Impact of genetic variations in the MAPK signaling pathway on outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI and bevacizumab

Data from FIRE-3 and TRIBE trials

M. D. Berger, S. Stintzing, V. Heinemann, D. Yang, S. Cao, Y. Sunakawa, Y. Ning, S. Matsusaka, S. Okazaki, Y. Miyamoto, M. Suenaga, M. Schirripa, S. Soni, W. Zhang, A. Falcone, F. Loupakis, H. J. Lenz

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E, a key player in translational control, whose expression is often upregulated in metastatic colorectal cancer patients (mCRC). Preclinical data suggest that MKNK1 increases angiogenesis by upregulating angiogenic factors. We therefore hypothesize that variations in the MKNK1 gene predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev). Patients and methods: A total of 567 patients with KRAS wild-type mCRC in the randomized phase III FIRE-3 and TRIBE trials treated with first-line FOLFIRI/bev (discovery and validation cohorts) or FOLFIRI and cetuximab (cet) (control cohort) were included in this study. Five single-nucleotide polymorphisms in the MAPK signaling pathway were analyzed. Results: AA genotype carriers of the MKNK1 rs8602 single-nucleotide polymorphism treated with FOLFIRI/bev in the discovery cohort (FIRE-3) had a shorter progression-free survival (PFS) than those harboring any C (7.9 versus 10.3 months, Hazard ratio (HR) 1.73, P=0.038). This association could be confirmed in the validation cohort (TRIBE) in multivariable analysis (PFS 9.0 versus 11.0 months, HR 3.04, P=0.029). Furthermore, AA carriers in the validation cohort had a decreased overall response rate (25% versus 66%, P=0.049). Conversely, AA genotype carriers in the control group receiving FOLFIRI/cet did not show a shorter PFS. By combining both FOLFIRI/bev cohorts the worse outcome among AA carriers became more significant (PFS 9.0 versus 10.5 months) in univariable (HR 1.74, P=0.015) and multivariable analysis (HR 1.76, P=0.022). Accordingly, AA carriers did also exhibit an inferior overall response rate compared with those harboring any C (36% versus 65%, P=0.005). Conclusion: MKNK1 polymorphism rs8602 might serve as a predictive marker in KRAS wild-type mCRC patients treated with FOLFIRI/bev in the first-line setting. Additionally, MKNK1 might be a promising target for drug development.

Original languageEnglish
Pages (from-to)2780-2785
Number of pages6
JournalAnnals of Oncology
Volume28
Issue number11
DOIs
Publication statusPublished - Jan 1 2017

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MAP Kinase Kinase 1
Colorectal Neoplasms
Disease-Free Survival
Single Nucleotide Polymorphism
Genotype
Eukaryotic Initiation Factor-4E
Eukaryotic Initiation Factors
Bevacizumab
Angiogenesis Inducing Agents
Phosphorylation
Control Groups

Keywords

  • FOLFIRI/bevacizumab
  • Metastatic colorectal cancer
  • MKNK1
  • Predictive biomarker
  • Single-nucleotide polymorphisms

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Impact of genetic variations in the MAPK signaling pathway on outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI and bevacizumab : Data from FIRE-3 and TRIBE trials. / Berger, M. D.; Stintzing, S.; Heinemann, V.; Yang, D.; Cao, S.; Sunakawa, Y.; Ning, Y.; Matsusaka, S.; Okazaki, S.; Miyamoto, Y.; Suenaga, M.; Schirripa, M.; Soni, S.; Zhang, W.; Falcone, A.; Loupakis, F.; Lenz, H. J.

In: Annals of Oncology, Vol. 28, No. 11, 01.01.2017, p. 2780-2785.

