KRAS and NRAS Mutations in Colorectal Cancer

by Jason Wasserman MD PhD FRCPC
March 24, 2026

KRAS and NRAS are two of the most commonly tested genes in colorectal cancer. When either gene carries a mutation — a change that causes it to malfunction — the result has direct consequences for your treatment plan. Most importantly, KRAS and NRAS mutations predict that a class of targeted drugs called anti-EGFR therapy will not work, which spares patients from treatments unlikely to help them and guides oncologists toward regimens that are more likely to be effective. For the small group of patients whose tumour carries a specific mutation called KRAS G12C, new targeted drugs have now been approved that directly attack the mutant protein for the first time. Understanding what your RAS mutation result means — and what it does not mean — is an important step in making sense of your treatment plan.

What KRAS and NRAS are and what they do

KRAS and NRAS are members of a family of genes called RAS genes. These genes provide instructions for making proteins that act like on/off switches inside cells, helping to control when a cell grows and divides. In a healthy cell, the KRAS and NRAS proteins switch on briefly when a growth signal arrives — for example, when a growth factor binds to a receptor on the cell surface — and then switch off again once the signal has been processed.

A mutation in KRAS or NRAS can disable the off switch, locking the protein in the “on” position permanently. The cell then receives a constant signal to keep growing and dividing, even when it should stop. This kind of always-active mutation is one of the most common ways that colorectal cancers develop and sustain their growth.

KRAS and NRAS mutations in colorectal cancer are almost always somatic — meaning they arose in the cancer cells during a person’s lifetime and were not inherited from a parent. They cannot be passed on to children. This distinguishes them from hereditary gene changes like those seen in Lynch syndrome.

How common are KRAS and NRAS mutations in colorectal cancer?

KRAS mutations are found in approximately 40 to 45% of colorectal cancers, making KRAS the most commonly mutated gene in this cancer type. Specific mutations occur at particular locations within the gene called codons; the most common are at codons 12 and 13, which together account for the majority of all KRAS mutations. Codon 12 mutations include several variants — G12D, G12V, G12C, G12A, G12R, and G12S — of which G12D and G12V are the most frequent. Codon 13 is most often affected by the G13D mutation. Less common mutations occur at codons 61, 117, and 146.

NRAS mutations are found in approximately 4 to 5% of colorectal cancers. The most common NRAS mutations affect codons 12, 13, and 61.

Taken together, mutations in either KRAS or NRAS (collectively called RAS mutations) are present in roughly 50% of all colorectal cancers — meaning one in two patients will have a RAS-mutated tumour. Testing for both genes is therefore standard practice in all patients with colorectal cancer, particularly those with metastatic disease.

Why the test is done

To determine eligibility for anti-EGFR therapy

The most important reason for KRAS and NRAS testing in colorectal cancer is to determine whether a class of drugs called anti-EGFR therapy can be used. Anti-EGFR drugs — cetuximab (Erbitux) and panitumumab (Vectibix) — work by blocking a protein on the surface of cancer cells called EGFR (epidermal growth factor receptor), which normally sends growth signals into the cell. These drugs can be highly effective in the right patients and are part of standard chemotherapy regimens for metastatic colorectal cancer.

The catch is that anti-EGFR drugs only work when the signalling pathway downstream of EGFR is not permanently switched on by a RAS mutation. If KRAS or NRAS is mutated, the cancer cell’s growth machinery is already stuck in the “on” position regardless of what happens at the EGFR receptor. Blocking EGFR with cetuximab or panitumumab has no meaningful effect in this situation — the signal bypasses the block and continues uninterrupted. Multiple large clinical trials have demonstrated clearly that patients with KRAS or NRAS mutations do not benefit from anti-EGFR therapy, and may actually experience toxicity without benefit.

For this reason, testing for KRAS and NRAS mutations is performed before anti-EGFR therapy is considered. Only patients whose tumours are KRAS and NRAS wild-type (meaning no mutation is detected in either gene) are candidates for cetuximab or panitumumab.

