Amphiregulin (AREG) and Epiregulin (EREG) Gene Expression as Predictor for Overall Survival (OS) in Oxaliplatin/Fluoropyrimidine Plus Bevacizumab Treated mCRC Patients—Analysis of the Phase III AIO KRK-0207 Trial
Background: The EGFR (epithelial growth factor receptor) ligands amphiregulin (AREG) and epiregulin (EREG) have been considered as predictors for EGFR-antibody efficacy. The effect of AREG and EREG expression levels in primary tumor samples on the outcome of bevacizumab-treated patients is unknown.P...
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| Format: | Article |
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Frontiers Media S.A.
2018-11-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2018.00474/full |
| _version_ | 1828462601522118656 |
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| author | Sebastian Stintzing Boryana Ivanova Boryana Ivanova Ingrid Ricard Andreas Jung Thomas Kirchner Andrea Tannapfel Hendrik Juette Susanna Hegewisch-Becker Dirk Arnold Anke Reinacher-Schick |
| author_facet | Sebastian Stintzing Boryana Ivanova Boryana Ivanova Ingrid Ricard Andreas Jung Thomas Kirchner Andrea Tannapfel Hendrik Juette Susanna Hegewisch-Becker Dirk Arnold Anke Reinacher-Schick |
| author_sort | Sebastian Stintzing |
| collection | DOAJ |
| description | Background: The EGFR (epithelial growth factor receptor) ligands amphiregulin (AREG) and epiregulin (EREG) have been considered as predictors for EGFR-antibody efficacy. The effect of AREG and EREG expression levels in primary tumor samples on the outcome of bevacizumab-treated patients is unknown.Patients and Methods: Formalin-fixed paraffin-embedded (FFPE) tumor samples from surgically removed primaries of the AIO KRK-0207 trial have been tested for AREG and EREG expression. The AIO KRK-0207 trial was a randomized phase-3 study to investigate the best maintenance strategy after oxaliplatin/fluoropyrimidine plus bevacizumab induction treatment in patients with mCRC. Association of AREG and EREG levels with outcome parameters were investigated, taking into account RAS and BRAF mutations.Results: A total of 331 tumor samples had measurable AREG and EREG tissue levels. In the total cohort using continuous expression levels, higher logAREG and logEREG levels were associated with a significant longer overall survival (OS) (HR 0.80; p = 0.003 and HR 0.78; p = 0.001, respectively). The subgroup of BRAF mutant tumors displayed significantly lower AREG and EREG levels compared to wild-type tumors. The prognostic effect of AREG and EREG expression was limited to the double wild-type subpopulation, whereas in the RAS mutant and BRAF mutant subgroups no prognostic effect was detected.Conclusion: Low logAREG and logEREG levels are associated with a shorter OS in oxaliplatin/fluoropyrimidine plus bevacizumab treated patients. As low AREG and EREG level are associated with BRAF mutations, the prognostic value of EREG and AREG levels is limited to the RAS and BRAF wild-type subpopulation. |
| first_indexed | 2024-12-11T02:38:37Z |
| format | Article |
| id | doaj.art-ef3d2981a94245169b5609cd64e66c97 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-11T02:38:37Z |
| publishDate | 2018-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-ef3d2981a94245169b5609cd64e66c972022-12-22T01:23:38ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2018-11-01810.3389/fonc.2018.00474415924Amphiregulin (AREG) and Epiregulin (EREG) Gene Expression as Predictor for Overall Survival (OS) in Oxaliplatin/Fluoropyrimidine Plus Bevacizumab Treated mCRC Patients—Analysis of the Phase III AIO KRK-0207 TrialSebastian Stintzing0Boryana Ivanova1Boryana Ivanova2Ingrid Ricard3Andreas Jung4Thomas Kirchner5Andrea Tannapfel6Hendrik Juette7Susanna Hegewisch-Becker8Dirk Arnold9Anke Reinacher-Schick10Department of Medicine III, University Hospital, Ludwig-Maximilians-University, Munich, GermanyDepartment of Medicine III, University Hospital, Ludwig-Maximilians-University, Munich, GermanyInstitute of Pathology, University of Munich, Munich, GermanyInstitute of Medical Informatics, Biometry, and Epidemiology, Ludwig-Maximilians-University, Munich, GermanyInstitute of Pathology, University of Munich, Munich, GermanyInstitute of Pathology, University of Munich, Munich, GermanyInstitute of