Association of <i>KRAS</i> G13D Tumor Mutations With Outcome in Patients With Metastatic Colorectal Cancer Treated With First-Line Chemotherapy With or Without Cetuximab

Tejpar, Sabine; Çelik, I.; Schlichting, Michael; Sartorius, Ute; Bokemeyer, Carsten; Cutsem, Éric Van

doi:10.1200/jco.2012.42.2592

Cited by 320 publications

(227 citation statements)

References 27 publications

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“…EGFR is a receptor tyrosine kinase that is positioned upstream of RAS. However, subsequent analyses has suggested that CRC patients with KRAS G13 mutations benefit from anti-EGFR therapy (Tejpar et al, 2012). This issue continues to evolve (Van Cutsem et al, 2015) because the National Comprehensive Cancer Network recommendation now indicates that CRC patients with any KRAS or NRAS mutation, including those of Q61 and A146, will not benefit from anti-EGFR therapy (Tran et al, 2015).…”

Section: Ras Mutation Hotspots -Structural Biological and Functionalmentioning

confidence: 99%

RAS isoforms and mutations in cancer at a glance

Hobbs

Der

Rossman

2016

Journal of Cell Science

782

709

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RAS proteins (KRAS4A, KRAS4B, NRAS and HRAS) function as GDP-GTP-regulated binary on-off switches, which regulate cytoplasmic signaling networks that control diverse normal cellular processes. Gain-of-function missense mutations in RAS genes are found in ∼25% of human cancers, prompting interest in identifying anti-RAS therapeutic strategies for cancer treatment. However, despite more than three decades of intense effort, no anti-RAS therapies have reached clinical application. Contributing to this failure has been an underestimation of the complexities of RAS. First, there is now appreciation that the four human RAS proteins are not functionally identical. Second, with >130 different missense mutations found in cancer, there is an emerging view that there are mutation-specific consequences on RAS structure, biochemistry and biology, and mutation-selective therapeutic strategies are needed. In this Cell Science at a Glance article and accompanying poster, we provide a snapshot of the differences between RAS isoforms and mutations, as well as the current status of anti-RAS drug-discovery efforts.

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Section: Ras Mutation Hotspots -Structural Biological and Functionalmentioning

confidence: 99%

RAS isoforms and mutations in cancer at a glance

Hobbs

Der

Rossman

2016

Journal of Cell Science

782

709

View full text Add to dashboard Cite

show abstract

“…Recent studies reported that patients with G13D mutant tumors benefit more from cetuximab than those with G12V mutant tumors [11,12]. In addition, a recent head-tohead comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for mCRC supports the conclusion that KRAS mutations should not be treated as a homogeneous group [22].…”

Section: Discussionmentioning

confidence: 91%

“…Thus, the FDA recently revised the indications for cetuximab, and currently recommends its use only for the ~60% of patients whose CRC tumors do not have KRAS mutations in codons 12 or 13 of exon 2 [10]. Two recent studies [11,12] indicated that addition of cetuximab to chemotherapy seems to benefit patients with KRAS G13D-mutant tumors. KRAS mutations have been also reported elsewhere, but these are rarer [10,11,13].…”

mentioning

confidence: 99%

“…Two recent studies [11,12] indicated that addition of cetuximab to chemotherapy seems to benefit patients with KRAS G13D-mutant tumors. KRAS mutations have been also reported elsewhere, but these are rarer [10,11,13]. A recent multicenter trial of European mCRC patients indicated that ~64% of patients had the wild-type KRAS gene, ~36% had the mutated gene [8], and that only those with the wild-type gene benefitted from cetuximab treatment.…”

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confidence: 99%

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Cetuximab plus chemotherapy as first-line treatment for metastatic colorectal cancer: Effect of KRAS mutation on treatment efficacy in Taiwanese patients

