Phase I Study of Epigenetic Priming with Azacitidine Prior to Standard Neoadjuvant Chemotherapy for Patients with Resectable Gastric and Esophageal Adenocarcinoma: Evidence of Tumor Hypomethylation as an Indicator of Major Histopathologic Response

Epigenetic silencing of tumor suppressor genes (TSG) is an acquired abnormality observed in cancer and is prototypically linked to DNA methylation. We postulated that pretreatment (priming) with 5-azacitidine would increase the efficacy of chemotherapy by reactivating TSGs. This study was conducted...

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Veröffentlicht in:Clinical cancer research 2017-06, Vol.23 (11), p.2673-2680
Hauptverfasser: Schneider, Bryan J, Shah, Manish A, Klute, Kelsey, Ocean, Allyson, Popa, Elizabeta, Altorki, Nasser, Lieberman, Michael, Schreiner, Andrew, Yantiss, Rhonda, Christos, Paul J, Palmer, Romae, You, Daoqi, Viale, Agnes, Kermani, Pouneh, Scandura, Joseph M
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container_end_page 2680
container_issue 11
container_start_page 2673
container_title Clinical cancer research
container_volume 23
creator Schneider, Bryan J
Shah, Manish A
Klute, Kelsey
Ocean, Allyson
Popa, Elizabeta
Altorki, Nasser
Lieberman, Michael
Schreiner, Andrew
Yantiss, Rhonda
Christos, Paul J
Palmer, Romae
You, Daoqi
Viale, Agnes
Kermani, Pouneh
Scandura, Joseph M
description Epigenetic silencing of tumor suppressor genes (TSG) is an acquired abnormality observed in cancer and is prototypically linked to DNA methylation. We postulated that pretreatment (priming) with 5-azacitidine would increase the efficacy of chemotherapy by reactivating TSGs. This study was conducted to identify a tolerable dose of 5-azacitidine prior to EOX (epirubicin, oxaliplatin, capecitabine) neoadjuvant chemotherapy in patients with locally advanced esophageal/gastric adenocarcinoma (EGC). Eligible patients had untreated, locally advanced, resectable EGC, ECOG 0-2, and adequate organ function. 5-Azacitidine (V, 75 mg/m ) was given subcutaneously for 3 (dose level, DL 1) or 5 (DL 2) days prior to each 21-day cycle of EOX (E, 50 mg/m ; O, 130 mg/m ; X, 625 mg/m twice daily for 21 days). Standard 3+3 methodology guided V dose escalation. DNA methylation at control and biomarker regions was measured by digital droplet, bisulfite qPCR in tumor samples collected at baseline and at resection. All subjects underwent complete resection of residual tumor (R0). Three of the 12 patients (25%) achieved a surgical complete response and 5 had partial responses. The overall response rate was 67%. The most common toxicities were gastrointestinal and hematologic. Hypomethylation of biomarker genes was observed at all dose levels and trended with therapeutic response. Neoadjuvant VEOX was well-tolerated with significant clinical and epigenetic responses, with preliminary evidence that priming with V prior to chemotherapy may augment chemotherapy efficacy. The recommended phase II trial schedule is 5-azacitidine 75 mg/m for 5 days followed by EOX chemotherapy every 21 days. .
