embedded (FFPE) tissue samples from 70 patients with PDAC. Of the 70 patients, 40 received gemcitabine-based adjuvant chemotherapy (AC). We measured hENT1, dCK, CDA, RRM1, and RRM2 messenger RNA (mRNA) levels by quantitative real-time reverse transcription-polymerase chain reaction and determined the combined score (GEM score), based on the expression levels of hENT1, dCK, RRM1, and RRM2, to investigate the association with survival time. By determining the expression levels of these genes in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytologic specimens, we investigated the feasibility of individualized chemotherapy. RESULTS: High dCK (P = .0067), low RRM2 (P = .003), and high GEM score (P = .0003) groups had a significantly longer disease-free survival in the gemcitabine-treated group. A low GEM score (
doi_str_mv 10.1593/neo.10458
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The aims of this study were to investigate the expression pattern of genes involved in gemcitabine sensitivity in resected PDAC tissues and to determine correlations of gene expression with treatment outcome. MATERIALS AND METHODS: We obtained formalin-fixed paraffin-embedded (FFPE) tissue samples from 70 patients with PDAC. Of the 70 patients, 40 received gemcitabine-based adjuvant chemotherapy (AC). We measured hENT1, dCK, CDA, RRM1, and RRM2 messenger RNA (mRNA) levels by quantitative real-time reverse transcription-polymerase chain reaction and determined the combined score (GEM score), based on the expression levels of hENT1, dCK, RRM1, and RRM2, to investigate the association with survival time. By determining the expression levels of these genes in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytologic specimens, we investigated the feasibility of individualized chemotherapy. RESULTS: High dCK (P = .0067), low RRM2 (P = .003), and high GEM score (P = .0003) groups had a significantly longer disease-free survival in the gemcitabine-treated group. A low GEM score (&lt;2) was an independent predictive marker for poor outcome to gemcitabine-based AC as shown by multivariate analysis (P = .0081). Altered expression levels of these genes were distinguishable in microdissected neoplastic cells from EUS-FNA cytologic specimens. CONCLUSIONS: Quantitative analyses of hENT1, dCK, RRM1, and RRM2 mRNA levels using FFPE tissue samples and microdissected neoplastic cells from EUS-FNA cytologic specimens may be useful in predicting the gemcitabine sensitivity of patients with PDAC.</description><identifier>ISSN: 1476-5586</identifier><identifier>ISSN: 1522-8002</identifier><identifier>EISSN: 1476-5586</identifier><identifier>EISSN: 1522-8002</identifier><identifier>DOI: 10.1593/neo.10458</identifier><identifier>PMID: 20927319</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenocarcinoma - drug therapy ; Adenocarcinoma - genetics ; Adult ; Aged ; Aged, 80 and over ; Antimetabolites, Antineoplastic - therapeutic use ; Biomarkers, Tumor - genetics ; Biopsy, Fine-Needle ; Carcinoma, Adenosquamous - drug therapy ; Carcinoma, Adenosquamous - genetics ; Cytidine Deaminase - genetics ; Cytidine Deaminase - metabolism ; Deoxycytidine - analogs &amp; derivatives ; Deoxycytidine - therapeutic use ; Deoxycytidine Kinase - genetics ; Deoxycytidine Kinase - metabolism ; Equilibrative Nucleoside Transporter 1 - genetics ; Equilibrative Nucleoside Transporter 1 - metabolism ; Feasibility Studies ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic - physiology ; Humans ; Immunoenzyme Techniques ; Male ; Middle Aged ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Ribonucleoside Diphosphate Reductase - genetics ; Ribonucleoside Diphosphate Reductase - metabolism ; RNA, Messenger - genetics ; Survival Rate ; Treatment Outcome ; Tumor Cells, Cultured ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism</subject><ispartof>Neoplasia (New York, N.Y.), 2010-10, Vol.12 (10), p.807,IN7-817,IN8</ispartof><rights>2010 Neoplasia