Chen

Chiang²,

Wang³

2013

neo

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Cetuximab, either alone or in combination with chemotherapy, is approved for treatment of patients with metastatic colorectal cancer (mCRC). We reviewed retrospectively records of 50 patients with mCRC from a single center in Taiwan. All patients had ECOG performance status grade 2, histological diagnosis of advanced CRC based on RECIST criteria, and were given at least three cycles of chemotherapy plus cetuximab. We compared the effectiveness of therapy in patients with wild-type and mutant KRAS genes, assessed the overall response (OR) rate of patients with locally advanced or metastatic non-resectable CRC, and assessed the progression-free survival (PFS) time. The ten patients with KRAS mutations had poorer response rates than the 40 patients with the wild-type KRAS gene. Patients with the wild-type and mutant genes had similar progression free survival (PFS) status and median time to PFS. The median overall survival time was significantly greater in patients with the wild-type gene than in those with the mutant gene (28.77 ± 6.43 months vs. 15.13 ± 0.50 months, p = 0.014). Taiwanese patients with mCRC respond better to a cetuximab plus chemotherapy regime if their tumors have the wild-type KRAS gene.

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“…A closer look at the mutation analysis reveals 1 patient having a KRAS G13D mutation. This specific mutation may not be as strongly associated with impaired response to cetuximab but appears to remain a negative prognostic factor [21]. …”

Section: Discussionmentioning

confidence: 99%

Efficacy of Triplet Combination Chemotherapy with Oxaliplatin, Irinotecan and Capecitabine (OCX) in Metastatic Colorectal Cancer in Relation to RAS/RAF Mutation Status: Results of a Retrospective Analysis

et al. 2014

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SummaryBackground: The triplet combination of fluorouracil, oxaliplatin and irinotecan for metastatic colorectal cancer improves efficacy at the cost of increased toxicity. Preliminary reports indicate that triplet combination regimens might improve outcome in the RAS/RAF-mutated subgroup. Patients and Methods: This retrospective analysis included 25 patients with metastatic colorectal cancer, who received treatment with OCX (oxaliplatin, irinotecan, capecitabine). The regimen consisted of oxaliplatin 70 mg/m² on days 1 and 15, irinotecan 100 mg/m² on days 8 and 22, and capecitabine 1,400 mg/m² on days 1-29 every 5 weeks. KRAS, NRAS, and BRAF mutations were determined by Sanger sequencing. Results: 23 patients received at least 1 cycle and were evaluable for efficacy. In 10 patients, a KRAS or BRAF mutation was detected. Partial remission rate was 61%, median progression-free survival 9.8 months, and median overall survival 32.9 months for all evaluable patients. No difference in efficacy was detected between the RAS/RAF wild-type and the mutant group. OCX was well tolerated with no grade 3/4 haematological events. Diarrhoea was the major non-haematological toxicity (24% grade 3). Conclusion: In this retrospective analysis, triplet chemotherapy with OCX was well tolerated and achieved encouraging efficacy in metastatic colorectal cancer irrespective of RAS/RAF mutation status.

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Association of KRAS G13D Tumor Mutations With Outcome in Patients With Metastatic Colorectal Cancer Treated With First-Line Chemotherapy With or Without Cetuximab

Abstract: The addition of cetuximab to first-line chemotherapy seems to benefit patients with KRAS G13D-mutant tumors. Relative treatment effects were similar to those in patients with KRAS wild-type tumors but with lower absolute values.

Cited by 320 publications

References 27 publications

RAS isoforms and mutations in cancer at a glance

RAS isoforms and mutations in cancer at a glance

Cetuximab plus chemotherapy as first-line treatment for metastatic colorectal cancer: Effect of KRAS mutation on treatment efficacy in Taiwanese patients

Efficacy of Triplet Combination Chemotherapy with Oxaliplatin, Irinotecan and Capecitabine (OCX) in Metastatic Colorectal Cancer in Relation to RAS/RAF Mutation Status: Results of a Retrospective Analysis

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