To identify eligibility for KRAS G12C-targeted therapy

A specific KRAS mutation called G12C — present in approximately 3 to 4% of colorectal cancers — is now targetable with newly approved drugs. Unlike most KRAS mutations, which have been extraordinarily difficult to drug, the G12C mutation creates a unique molecular pocket that allows a class of drugs called KRAS G12C inhibitors to bind to the mutant protein and lock it in its inactive state. Two such inhibitor combinations are now FDA-approved for metastatic colorectal cancer (see the treatment section below). Identifying a KRAS G12C mutation therefore opens a specific treatment pathway that would not otherwise be available.

To provide prognostic information

Certain KRAS mutations — particularly those at codon 12 — are associated with a somewhat more aggressive disease course and a modestly worse prognosis compared to RAS wild-type colorectal cancers. This information does not change the overall approach to treatment but may inform discussions about disease trajectory and monitoring.

How the test is performed

KRAS and NRAS testing is performed on tumour tissue from a biopsy or surgically removed specimen. The test looks for mutations in the DNA of the cancer cells using one of two main methods:

PCR-based testing. Polymerase chain reaction (PCR) methods amplify specific regions of the KRAS and NRAS genes and check for mutations at the most clinically important codons. PCR-based tests are fast, sensitive, and widely available. Some assays are specifically designed to detect the most common mutations at codons 12, 13, 61, and 146.
Next-generation sequencing (NGS). NGS panels examine large portions of the KRAS and NRAS genes simultaneously, and typically test many other cancer-related genes at the same time. NGS can detect a wider range of mutations than standard PCR tests and is increasingly the preferred approach because it provides a comprehensive view of the tumour’s molecular profile in a single test.

In some situations — particularly when tumour tissue is not available or is insufficient — KRAS and NRAS mutations can also be detected in a blood sample through a technique called liquid biopsy, which looks for tumour DNA circulating in the bloodstream. Liquid biopsy is not yet universally used for initial testing but is increasingly available and may be particularly useful for monitoring the cancer’s evolution over time.

KRAS and NRAS testing is usually reported in a section of your pathology report called molecular testing, biomarker testing, or ancillary studies.

How results are reported

Your report will state whether a KRAS or NRAS mutation was detected. If a mutation is found, the report will identify the specific mutation — for example, “KRAS exon 2 codon 12 mutation, p.G12D” or “NRAS exon 3 codon 61 mutation, p.Q61K.” The exact mutation name follows a standardized notation used by molecular pathology laboratories worldwide.

KRAS wild-type / no mutation detected. No mutation was found in the KRAS gene at the regions tested. (Note: this result is meaningful only when combined with NRAS results — both genes must be wild-type for a patient to be considered a candidate for anti-EGFR therapy.)
KRAS mutation detected. A mutation was found in the KRAS gene. The specific mutation will be named. The tumour is not expected to respond to anti-EGFR therapy with cetuximab or panitumumab. If the mutation is KRAS G12C, eligibility for KRAS G12C-targeted therapy will be relevant.
NRAS wild-type / no mutation detected. No mutation was found in the NRAS gene at the regions tested.
NRAS mutation detected. A mutation was found in the NRAS gene. The specific mutation will be named. The tumour is not expected to respond to anti-EGFR therapy.
RAS wild-type. Some reports use this combined term to indicate that both KRAS and NRAS were tested and neither showed a mutation. This is the result required for anti-EGFR therapy eligibility (along with a normal BRAF result — see below).

Some reports may also note the variant allele frequency (VAF) — the proportion of tumour DNA that carries the mutation. A high VAF suggests the mutation is present in the majority of cancer cells; a low VAF may indicate a subclonal mutation (present in only a fraction of cells) or may reflect technical factors. Your oncologist or pathologist can explain the clinical significance of VAF in your specific case.

What the result means

RAS wild-type (no KRAS or NRAS mutation detected)

A RAS wild-type result is the prerequisite for anti-EGFR therapy consideration. Approximately 50% of patients will have this result. However, RAS wild-type status alone is not sufficient — your oncologist will also check the BRAF mutation status and, in some cases, HER2 amplification status, because mutations in those genes can also predict resistance to anti-EGFR therapy. Additionally, there is strong evidence that anti-EGFR therapy works better in left-sided colorectal cancers (tumours originating in the descending colon, sigmoid colon, or rectum) than in right-sided ones (tumours in the ascending colon, cecum, or transverse colon). Your oncologist will consider tumour location alongside RAS status when determining whether anti-EGFR therapy is appropriate for you.