Research output: Contribution to journalArticle

Berger, MD, Stintzing, S, Heinemann, V, Yang, D, Cao, S, Sunakawa, Y, Ning, Y, Matsusaka, S, Okazaki, S, Miyamoto, Y, Suenaga, M, Schirripa, M, Soni, S, Zhang, W, Falcone, A, Loupakis, F & Lenz, HJ 2017, 'Impact of genetic variations in the MAPK signaling pathway on outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI and bevacizumab: Data from FIRE-3 and TRIBE trials', Annals of Oncology, vol. 28, no. 11, pp. 2780-2785. https://doi.org/10.1093/annonc/mdx412
Berger, M. D. ; Stintzing, S. ; Heinemann, V. ; Yang, D. ; Cao, S. ; Sunakawa, Y. ; Ning, Y. ; Matsusaka, S. ; Okazaki, S. ; Miyamoto, Y. ; Suenaga, M. ; Schirripa, M. ; Soni, S. ; Zhang, W. ; Falcone, A. ; Loupakis, F. ; Lenz, H. J. / Impact of genetic variations in the MAPK signaling pathway on outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI and bevacizumab : Data from FIRE-3 and TRIBE trials. In: Annals of Oncology. 2017 ; Vol. 28, No. 11. pp. 2780-2785.
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abstract = "Background: The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E, a key player in translational control, whose expression is often upregulated in metastatic colorectal cancer patients (mCRC). Preclinical data suggest that MKNK1 increases angiogenesis by upregulating angiogenic factors. We therefore hypothesize that variations in the MKNK1 gene predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev). Patients and methods: A total of 567 patients with KRAS wild-type mCRC in the randomized phase III FIRE-3 and TRIBE trials treated with first-line FOLFIRI/bev (discovery and validation cohorts) or FOLFIRI and cetuximab (cet) (control cohort) were included in this study. Five single-nucleotide polymorphisms in the MAPK signaling pathway were analyzed. Results: AA genotype carriers of the MKNK1 rs8602 single-nucleotide polymorphism treated with FOLFIRI/bev in the discovery cohort (FIRE-3) had a shorter progression-free survival (PFS) than those harboring any C (7.9 versus 10.3 months, Hazard ratio (HR) 1.73, P=0.038). This association could be confirmed in the validation cohort (TRIBE) in multivariable analysis (PFS 9.0 versus 11.0 months, HR 3.04, P=0.029). Furthermore, AA carriers in the validation cohort had a decreased overall response rate (25{\%} versus 66{\%}, P=0.049). Conversely, AA genotype carriers in the control group receiving FOLFIRI/cet did not show a shorter PFS. By combining both FOLFIRI/bev cohorts the worse outcome among AA carriers became more significant (PFS 9.0 versus 10.5 months) in univariable (HR 1.74, P=0.015) and multivariable analysis (HR 1.76, P=0.022). Accordingly, AA carriers did also exhibit an inferior overall response rate compared with those harboring any C (36{\%} versus 65{\%}, P=0.005). Conclusion: MKNK1 polymorphism rs8602 might serve as a predictive marker in KRAS wild-type mCRC patients treated with FOLFIRI/bev in the first-line setting. Additionally, MKNK1 might be a promising target for drug development.",
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TY - JOUR

T1 - Impact of genetic variations in the MAPK signaling pathway on outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI and bevacizumab

T2 - Data from FIRE-3 and TRIBE trials

AU - Berger, M. D.

AU - Stintzing, S.

AU - Heinemann, V.

AU - Yang, D.

AU - Cao, S.

AU - Sunakawa, Y.

AU - Ning, Y.

AU - Matsusaka, S.

AU - Okazaki, S.

AU - Miyamoto, Y.

AU - Suenaga, M.

AU - Schirripa, M.

AU - Soni, S.

AU - Zhang, W.

AU - Falcone, A.

AU - Loupakis, F.