Pathology, Ruhr-University Bochum, Bochum, GermanyInstitute of Pathology, Ruhr-University Bochum, Bochum, GermanyHematological and Oncological Practice Eppendorf (HOPE), Hamburg, GermanyAsklepios Tumorzentrum Hamburg, Asklepios Klinik Altona, Hamburg, GermanyDepartment of Hematology, Oncology and Palliative Care, St Josef-Hospital, Ruhr University Bochum, Bochum, GermanyBackground: The EGFR (epithelial growth factor receptor) ligands amphiregulin (AREG) and epiregulin (EREG) have been considered as predictors for EGFR-antibody efficacy. The effect of AREG and EREG expression levels in primary tumor samples on the outcome of bevacizumab-treated patients is unknown.Patients and Methods: Formalin-fixed paraffin-embedded (FFPE) tumor samples from surgically removed primaries of the AIO KRK-0207 trial have been tested for AREG and EREG expression. The AIO KRK-0207 trial was a randomized phase-3 study to investigate the best maintenance strategy after oxaliplatin/fluoropyrimidine plus bevacizumab induction treatment in patients with mCRC. Association of AREG and EREG levels with outcome parameters were investigated, taking into account RAS and BRAF mutations.Results: A total of 331 tumor samples had measurable AREG and EREG tissue levels. In the total cohort using continuous expression levels, higher logAREG and logEREG levels were associated with a significant longer overall survival (OS) (HR 0.80; p = 0.003 and HR 0.78; p = 0.001, respectively). The subgroup of BRAF mutant tumors displayed significantly lower AREG and EREG levels compared to wild-type tumors. The prognostic effect of AREG and EREG expression was limited to the double wild-type subpopulation, whereas in the RAS mutant and BRAF mutant subgroups no prognostic effect was detected.Conclusion: Low logAREG and logEREG levels are associated with a shorter OS in oxaliplatin/fluoropyrimidine plus bevacizumab treated patients. As low AREG and EREG level are associated with BRAF mutations, the prognostic value of EREG and AREG levels is limited to the RAS and BRAF wild-type subpopulation.https://www.frontiersin.org/article/10.3389/fonc.2018.00474/fullcolorectal cancermaintenanceoxaliplatin5-FUBevacizumabamphiregulin |
| spellingShingle | Sebastian Stintzing Boryana Ivanova Boryana Ivanova Ingrid Ricard Andreas Jung Thomas Kirchner Andrea Tannapfel Hendrik Juette Susanna Hegewisch-Becker Dirk Arnold Anke Reinacher-Schick Amphiregulin (AREG) and Epiregulin (EREG) Gene Expression as Predictor for Overall Survival (OS) in Oxaliplatin/Fluoropyrimidine Plus Bevacizumab Treated mCRC Patients—Analysis of the Phase III AIO KRK-0207 Trial Frontiers in Oncology colorectal cancer maintenance oxaliplatin 5-FU Bevacizumab amphiregulin |
| title | Amphiregulin (AREG) and Epiregulin (EREG) Gene Expression as Predictor for Overall Survival (OS) in Oxaliplatin/Fluoropyrimidine Plus Bevacizumab Treated mCRC Patients—Analysis of the Phase III AIO KRK-0207 Trial |
| title_full | Amphiregulin (AREG) and Epiregulin (EREG) Gene Expression as Predictor for Overall Survival (OS) in Oxaliplatin/Fluoropyrimidine Plus Bevacizumab Treated mCRC Patients—Analysis of the Phase III AIO KRK-0207 Trial |
| title_fullStr | Amphiregulin (AREG) and Epiregulin (EREG) Gene Expression as Predictor for Overall Survival (OS) in Oxaliplatin/Fluoropyrimidine Plus Bevacizumab Treated mCRC Patients—Analysis of the Phase III AIO KRK-0207 Trial |
| title_full_unstemmed | Amphiregulin (AREG) and Epiregulin (EREG) Gene Expression as Predictor for Overall Survival (OS) in Oxaliplatin/Fluoropyrimidine Plus Bevacizumab Treated mCRC Patients—Analysis of the Phase III AIO KRK-0207 Trial |
| title_short | Amphiregulin (AREG) and Epiregulin (EREG) Gene Expression as Predictor for Overall Survival (OS) in Oxaliplatin/Fluoropyrimidine Plus Bevacizumab Treated mCRC Patients—Analysis of the Phase III AIO KRK-0207 Trial |
| title_sort | amphiregulin areg and epiregulin ereg gene expression as predictor for overall survival os in oxaliplatin fluoropyrimidine plus bevacizumab treated mcrc patients analysis of the phase iii aio krk 0207 trial |
| topic | colorectal cancer maintenance oxaliplatin 5-FU Bevacizumab amphiregulin |
| url | https://www.frontiersin.org/article/10.3389/fonc.2018.00474/full |
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