Prognostic Role of <i>KRAS</i> and <i>BRAF</i> 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; Tejpar, Sabine; Delorenzi, Mauro; Yan, Ping; Fiocca, Roberto; Klingbiel, Dirk; Dietrich, Daniel; Biesmans, Bart; Bodoky, G.; Barone, Carlo; Aranda, Enrique; Nordlinger, Bernard; Cisar, Laura A.; Labianca, Roberto; Cunningham, David; Cutsem, Éric Van; Bosman, Fred T.

doi:10.1200/jco.2009.23.3452

Cited by 1,077 publications

(1,003 citation statements)

References 34 publications

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“…Larger studies are therefore required in order to confirm whether a specific KRAS mutation might lead to a clinically relevant prognostic effect in patients with CRC. 35 …”

Section: Prognostic Role Of Kras Gene Mutationsmentioning

confidence: 99%

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Rizzo

Bronte

Fanale

et al. 2010

Cancer Treatment Reviews

103

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s u m m a r yAn important molecular target for metastatic CRC treatment is the epidermal growth factor receptor (EGFR). Many potential biomarkers predictive of response to anti-EGFR monoclonal antibodies (cetuximab and panitumumab) have been retrospectively evaluated, including EGFR activation markers and EGFR ligands activation markers. With regard to the "negative predictive factors" responsible for primary or intrinsic resistance to anti-EGFR antibodies a lot of data are now available. Among these, KRAS mutations have emerged as a major predictor of resistance to panitumumab or cetuximab in the clinical setting and several studies of patients receiving first and subsequent lines of treatment have shown that those with tumors carrying KRAS mutations do not respond to EGFR-targeted monoclonal antibodies or show any survival benefit from such treatments. The role of B-RAF mutations, mutually exclusive with KRAS mutations, in predicting resistance to anti-EGFR mAbs is not yet consolidated. It therefore appears that BRAF mutations may play a strong negative prognostic role and only a slight role in resistance to anti-EGFR Abs.

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“…Larger studies are therefore required in order to confirm whether a specific KRAS mutation might lead to a clinically relevant prognostic effect in patients with CRC. 35 …”

Section: Prognostic Role Of Kras Gene Mutationsmentioning

confidence: 99%

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Rizzo

Bronte

Fanale

et al. 2010

Cancer Treatment Reviews

103

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“…2. Prognosis -Several studies have shown dMMR CRC has a better prognosis than MMR proficient (pMMR) CRC Guastadisegni et al, 2010;Klingbiel et al, 2015;Popat et al, 2005;Roth et al, 2010;Sinicrope et al, 2015). MSI tumours are less prone to lymph node (Mohan et al, 2016) and synchronous liver metastasis (Nordholm-Carstensen et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Ryan

Sheahan

Creavin

et al. 2017

Critical Reviews in Oncology/Hematology

100

118

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“…For example, KRAS mutation has been associated with poor CRC prognosis in the QUASAR trial (1,583 patients) ( 24 ) and the RASCALII study (3,439 patients, stages II -IV) ( 25 ). In contrast, the PETACC-3 trial (1,564 patients, stages II and III) found no evidence for association of KRAS mutation with relapse-free survival or overall survival ( 26 ). Overall, the data are inconclusive as regards an association between KRAS and CRC prognosis, and a recent meta-analysis covering studies published between 1992 and 2011 showed no overall association ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

Mouradov

Domingo

Gibbs

et al. 2013

American Journal of Gastroenterology

128

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Microsatellite instability (MSI) is an established marker of good prognosis in colorectal cancer (CRC).Chromosomal instability (CIN) is strongly negatively associated with MSI and has been shown to be a marker of poor prognosis in a small number of studies. However, a substantial group of " doublenegative " (MSI − / CIN − ) CRCs exists. The prognosis of these patients is unclear. Furthermore, MSI and CIN are each associated with specifi c molecular changes, such as mutations in KRAS and BRAF , that have been associated with prognosis. It is not known which of MSI, CIN, and the specifi c gene mutations are primary predictors of survival. METHODS:We evaluated the prognostic value (disease-free survival, DFS) of CIN, MSI, mutations in KRAS , NRAS , BRAF , PIK3CA , FBXW7 , and TP53 , and chromosome 18q loss-of-heterozygosity (LOH) in 822 patients from the VICTOR trial of stage II / III CRC. We followed up promising associations in an Australian community-based cohort ( N = 375). RESULTS:In the VICTOR patients, no specifi c mutation was associated with DFS, but individually MSI and CIN showed signifi cant associations after adjusting for stage, age, gender, tumor location, and therapy. A combined analysis of the VICTOR and community-based cohorts showed that MSI and CIN were independent predictors of DFS (for MSI, hazard ratio (HR) = 0.58, 95 % confi dence interval (CI) 0.36 -0.93, and P = 0.021; for CIN, HR = 1.54, 95 % CI 1.14 -2.08, and P = 0.005), and joint CIN / MSI testing signifi cantly improved the prognostic prediction of MSI alone ( P = 0.028). Higher levels of CIN were monotonically associated with progressively poorer DFS, and a semi-quantitative measure of CIN was a better predictor of outcome than a simple CIN + / − variable . All measures of CIN predicted DFS better than the recently described Watanabe LOH ratio. SUPPLEMENTARY MATERIAL is linked to the online version of the paper at

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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

Abstract: 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.

Cited by 1,077 publications

References 34 publications

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

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