• What is KRAS?
  • KRAS in Colorectal Cancer
  • KRAS No Mutation Detected
  • Clinical Trials

KRAS

Three different human RAS genes have been identified: KRAS (homologous to the oncogene from the Kirsten rat sarcoma virus), HRAS (homologous to the oncogene from the Harvey rat sarcoma virus), and NRAS (first isolated from a human neuroblastoma). The different RAS genes are highly homologous but functionally distinct; the degree of redundancy remains a topic of investigation (reviewed in Pylayeva-Gupta et al. 2011). RAS proteins are small GTPases which cycle between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound forms. RAS proteins are central mediators downstream of growth factor receptor signaling and therefore are critical for cell proliferation, survival, and differentiation. RAS can activate several downstream effectors, including the PI3K-AKT-mTOR pathway, which is involved in cell survival, and the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation (Figure 1).

RAS has been implicated in the pathogenesis of several cancers. Activating mutations within the RAS gene result in constitutive activation of the RAS GTPase, even in the absence of growth factor signaling. The result is a sustained proliferation signal within the cell.

Specific RAS genes are recurrently mutated in different malignancies. KRAS mutations are particularly common in colon cancer, lung cancer, and pancreatic cancer (for reviews see Karnoub and Weinberg 2008 and Schubbert, Shannon, and Bollag 2007).

mapk-pk13.png

Figure 1.
Schematic of the MAPK and PI3K pathways. Growth factor binding to receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2014. KRAS. My Cancer Genome http://www.mycancergenome.org/content/disease/colorectal-cancer/kras?tab=0 (Updated August 6).

Last Updated: August 6, 2014

KRAS Mutations in Colorectal Cancer

Approximately 36–40% of patients with colorectal cancer have tumor-associated KRAS mutations (Amado et al. 2008; COSMIC; Faulkner et al. 2010; Neumann et al. 2009). The concordance between primary tumor and metastases is high (Cejas et al. 2009; Mariani et al. 2010; Santini et al. 2008), with only 3–7% of the tumors discordant. The majority of the mutations occur at codons 12, 13, and 61 of the KRAS gene. The result of these mutations is constitutive activation of KRAS signaling pathways.

Multiple studies have now shown that patients with tumors harboring mutations in KRAS are unlikely to benefit from anti-EGFR antibody therapy, either as monotherapy (Amado et al. 2008) or in combination with chemotherapy (Bokemeyer et al. 2009; Bokemeyer et al. 2011; Douillard et al. 2010; Lievre et al. 2006; Peeters et al. 2010). Further, in trials of oxaliplatin based chemotherapy, the patients with KRAS mutated tumors appeared to do worse when treated with EGFR antibody therapy combined with an oxaliplatin based chemotherapy compared to the patients treated with an oxaliplatin based treatment alone.

Contributors: Emily Chan, M.D., Ph.D.

Suggested Citation: Chan, E. 2014. KRAS Mutations in Colorectal Cancer. My Cancer Genome http://www.mycancergenome.org/content/disease/colorectal-cancer/kras (Updated August 8).

Last Updated: August 8, 2014

No KRAS and No NRAS Mutation Detected in Colorectal Cancer

Properties
Location of mutation N/A
Frequency of no KRAS or NRAS mutation detected in colorectal cancer 50% (Douillard et al. 2013)
Implications for Targeted Therapeutics
Response to erlotinib/gefitinib (EGFR TKIs) Unknown at this timea
Response to cetuximab/panitumumab (anti-EGFR antibodies) Confers increased sensitivityb

Approximately 50% of all colorectal cancers have no mutations detected in exons 2, 3, or 4 of RAS genes KRAS or NRAS. While the FDA currently recommends the use of EGFR antibody therapy only in colon cancers wild type at codons 12 and 13 of KRAS, more recent data shows that EGFR antibody therapy is unlikely to be beneficial in tumors with any KRAS or NRAS mutations. Based on this data, the NCCN updated their guidelines to recommend testing metastatic colorectal cancers for mutations in both KRAS and NRAS; previous standard of care was to test only exon 2 of KRAS (NCCN 2014). The EMEA requires testing of KRAS and NRAS eons 2, 3, and 4 for use of cetuximab (2014a) and panitumumab (2014b).

Of note, KRAS or NRAS "no mutation detected" means that tumors were tested for one or more KRAS or NRAS mutations and none were detected. KRAS or NRAS with no mutation detected is sometimes referred to as KRAS or NRAS "wild type." However, these two nomenclatures do not necessarily refer to the same thing. Strictly speaking, the mutation status should be qualified based on the testing method used. For example, if the testing only included amino acids G12, G13, and Q61 in KRAS, and no mutation was detected, then the KRAS mutation status for that tumor would be "wild type at amino acids G12, G13, and Q61."

a Gefitinib monotherapy is not active in metastatic colorectal cancer (Rothenberg et al. 2005).

b Prospective–retrospective analyses of the PRIME (Douillard et al. 2013), PEAK (Karthaus et al. 2013), OPUS (Tejpar et al. 2014), CRYSTAL (Ciardiello et al. 2014), FIRE-3 (Stintzing et al. 2014), and 20050181 (Peeters et al. 2014) clinical trials indicate that patients with tumors harboring KRAS and NRAS with no mutations detected in exons 2, 3, and 4 predict benefit from anti-EGFR antibody therapy given in combination with chemotherapy; benefits included increased progression-free survival and overall survival. In addition, patients with tumors harboring wild type KRAS may benefit from anti-EGFR antibody monotherapy (Amado et al. 2008). While KRAS and NRAS testing is not required by the FDA, testing is recommended by NCCN (2014) and is required by EMEA (2014a; 2014b).

Note that this page is cross-listed under NRAS no mutation detected in colorectal cancer.

Contributors: Emily Chan, M.D., Ph.D.

Suggested Citation: Chan, E. 2014. No KRAS and No NRAS Mutation Detected in Colorectal Cancer. My Cancer Genome http://www.mycancergenome.org/content/disease/colorectal-cancer/kras/44 (Updated August 6).

Last Updated: August 6, 2014

KRAS-Associated Colorectal Cancer Clinical Trials

Great effort was made to include all clinical trials relevant for this mutation. However, the completeness of this information cannot be guaranteed.

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