Press, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c527t-c26a128fd6598b7a315ba3170f902f16b4e25afd1d2719cd48348c3094e388723</citedby><cites>FETCH-LOGICAL-c527t-c26a128fd6598b7a315ba3170f902f16b4e25afd1d2719cd48348c3094e388723</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S147655861080048X$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3549,27924,27925,45780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20927319$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fujita, Hayato</creatorcontrib><creatorcontrib>Ohuchida, Kenoki</creatorcontrib><creatorcontrib>Mizumoto, Kazuhiro</creatorcontrib><creatorcontrib>Itaba, Soichi</creatorcontrib><creatorcontrib>Ito, Tetsuhide</creatorcontrib><creatorcontrib>Nakata, Kohei</creatorcontrib><creatorcontrib>Yu, Jun</creatorcontrib><creatorcontrib>Kayashima, Tadashi</creatorcontrib><creatorcontrib>Souzaki, Ryota</creatorcontrib><creatorcontrib>Tajiri, Tatsuro</creatorcontrib><creatorcontrib>Manabe, Tatsuya</creatorcontrib><creatorcontrib>Ohtsuka, Takao</creatorcontrib><creatorcontrib>Tanaka, Masao</creatorcontrib><title>Gene Expression Levels as Predictive Markers of Outcome in Pancreatic Cancer after Gemcitabine-Based Adjuvant Chemotherapy</title><title>Neoplasia (New York, N.Y.)</title><addtitle>Neoplasia</addtitle><description>BACKGROUND AND AIMS: The standard palliative chemotherapy for pancreatic ductal adenocarcinoma (PDAC) is gemcitabine-based chemotherapy; however, PDAC still presents a major therapeutic challenge. The aims of this study were to investigate the expression pattern of genes involved in gemcitabine sensitivity in resected PDAC tissues and to determine correlations of gene expression with treatment outcome. MATERIALS AND METHODS: We obtained formalin-fixed paraffin-embedded (FFPE) tissue samples from 70 patients with PDAC. Of the 70 patients, 40 received gemcitabine-based adjuvant chemotherapy (AC). We measured hENT1, dCK, CDA, RRM1, and RRM2 messenger RNA (mRNA) levels by quantitative real-time reverse transcription-polymerase chain reaction and determined the combined score (GEM score), based on the expression levels of hENT1, dCK, RRM1, and RRM2, to investigate the association with survival time. By determining the expression levels of these genes in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytologic specimens, we investigated the feasibility of individualized chemotherapy. RESULTS: High dCK (P = .0067), low RRM2 (P = .003), and high GEM score (P = .0003) groups had a significantly longer disease-free survival in the gemcitabine-treated group. A low GEM score (&lt;2) was an independent predictive marker for poor outcome to gemcitabine-based AC as shown by multivariate analysis (P = .0081). Altered expression levels of these genes were distinguishable in microdissected neoplastic cells from EUS-FNA cytologic specimens. 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Ohuchida, Kenoki ; Mizumoto, Kazuhiro ; Itaba, Soichi ; Ito, Tetsuhide ; Nakata, Kohei ; Yu, Jun ; Kayashima, Tadashi ; Souzaki, Ryota ; Tajiri, Tatsuro ; Manabe, Tatsuya ; Ohtsuka, Takao ; Tanaka, Masao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c527t-c26a128fd6598b7a315ba3170f902f16b4e25afd1d2719cd48348c3094e388723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adenocarcinoma - drug therapy</topic><topic>Adenocarcinoma - genetics</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antimetabolites, Antineoplastic - therapeutic use</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biopsy, Fine-Needle</topic><topic>Carcinoma, Adenosquamous - drug therapy</topic><topic>Carcinoma, Adenosquamous - genetics</topic><topic>Cytidine Deaminase - genetics</topic><topic>Cytidine Deaminase - metabolism</topic><topic>Deoxycytidine - analogs &amp; derivatives</topic><topic>Deoxycytidine - therapeutic use</topic><topic>Deoxycytidine Kinase - genetics</topic><topic>Deoxycytidine Kinase - metabolism</topic><topic>Equilibrative Nucleoside Transporter 1 - genetics</topic><topic>Equilibrative Nucleoside Transporter 1 - metabolism</topic><topic>Feasibility Studies</topic><topic>Female</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic - physiology</topic><topic>Humans</topic><topic>Immunoenzyme Techniques</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Ribonucleoside Diphosphate Reductase - genetics</topic><topic>Ribonucleoside Diphosphate Reductase - metabolism</topic><topic>RNA, Messenger - genetics</topic><topic>Survival Rate</topic><topic>Treatment Outcome</topic><topic>Tumor Cells, Cultured</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fujita, Hayato</creatorcontrib><creatorcontrib>Ohuchida, Kenoki</creatorcontrib><creatorcontrib>Mizumoto, Kazuhiro</creatorcontrib><creatorcontrib>Itaba, Soichi</creatorcontrib><creatorcontrib>Ito, Tetsuhide</creatorcontrib><creatorcontrib>Nakata, Kohei</creatorcontrib><creatorcontrib>Yu, Jun</creatorcontrib><creatorcontrib>Kayashima, Tadashi</creatorcontrib><creatorcontrib>Souzaki, Ryota</creatorcontrib><creatorcontrib>Tajiri, Tatsuro</creatorcontrib><creatorcontrib>Manabe, Tatsuya</creatorcontrib><creatorcontrib>Ohtsuka, Takao</creatorcontrib><creatorcontrib>Tanaka, Masao</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Neoplasia (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fujita, Hayato</au><au>Ohuchida, Kenoki</au><au>Mizumoto, Kazuhiro</au><au>Itaba, Soichi</au><au>Ito, Tetsuhide</au><au>Nakata, Kohei</au><au>Yu, Jun</au><au>Kayashima, Tadashi</au><au>Souzaki, Ryota</au><au>Tajiri, Tatsuro</au><au>Manabe, Tatsuya</au><au>Ohtsuka, Takao</au><au>Tanaka, Masao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gene Expression Levels as Predictive Markers of Outcome in Pancreatic Cancer after Gemcitabine-Based Adjuvant Chemotherapy</atitle><jtitle>Neoplasia (New York, N.Y.)</jtitle><addtitle>Neoplasia</addtitle><date>2010-10-01</date><risdate>2010</risdate><volume>12</volume><issue>10</issue><spage>807,IN7</spage><epage>817,IN8</epage><pages>807,IN7-817,IN8</pages><issn>1476-5586</issn><issn>1522-8002</issn><eissn>1476-5586</eissn><eissn>1522-8002</eissn><abstract>BACKGROUND AND AIMS: The standard palliative chemotherapy for pancreatic ductal adenocarcinoma (PDAC) is gemcitabine-based chemotherapy; however, PDAC still presents a major therapeutic challenge. The aims of this study were to investigate the expression pattern of genes involved in gemcitabine sensitivity in resected PDAC tissues and to determine correlations of gene expression with treatment outcome. MATERIALS AND METHODS: We obtained formalin-fixed paraffin-embedded (FFPE) tissue samples from 70 patients with PDAC. Of the 70 patients, 40 received gemcitabine-based adjuvant chemotherapy (AC). We measured hENT1, dCK, CDA, RRM1, and RRM2 messenger RNA (mRNA) levels by quantitative real-time reverse transcription-polymerase chain reaction and determined the combined score (GEM score), based on the expression levels of hENT1, dCK, RRM1, and RRM2, to investigate the association with survival time. By determining the expression levels of these genes in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytologic specimens, we investigated the feasibility of individualized chemotherapy. RESULTS: High dCK (P = .0067), low RRM2 (P = .003), and high GEM score (P = .0003) groups had a significantly longer disease-free survival in the gemcitabine-treated group. A low GEM score (&lt;2) was an independent predictive marker for poor outcome to gemcitabine-based AC as shown by multivariate analysis (P = .0081). Altered expression levels of these genes were distinguishable in microdissected neoplastic cells from EUS-FNA cytologic specimens. CONCLUSIONS: Quantitative analyses of hENT1, dCK, RRM1, and RRM2 mRNA levels using FFPE tissue samples and microdissected neoplastic cells from EUS-FNA cytologic specimens may be useful in predicting the gemcitabine sensitivity of patients with PDAC.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>20927319</pmid><doi>10.1593/neo.10458</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record>
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subjects Adenocarcinoma - drug therapy
Adenocarcinoma - genetics
Adult
Aged
Aged, 80 and over
Antimetabolites, Antineoplastic - therapeutic use
Biomarkers, Tumor - genetics
Biopsy, Fine-Needle
Carcinoma, Adenosquamous - drug therapy
Carcinoma, Adenosquamous - genetics
Cytidine Deaminase - genetics
Cytidine Deaminase - metabolism
Deoxycytidine - analogs & derivatives
Deoxycytidine - therapeutic use
Deoxycytidine Kinase - genetics
Deoxycytidine Kinase - metabolism
Equilibrative Nucleoside Transporter 1 - genetics
Equilibrative Nucleoside Transporter 1 - metabolism
Feasibility Studies
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic - physiology
Humans
Immunoenzyme Techniques
Male
Middle Aged
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - genetics
Reverse Transcriptase Polymerase Chain Reaction
Ribonucleoside Diphosphate Reductase - genetics
Ribonucleoside Diphosphate Reductase - metabolism
RNA, Messenger - genetics
Survival Rate
Treatment Outcome
Tumor Cells, Cultured
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
title Gene Expression Levels as Predictive Markers of Outcome in Pancreatic Cancer after Gemcitabine-Based Adjuvant Chemotherapy
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