Impact of <i>KRAS</i> and <i>BRAF</i> Gene Mutation Status on Outcomes From the Phase III AGITG MAX Trial of Capecitabine Alone or in Combination With Bevacizumab and Mitomycin in Advanced Colorectal Cancer

Price, Tim; Hardingham, Jennifer E.; Lee, Chee Khoon; Weickhardt, Andrew; Townsend, Amanda; Wrin, Joe; Chua, Ann; Shivasami, Aravind; Cummins, M.; Murone, Carmel; Tebbutt, Niall C.

doi:10.1200/jco.2010.34.5520

Cited by 204 publications

(146 citation statements)

References 25 publications

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“…Hurwitz et al observed no apparent association between the improved PFS and KRAS status for patients treated with bevacizumab and irinotecan and fluoropyrimidine chemotherapy (28). More recently, the MAX study confirmed that KRAS mutation status was neither prognostic for OS nor predictive for bevacizumab outcome in patients with advanced CRC (29). These two studies analyzed the role of KRAS mutations in patients treated with irinotecan-or mytomicin-based chemotherapy plus bevacizumab, which are not the most commonly used chemotherapeutic regimens worldwide in the first-line setting.…”

Section: Discussionsupporting

confidence: 65%

Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first-line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab: A retrospective analysis

Noguera

Jantus‐Lewintre²,

Gil‐Raga

et al. 2017

Molecular and Clinical Oncology

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Abstract. The role of Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) mutations as negative predictors for anti-epidermal growth factor receptor (EGFR) therapies in metastatic colorectal cancer (CRC) has been firmly established. However, whether the RAS mutation status plays a role as a biomarker for anti-vascular endothelial growth factor (VEGF) treatment remains controversial. Data from 93 CRC patients who received first-line cytotoxic chemotherapy with fluoropyrimidines and oxaliplatin, with or without bevacizumab, were analyzed. We investigated the association between the RAS mutation status and clinical outcomes in terms of response rate, progression-free survival (PFS) and overall survival (OS). Mutations in RAS genes were observed in 47 (52.6%) patients (45 KRAS and 2 NRAS mutations). Patients with tumours harbouring RAS mutations were less suitable for primary tumour resection, were more likely to develop lung metastases, and received bevacizumab treatment for a shorter time period compared with those with wild-type tumours. The response rate to chemotherapy did not differ according to the RAS mutation status, and there were no significant differences in PFS [RAS mutation: 12 months, 95% confidence interval (CI): 8.7-15.2 vs. RAS wild-type: 12 months, 95% CI: 9.67-14.32; P=0.857] or OS (RAS mutation: 20 months, 95% CI: 14.3-25.6 vs. RAS wild-type: 24 months, 95% CI: 18.7-29.2; P=0.631). Patients with RAS mutation vs. those with RAS wild-type exhibited a favourable trend in PFS when treated with bevacizumab (13 months, 95% CI: 6.5-19.4 vs. 10 months, 95% CI: 4.2-15.7, respectively; P=0.07) and OS (27 months, 95% CI: 18.5-35.4 vs. 15 months, 95% CI: 12.4-17.5, respectively; P=0.22). In conclusion, RAS mutations are not a prognostic marker for PFS and OS in CRC patients receiving fluoropyrimidine-oxaliplatine treatment, with or without bevacizumab. RAS mutations are not predictive of the lack of efficacy of bevacizumab, and these patients appear to benefit from anti-angiogenic treatment.

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Section: Discussionsupporting

confidence: 65%

Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first-line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab: A retrospective analysis

Noguera

Jantus‐Lewintre²,

Gil‐Raga

et al. 2017

Molecular and Clinical Oncology

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“…RAS mutations represent the only, molecular, predictive biomarker approved for clinical use, while their prognostic role is still debated. Several randomized studies have shown no significant survival differences between KRAS mutated and KRAS wild-type, CRC patients, independently of anti-EGFR therapy (Price et al, 2011;Hecht et al, 2009;Kastrinakis et al, 1995;Russo et al, 1998;Tol et al, 2010), while others have demonstrated a prognostic role of KRAS in advanced disease (Richman et al, 2009;Maughan et al, 2011;Tejpar et al, 2012). BRAF mutations have been described in about 10% of primary CRC, representing a well-known negative prognostic factor, associated with worse survival outcomes, regardless of any treatment received (Ahn et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Can KRAS and BRAF mutations limit the benefit of liver resection in metastatic colorectal cancer patients? A systematic review and meta-analysis

Passiglia

Bronte

Bazan

et al. 2016

Critical Reviews in Oncology/Hematology

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Background: Clinical trials investigated the potential role of both KRAS and BRAF mutations, as prognostic biomarkers, in colorectal cancer (CRC) patients who underwent surgical treatment of CRC-related liver metastases (CLM), showing conflicting results. This meta-analysis aims to review all the studies reporting survival outcomes (recurrence free survival (RFS), and/or overall survival (OS)) of patients undergoing resection of CLM, stratified according to KRAS and/or BRAF mutation status. Materials and methods: Data from all published studies reporting survival outcomes (RFS and/or OS) of CRC patients who received resection of CLM, stratified by KRAS and/or BRAF mutation status were collected, according to the PRISMA guidelines. Pooled HRs were calculated for both the OS and/or RFS. Results: Seven eligible trials (1403 patients) were included. Pooled analysis showed that KRAS mutations predicted a significantly worse both RFS (HR: 1.65; 95% CI: 1.23-2.21) and OS (HR: 1.86; 95% CI: 1.51-2.30) in patients who underwent surgical resection of CLM. BRAF mutations were also associated with a significantly worse OS (HR: 3.90; 95% CI: 1.96-7.73) in this subgroup of patients. Conclusions: This meta-analysis suggests both KRAS and BRAF mutations as poor, prognostic biomarkers, associated with worse survival outcomes, in patients undergoing hepatic resection of CLM

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“…[3] The mechanism for the poor prognosis is poorly understood, and it is unclear at what point in the aCRC treatment pathway that Bmutant outcomes diverge from wildBtypes; whilst OS is uniformly poor, less impact is seen with PFS compared with wildBtypes. [4,5] It has been hypothesised that poor outcomes are secondary to intrinisc chemoresistance but there is a paucity of data describing the outcomes of Bmutant aCRC with chemotherapy alone, particularly beyond the firstBline. This is particularly important as B mutant patients have questionable benefit from antiBepidermal growth factor receptor (antiBEGFR) therapies [6] and Btargeted strategies have yet to make clinical impact in aCRC.…”

Section: Introductionmentioning

confidence: 99%

Investigating the poor outcomes ofBRAF-mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials

et al. 2017

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Impact of KRAS and BRAF Gene Mutation Status on Outcomes From the Phase III AGITG MAX Trial of Capecitabine Alone or in Combination With Bevacizumab and Mitomycin in Advanced Colorectal Cancer

Abstract: KRAS gene mutation status was neither prognostic for OS nor predictive of bevacizumab outcome in patients with advanced CRC. BRAF gene mutation status was prognostic for OS but was not predictive of outcome with bevacizumab.

Cited by 204 publications

References 25 publications

Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first-line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab: A retrospective analysis

Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first-line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab: A retrospective analysis

Can KRAS and BRAF mutations limit the benefit of liver resection in metastatic colorectal cancer patients? A systematic review and meta-analysis

Investigating the poor outcomes ofBRAF-mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials

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