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We postulated that pretreatment (priming) with 5-azacitidine would increase the efficacy of chemotherapy by reactivating TSGs. This study was conducted to identify a tolerable dose of 5-azacitidine prior to EOX (epirubicin, oxaliplatin, capecitabine) neoadjuvant chemotherapy in patients with locally advanced esophageal/gastric adenocarcinoma (EGC). Eligible patients had untreated, locally advanced, resectable EGC, ECOG 0-2, and adequate organ function. 5-Azacitidine (V, 75 mg/m ) was given subcutaneously for 3 (dose level, DL 1) or 5 (DL 2) days prior to each 21-day cycle of EOX (E, 50 mg/m ; O, 130 mg/m ; X, 625 mg/m twice daily for 21 days). Standard 3+3 methodology guided V dose escalation. DNA methylation at control and biomarker regions was measured by digital droplet, bisulfite qPCR in tumor samples collected at baseline and at resection. All subjects underwent complete resection of residual tumor (R0). Three of the 12 patients (25%) achieved a surgical complete response and 5 had partial responses. The overall response rate was 67%. The most common toxicities were gastrointestinal and hematologic. Hypomethylation of biomarker genes was observed at all dose levels and trended with therapeutic response. Neoadjuvant VEOX was well-tolerated with significant clinical and epigenetic responses, with preliminary evidence that priming with V prior to chemotherapy may augment chemotherapy efficacy. 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Three of the 12 patients (25%) achieved a surgical complete response and 5 had partial responses. The overall response rate was 67%. The most common toxicities were gastrointestinal and hematologic. Hypomethylation of biomarker genes was observed at all dose levels and trended with therapeutic response. Neoadjuvant VEOX was well-tolerated with significant clinical and epigenetic responses, with preliminary evidence that priming with V prior to chemotherapy may augment chemotherapy efficacy. The recommended phase II trial schedule is 5-azacitidine 75 mg/m for 5 days followed by EOX chemotherapy every 21 days. .</description><subject>Adenocarcinoma</subject><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma - pathology</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antineoplastic Combined Chemotherapy Protocols - administration &amp; dosage</subject><subject>Azacitidine - administration &amp; dosage</subject><subject>Bioindicators</subject><subject>Biomarkers</subject><subject>Bisulfite</subject><subject>Cancer</subject><subject>Chemotherapy</subject><subject>Cisplatin - administration &amp; dosage</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA Methylation - genetics</subject><subject>Dose-Response Relationship, Drug</subject><subject>Epigenesis, Genetic - genetics</subject><subject>Epigenetics</subject><subject>Epirubicin</subject><subject>Epirubicin - administration &amp; dosage</subject><subject>Esophageal Neoplasms - drug therapy</subject><subject>Esophageal Neoplasms - genetics</subject><subject>Esophageal Neoplasms - pathology</subject><subject>Esophagus</subject><subject>Experimental design</subject><subject>Female</subject><subject>Fluorouracil - administration &amp; dosage</subject><subject>Genes</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Neoadjuvant Therapy</subject><subject>Organoplatinum Compounds - administration &amp; dosage</subject><subject>Oxaliplatin</subject><subject>Patients</subject><subject>Priming</subject><subject>Stomach Neoplasms - drug therapy</subject><subject>Stomach Neoplasms - genetics</subject><subject>Stomach Neoplasms - pathology</subject><subject>Surgery</subject><subject>Toxicity</subject><subject>Tumor suppressor genes</subject><subject>Tumor Suppressor Proteins - drug effects</subject><subject>Tumor Suppressor Proteins - genetics</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkkFv1DAQhSMEoqXwE0CWuHBJie3Ym3BAWq2WtlKBVSlna-LMbrxK7GA7Rcsf54qjbSvgZMvzzXvj0cuy17Q4p1RU72mxqPKi5Ox8tbrJqcxpVcsn2SkVYpFzJsXTdH9gTrIXIeyLgpa0KJ9nJ2xRcVlJdpr93nQQkFyRb3FqD8RtyXo0O7QYjSYbbwZjd-SniR1Z_gJtommNxbngPIkudYFtwbfkCzpo99Md2EhWHQ4uduhhPJBtAjcQDdoYjkI3GFBHaHokFxCiT0ZJhKyDGzvYIfRk2aJ1Grw21g3wgazvTHrROI93Ow1J8fIwugFjd-iTtLMEQtIgV7Y1GmKqJ_Az7GfQhOhGiJ3r3S45JfPR2YAvs2db6AO-uj_Psu-f1rery_z668XVanmda8HKmDdaNFBTTnnZ1rWsyoKl3coGsKAgdVsyhuWiaQSAZrqpi7qugHOkTculoIKfZR-PuuPUDNjqtAYPvRrTZsEflAOj_q1Y06mdu1OiZIIn37Ps3b2Adz8mDFENJmjse7DopqBoTamkdVHNXm__Q_du8jZ9L1EVL6lkrE6UOFLauxA8bh-HoYWao6Xm2Kg5NipFS1Gp5milvjd__-Sx6yFL_A8PvtDy</recordid><startdate>20170601</startdate><enddate>20170601</enddate><creator>Schneider, Bryan