AU - Lenz, H. J.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background: The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E, a key player in translational control, whose expression is often upregulated in metastatic colorectal cancer patients (mCRC). Preclinical data suggest that MKNK1 increases angiogenesis by upregulating angiogenic factors. We therefore hypothesize that variations in the MKNK1 gene predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev). Patients and methods: A total of 567 patients with KRAS wild-type mCRC in the randomized phase III FIRE-3 and TRIBE trials treated with first-line FOLFIRI/bev (discovery and validation cohorts) or FOLFIRI and cetuximab (cet) (control cohort) were included in this study. Five single-nucleotide polymorphisms in the MAPK signaling pathway were analyzed. Results: AA genotype carriers of the MKNK1 rs8602 single-nucleotide polymorphism treated with FOLFIRI/bev in the discovery cohort (FIRE-3) had a shorter progression-free survival (PFS) than those harboring any C (7.9 versus 10.3 months, Hazard ratio (HR) 1.73, P=0.038). This association could be confirmed in the validation cohort (TRIBE) in multivariable analysis (PFS 9.0 versus 11.0 months, HR 3.04, P=0.029). Furthermore, AA carriers in the validation cohort had a decreased overall response rate (25% versus 66%, P=0.049). Conversely, AA genotype carriers in the control group receiving FOLFIRI/cet did not show a shorter PFS. By combining both FOLFIRI/bev cohorts the worse outcome among AA carriers became more significant (PFS 9.0 versus 10.5 months) in univariable (HR 1.74, P=0.015) and multivariable analysis (HR 1.76, P=0.022). Accordingly, AA carriers did also exhibit an inferior overall response rate compared with those harboring any C (36% versus 65%, P=0.005). Conclusion: MKNK1 polymorphism rs8602 might serve as a predictive marker in KRAS wild-type mCRC patients treated with FOLFIRI/bev in the first-line setting. Additionally, MKNK1 might be a promising target for drug development.

AB - Background: The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E, a key player in translational control, whose expression is often upregulated in metastatic colorectal cancer patients (mCRC). Preclinical data suggest that MKNK1 increases angiogenesis by upregulating angiogenic factors. We therefore hypothesize that variations in the MKNK1 gene predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev). Patients and methods: A total of 567 patients with KRAS wild-type mCRC in the randomized phase III FIRE-3 and TRIBE trials treated with first-line FOLFIRI/bev (discovery and validation cohorts) or FOLFIRI and cetuximab (cet) (control cohort) were included in this study. Five single-nucleotide polymorphisms in the MAPK signaling pathway were analyzed. Results: AA genotype carriers of the MKNK1 rs8602 single-nucleotide polymorphism treated with FOLFIRI/bev in the discovery cohort (FIRE-3) had a shorter progression-free survival (PFS) than those harboring any C (7.9 versus 10.3 months, Hazard ratio (HR) 1.73, P=0.038). This association could be confirmed in the validation cohort (TRIBE) in multivariable analysis (PFS 9.0 versus 11.0 months, HR 3.04, P=0.029). Furthermore, AA carriers in the validation cohort had a decreased overall response rate (25% versus 66%, P=0.049). Conversely, AA genotype carriers in the control group receiving FOLFIRI/cet did not show a shorter PFS. By combining both FOLFIRI/bev cohorts the worse outcome among AA carriers became more significant (PFS 9.0 versus 10.5 months) in univariable (HR 1.74, P=0.015) and multivariable analysis (HR 1.76, P=0.022). Accordingly, AA carriers did also exhibit an inferior overall response rate compared with those harboring any C (36% versus 65%, P=0.005). Conclusion: MKNK1 polymorphism rs8602 might serve as a predictive marker in KRAS wild-type mCRC patients treated with FOLFIRI/bev in the first-line setting. Additionally, MKNK1 might be a promising target for drug development.

KW - FOLFIRI/bevacizumab

KW - Metastatic colorectal cancer

KW - MKNK1

KW - Predictive biomarker

KW - Single-nucleotide polymorphisms

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U2 - 10.1093/annonc/mdx412

DO - 10.1093/annonc/mdx412

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