CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup
Background: Survival of metastatic colorectal cancer (mCRC) patients has improved, but mainly for trial patients. New predictive and prognostic biomarkers validated in the general mCRC population are needed. Caudal-type homeobox 2 (CDX2) is an intestine-specific transcription factor with potential p...
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Format: | Article |
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Frontiers Media S.A.
2020-02-01
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Series: | Frontiers in Oncology |
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Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.00008/full |
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doaj-b837c69e9b124f41bf850ea28727f6ad |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kristine Aasebø Anca Dragomir Anca Dragomir Magnus Sundström Magnus Sundström Artur Mezheyeuski Per-Henrik Edqvist Geir Egil Eide Geir Egil Eide Fredrik Ponten Fredrik Ponten Per Pfeiffer Bengt Glimelius Halfdan Sorbye Halfdan Sorbye |
spellingShingle |
Kristine Aasebø Anca Dragomir Anca Dragomir Magnus Sundström Magnus Sundström Artur Mezheyeuski Per-Henrik Edqvist Geir Egil Eide Geir Egil Eide Fredrik Ponten Fredrik Ponten Per Pfeiffer Bengt Glimelius Halfdan Sorbye Halfdan Sorbye CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup Frontiers in Oncology caudal type homeobox transcription factor CDX2 colorectal cancer metastatic disease stage 4 colorectal cancer prognosis |
author_facet |
Kristine Aasebø Anca Dragomir Anca Dragomir Magnus Sundström Magnus Sundström Artur Mezheyeuski Per-Henrik Edqvist Geir Egil Eide Geir Egil Eide Fredrik Ponten Fredrik Ponten Per Pfeiffer Bengt Glimelius Halfdan Sorbye Halfdan Sorbye |
author_sort |
Kristine Aasebø |
title |
CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup |
title_short |
CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup |
title_full |
CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup |
title_fullStr |
CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup |
title_full_unstemmed |
CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup |
title_sort |
cdx2: a prognostic marker in metastatic colorectal cancer defining a better braf mutated and a worse kras mutated subgroup |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2020-02-01 |
description |
Background: Survival of metastatic colorectal cancer (mCRC) patients has improved, but mainly for trial patients. New predictive and prognostic biomarkers validated in the general mCRC population are needed. Caudal-type homeobox 2 (CDX2) is an intestine-specific transcription factor with potential prognostic and predictive effect, but the importance in mCRC has not been fully investigated.Methods: Immunohistochemistry analysis of CDX2 was performed in a Scandinavian population-based cohort of mCRC (n = 796). Frequency, clinical and tumor characteristics, response rate, progression-free survival, and overall survival (OS) were estimated.Results: Loss of CDX2 expression was found in 87 (19%) of 452 stained cases, in 53% if BRAF mutated (BRAFmut) and in 9% if KRAS mutated (KRASmut). CDX2 loss was associated with microsatellite instability, BRAFmut, and poor differentiation and inversely associated with KRASmut. Patients with CDX2 loss received less first-line (53 vs. 64%, p = 0.050) and second-line (23 vs. 39%, p = 0.006) chemotherapy and secondary surgery (1 vs. 9%, p = 0.019). Median progression-free survival and OS for patients given first-line combination chemotherapy was 4 and 10 months if CDX2 loss vs. 9 and 24 months if CDX2 expressed (p = 0.001, p < 0.001). Immediate progression on first-line combination chemotherapy was seen in 35% of patients with CDX2 loss vs. 10% if CDX2 expressed (p = 0.003). Median OS in patients with BRAFmut or KRASmut and CDX2 expressed in tumor (both 21 months) was comparable to wild-type patients (27 months). However, if CDX2 loss, median OS was only 8 and 11 months in BRAFmut and KRASmut cases, respectively, and 10 months in double wild-type patients. In multivariate analysis, CDX2 loss (hazard ratio: 1.50, p = 0.027) and BRAFmut (hazard ratio: 1.62, p = 0.012) were independent poor prognostic markers for OS.Conclusion: In a population-based cohort of mCRC patients, CDX2 loss is an independent poor prognostic marker. Expression of CDX2 defines a new subgroup of BRAFmut cases with a much better prognosis. Loss of CDX2 defines a small group of KRASmut cases with a worse prognosis. Patients with CDX2 loss receive less palliative chemotherapy with less benefit and rarely reach secondary surgery. |