J</creator><creator>Shah, Manish A</creator><creator>Klute, Kelsey</creator><creator>Ocean, Allyson</creator><creator>Popa, Elizabeta</creator><creator>Altorki, Nasser</creator><creator>Lieberman, Michael</creator><creator>Schreiner, Andrew</creator><creator>Yantiss, Rhonda</creator><creator>Christos, Paul J</creator><creator>Palmer, Romae</creator><creator>You, Daoqi</creator><creator>Viale, Agnes</creator><creator>Kermani, Pouneh</creator><creator>Scandura, Joseph M</creator><general>American Association for Cancer Research Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7T5</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7TM</scope><scope>5PM</scope></search><sort><creationdate>20170601</creationdate><title>Phase I Study of Epigenetic Priming with Azacitidine Prior to Standard Neoadjuvant Chemotherapy for Patients with Resectable Gastric and Esophageal Adenocarcinoma: Evidence of Tumor Hypomethylation as an Indicator of Major Histopathologic Response</title><author>Schneider, Bryan J ; Shah, Manish A ; Klute, Kelsey ; Ocean, Allyson ; Popa, Elizabeta ; Altorki, Nasser ; Lieberman, Michael ; Schreiner, Andrew ; Yantiss, Rhonda ; Christos, Paul J ; Palmer, Romae ; You, Daoqi ; Viale, Agnes ; Kermani, Pouneh ; Scandura, Joseph M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c524t-bc5ba913134d99684023266bae01a6cd422e47bb5aac2cb90998a33e1bd365153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adenocarcinoma</topic><topic>Adenocarcinoma - drug therapy</topic><topic>Adenocarcinoma - genetics</topic><topic>Adenocarcinoma - pathology</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antineoplastic Combined Chemotherapy Protocols - administration &amp; dosage</topic><topic>Azacitidine - administration &amp; dosage</topic><topic>Bioindicators</topic><topic>Biomarkers</topic><topic>Bisulfite</topic><topic>Cancer</topic><topic>Chemotherapy</topic><topic>Cisplatin - administration &amp; 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Three of the 12 patients (25%) achieved a surgical complete response and 5 had partial responses. The overall response rate was 67%. The most common toxicities were gastrointestinal and hematologic. Hypomethylation of biomarker genes was observed at all dose levels and trended with therapeutic response. Neoadjuvant VEOX was well-tolerated with significant clinical and epigenetic responses, with preliminary evidence that priming with V prior to chemotherapy may augment chemotherapy efficacy. The recommended phase II trial schedule is 5-azacitidine 75 mg/m for 5 days followed by EOX chemotherapy every 21 days. .</abstract><cop>United States</cop><pub>American Association for Cancer Research Inc</pub><pmid>27836862</pmid><doi>10.1158/1078-0432.CCR-16-1896</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research; Alma/SFX Local Collection
subjects Adenocarcinoma
Adenocarcinoma - drug therapy
Adenocarcinoma - genetics
Adenocarcinoma - pathology
Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols - administration & dosage
Azacitidine - administration & dosage
Bioindicators
Biomarkers
Bisulfite
Cancer
Chemotherapy
Cisplatin - administration & dosage
Deoxyribonucleic acid
DNA
DNA methylation
DNA Methylation - genetics
Dose-Response Relationship, Drug
Epigenesis, Genetic - genetics
Epigenetics
Epirubicin
Epirubicin - administration & dosage
Esophageal Neoplasms - drug therapy
Esophageal Neoplasms - genetics
Esophageal Neoplasms - pathology
Esophagus
Experimental design
Female
Fluorouracil - administration & dosage
Genes
Humans
Male
Middle Aged
Neoadjuvant Therapy
Organoplatinum Compounds - administration & dosage
Oxaliplatin
Patients
Priming
Stomach Neoplasms - drug therapy
Stomach Neoplasms - genetics
Stomach Neoplasms - pathology
Surgery
Toxicity
Tumor suppressor genes
Tumor Suppressor Proteins - drug effects
Tumor Suppressor Proteins - genetics
title Phase I Study of Epigenetic Priming with Azacitidine Prior to Standard Neoadjuvant Chemotherapy for Patients with Resectable Gastric and Esophageal Adenocarcinoma: Evidence of Tumor Hypomethylation as an Indicator of Major Histopathologic Response
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