Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: Results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial

Arnaud D. Roth, Sabine Tejpar, Mauro Delorenzi, Pu Yan, Roberto Fiocca, Dirk Klingbiel, Daniel Dietrich, Bart Biesmans, G. Bodoky, Carlo Barone, Enrique Aranda, Bernard Nordlinger, Laura Cisar, Roberto Labianca, David Cunningham, Eric Van Cutsem, Fred Bosman

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Abstract

Purpose: Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278 patients with stage II to III colon cancer, to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting. Patients and Methods: Formalin-fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively collected and DNA was extracted from tissue sections from 1,404 cases. Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction. Survival analyses were based on univariate and multivariate proportional hazard regression models. Results: KRAS and BRAF tumor mutation rates were 37.0% and 7.9%, respectively, and were not significantly different according to tumor stage. In a multivariate analysis containing stage, tumor site, nodal status, sex, age, grade, and microsatellite instability (MSI) status, KRAS mutation was associated with grade (P = .0016), while BRAF mutation was significantly associated with female sex (P = .017), and highly significantly associated with right-sided tumors, older age, high grade, and MSI-high tumors (all P <10-4). In univariate and multivariate analysis, KRAS mutations did not have a major prognostic value regarding relapse-free survival (RFS) or overall survival (OS). BRAF mutation was not prognostic for RFS, but was for OS, particularly in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard ratio, 2.2; 95% CI, 1.4 to 3.4; P = .0003). Conclusion: In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.

Original languageEnglish
Pages (from-to)466-474
Number of pages9
JournalJournal of Clinical Oncology
Volume28
Issue number3
DOIs
Publication statusPublished - Jan 20 2010

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Colonic Neoplasms
Microsatellite Instability
Mutation
Neoplasms
Survival
Exons
Multivariate Analysis
Recurrence
Proto-Oncogenes
Mutation Rate
Survival Analysis
Proportional Hazards Models
Paraffin
Formaldehyde
Real-Time Polymerase Chain Reaction
Colorectal Neoplasms
Alleles
DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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Prognostic role of KRAS and BRAF in stage II and III resected colon cancer : Results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. / Roth, Arnaud D.; Tejpar, Sabine; Delorenzi, Mauro; Yan, Pu; Fiocca, Roberto; Klingbiel, Dirk; Dietrich, Daniel; Biesmans, Bart; Bodoky, G.; Barone, Carlo; Aranda, Enrique; Nordlinger, Bernard; Cisar, Laura; Labianca, Roberto; Cunningham, David; Van Cutsem, Eric; Bosman, Fred.

In: Journal of Clinical Oncology, Vol. 28, No. 3, 20.01.2010, p. 466-474.

Research output: Contribution to journalArticle

Roth, AD, Tejpar, S, Delorenzi, M, Yan, P, Fiocca, R, Klingbiel, D, Dietrich, D, Biesmans, B, Bodoky, G, Barone, C, Aranda, E, Nordlinger, B, Cisar, L, Labianca, R, Cunningham, D, Van Cutsem, E & Bosman, F 2010, 'Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: Results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial', Journal of Clinical Oncology, vol. 28, no. 3, pp. 466-474. https://doi.org/10.1200/JCO.2009.23.3452
Roth, Arnaud D. ; Tejpar, Sabine ; Delorenzi, Mauro ; Yan, Pu ; Fiocca, Roberto ; Klingbiel, Dirk ; Dietrich, Daniel ; Biesmans, Bart ; Bodoky, G. ; Barone, Carlo ; Aranda, Enrique ; Nordlinger, Bernard ; Cisar, Laura ; Labianca, Roberto ; Cunningham, David ; Van Cutsem, Eric ; Bosman, Fred. / Prognostic role of KRAS and BRAF in stage II and III resected colon cancer : Results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 3. pp. 466-474.
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abstract = "Purpose: Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278 patients with stage II to III colon cancer, to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting. Patients and Methods: Formalin-fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively collected and DNA was extracted from tissue sections from 1,404 cases. Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction. Survival analyses were based on univariate and multivariate proportional hazard regression models. Results: KRAS and BRAF tumor mutation rates were 37.0{\%} and 7.9{\%}, respectively, and were not significantly different according to tumor stage. In a multivariate analysis containing stage, tumor site, nodal status, sex, age, grade, and microsatellite instability (MSI) status, KRAS mutation was associated with grade (P = .0016), while BRAF mutation was significantly associated with female sex (P = .017), and highly significantly associated with right-sided tumors, older age, high grade, and MSI-high tumors (all P <10-4). In univariate and multivariate analysis, KRAS mutations did not have a major prognostic value regarding relapse-free survival (RFS) or overall survival (OS). BRAF mutation was not prognostic for RFS, but was for OS, particularly in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard ratio, 2.2; 95{\%} CI, 1.4 to 3.4; P = .0003). Conclusion: In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.",
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T1 - Prognostic role of KRAS and BRAF in stage II and III resected colon cancer

T2 - Results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial

AU - Roth, Arnaud D.

AU - Tejpar, Sabine

AU - Delorenzi, Mauro

AU - Yan, Pu

AU - Fiocca, Roberto

AU - Klingbiel, Dirk

AU - Dietrich, Daniel

AU - Biesmans, Bart

AU - Bodoky, G.

AU - Barone, Carlo

AU - Aranda, Enrique

AU - Nordlinger, Bernard

AU - Cisar, Laura

AU - Labianca, Roberto

AU - Cunningham, David

AU - Van Cutsem, Eric

AU - Bosman, Fred

PY - 2010/1/20

Y1 - 2010/1/20

N2 - Purpose: Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278 patients with stage II to III colon cancer, to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting. Patients and Methods: Formalin-fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively collected and DNA was extracted from tissue sections from 1,404 cases. Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction. Survival analyses were based on univariate and multivariate proportional hazard regression models. Results: KRAS and BRAF tumor mutation rates were 37.0% and 7.9%, respectively, and were not significantly different according to tumor stage. In a multivariate analysis containing stage, tumor site, nodal status, sex, age, grade, and microsatellite instability (MSI) status, KRAS mutation was associated with grade (P = .0016), while BRAF mutation was significantly associated with female sex (P = .017), and highly significantly associated with right-sided tumors, older age, high grade, and MSI-high tumors (all P <10-4). In univariate and multivariate analysis, KRAS mutations did not have a major prognostic value regarding relapse-free survival (RFS) or overall survival (OS). BRAF mutation was not prognostic for RFS, but was for OS, particularly in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard ratio, 2.2; 95% CI, 1.4 to 3.4; P = .0003). Conclusion: In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.

AB - Purpose: Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278 patients with stage II to III colon cancer, to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting. Patients and Methods: Formalin-fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively collected and DNA was extracted from tissue sections from 1,404 cases. Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction. Survival analyses were based on univariate and multivariate proportional hazard regression models. Results: KRAS and BRAF tumor mutation rates were 37.0% and 7.9%, respectively, and were not significantly different according to tumor stage. In a multivariate analysis containing stage, tumor site, nodal status, sex, age, grade, and microsatellite instability (MSI) status, KRAS mutation was associated with grade (P = .0016), while BRAF mutation was significantly associated with female sex (P = .017), and highly significantly associated with right-sided tumors, older age, high grade, and MSI-high tumors (all P <10-4). In univariate and multivariate analysis, KRAS mutations did not have a major prognostic value regarding relapse-free survival (RFS) or overall survival (OS). BRAF mutation was not prognostic for RFS, but was for OS, particularly in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard ratio, 2.2; 95% CI, 1.4 to 3.4; P = .0003). Conclusion: In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.

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