topic |
caudal type homeobox transcription factor CDX2 colorectal cancer metastatic disease stage 4 colorectal cancer prognosis |
url |
https://www.frontiersin.org/article/10.3389/fonc.2020.00008/full |
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doaj-b837c69e9b124f41bf850ea28727f6ad2020-11-25T03:08:36ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-02-011010.3389/fonc.2020.00008508566CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated SubgroupKristine Aasebø0Anca Dragomir1Anca Dragomir2Magnus Sundström3Magnus Sundström4Artur Mezheyeuski5Per-Henrik Edqvist6Geir Egil Eide7Geir Egil Eide8Fredrik Ponten9Fredrik Ponten10Per Pfeiffer11Bengt Glimelius12Halfdan Sorbye13Halfdan Sorbye14Department of Clinical Science, University of Bergen, Bergen, NorwayDepartment of Pathology, Uppsala University Hospital, Uppsala, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenDepartment of Pathology, Uppsala University Hospital, Uppsala, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenDepartment of Global Public Health and Primary Care, Lifestyle Epidemiology Group, University of Bergen, Bergen, NorwayCentre for Clinical Research, Haukeland University Hospital, Bergen, NorwayDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenScience for Life Laboratory, Uppsala University, Uppsala, SwedenDepartment of Oncology, Odense University Hospital, Odense, DenmarkDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SwedenDepartment of Clinical Science, University of Bergen, Bergen, NorwayDepartment of Oncology, Haukeland University Hospital, Bergen, NorwayBackground: Survival of metastatic colorectal cancer (mCRC) patients has improved, but mainly for trial patients. New predictive and prognostic biomarkers validated in the general mCRC population are needed. Caudal-type homeobox 2 (CDX2) is an intestine-specific transcription factor with potential prognostic and predictive effect, but the importance in mCRC has not been fully investigated.Methods: Immunohistochemistry analysis of CDX2 was performed in a Scandinavian population-based cohort of mCRC (n = 796). Frequency, clinical and tumor characteristics, response rate, progression-free survival, and overall survival (OS) were estimated.Results: Loss of CDX2 expression was found in 87 (19%) of 452 stained cases, in 53% if BRAF mutated (BRAFmut) and in 9% if KRAS mutated (KRASmut). CDX2 loss was associated with microsatellite instability, BRAFmut, and poor differentiation and inversely associated with KRASmut. Patients with CDX2 loss received less first-line (53 vs. 64%, p = 0.050) and second-line (23 vs. 39%, p = 0.006) chemotherapy and secondary surgery (1 vs. 9%, p = 0.019). Median progression-free survival and OS for patients given first-line combination chemotherapy was 4 and 10 months if CDX2 loss vs. 9 and 24 months if CDX2 expressed (p = 0.001, p < 0.001). Immediate progression on first-line combination chemotherapy was seen in 35% of patients with CDX2 loss vs. 10% if CDX2 expressed (p = 0.003). Median OS in patients with BRAFmut or KRASmut and CDX2 expressed in tumor (both 21 months) was comparable to wild-type patients (27 months). However, if CDX2 loss, median OS was only 8 and 11 months in BRAFmut and KRASmut cases, respectively, and 10 months in double wild-type patients. In multivariate analysis, CDX2 loss (hazard ratio: 1.50, p = 0.027) and BRAFmut (hazard ratio: 1.62, p = 0.012) were independent poor prognostic markers for OS.Conclusion: In a population-based cohort of mCRC patients, CDX2 loss is an independent poor prognostic marker. Expression of CDX2 defines a new subgroup of BRAFmut cases with a much better prognosis. Loss of CDX2 defines a small group of KRASmut cases with a worse prognosis. Patients with CDX2 loss receive less palliative chemotherapy with less benefit and rarely reach secondary surgery.https://www.frontiersin.org/article/10.3389/fonc.2020.00008/fullcaudal type homeobox transcription factorCDX2colorectal cancermetastatic diseasestage 4 colorectal cancerprognosis |