KRAS mutation detected (other than G12C)

A KRAS mutation — at codon 12, 13, 61, 117, or 146 — means anti-EGFR therapy is not expected to be effective and will generally not be offered. Your treatment plan will instead focus on chemotherapy regimens (such as FOLFOX, CAPOX, or FOLFIRI) combined with a different type of targeted drug called a VEGF inhibitor — most commonly bevacizumab (Avastin), which works by cutting off the blood supply to the tumour. VEGF inhibitors are effective in both RAS-mutated and RAS wild-type colorectal cancers. KRAS mutation status does not affect eligibility for immunotherapy, which is determined by MMR/MSI status.

Most KRAS mutations currently do not have a specific targeted therapy beyond the KRAS G12C inhibitors discussed below. Research into inhibitors targeting other KRAS mutations (particularly G12D and G12V, which are the most common) is actively ongoing, and clinical trials may be relevant for some patients.

KRAS G12C mutation detected

The KRAS G12C mutation is present in approximately 3 to 4% of colorectal cancers. Until recently, KRAS mutations were considered undruggable — scientists could not find a way to block the mutant protein. The development of KRAS G12C inhibitors changed this. Two combination regimens are now FDA-approved for previously treated metastatic KRAS G12C-mutated colorectal cancer:

Adagrasib (Krazati) plus cetuximab. Adagrasib directly inhibits the KRAS G12C protein by binding to it and locking it in its inactive state. In the KRYSTAL-1 trial of 94 patients, the combination of adagrasib and cetuximab produced an overall response rate of approximately 34%, with disease control (tumour shrinkage or stabilization) in over 85% of patients. This combination received accelerated FDA approval in June 2024.
Sotorasib (Lumakras) plus panitumumab. Sotorasib is another KRAS G12C inhibitor with a similar mechanism. In the CodeBreaK 300 phase III trial, sotorasib plus panitumumab produced a response rate of 26% and reduced the risk of disease progression by 52% compared to standard third-line chemotherapy. This combination received full FDA approval in January 2025.

Both regimens combine a KRAS G12C inhibitor with an anti-EGFR antibody. This combination approach addresses a key resistance mechanism: when KRAS G12C is blocked, some cancer cells attempt to circumvent this by increasing signalling through EGFR, so blocking EGFR at the same time makes the inhibition more durable.

These approvals are currently for patients who have already received prior chemotherapy containing fluoropyrimidine, oxaliplatin, and irinotecan. Research into these drugs in earlier lines of treatment and in combination with other agents is ongoing. If you have a KRAS G12C mutation, your oncologist will discuss whether you are eligible for one of these regimens and whether relevant clinical trials might be appropriate.

NRAS mutation detected

An NRAS mutation, like a KRAS mutation, predicts resistance to anti-EGFR therapy with cetuximab or panitumumab, which will not be offered. Treatment will follow the same principles as for KRAS-mutated colorectal cancer, using chemotherapy regimens combined with VEGF inhibitors such as bevacizumab. At present, there are no specifically approved targeted therapies for NRAS-mutated colorectal cancers outside of clinical trials, though research into broader RAS inhibitors is ongoing.

The relationship between RAS mutations, BRAF, and treatment eligibility

KRAS, NRAS, and BRAF are all part of the same signalling pathway — the RAS-RAF-MEK-ERK pathway — that drives cell growth. Mutations in any one of these genes can short-circuit the pathway in a way that renders anti-EGFR therapy ineffective. This is why a complete assessment of anti-EGFR eligibility requires testing of all three:

If KRAS is mutated → anti-EGFR therapy not effective
If NRAS is mutated → anti-EGFR therapy not effective
If BRAF V600E is mutated → anti-EGFR therapy not effective (and specific BRAF-targeted combinations may be relevant)
If all three are wild-type, and the tumour is left-sided → anti-EGFR therapy is a candidate option

Your oncologist will review all of these results together to determine the best treatment approach. The BRAF article in the colorectal cancer biomarker section covers BRAF testing and its implications in detail.

Do KRAS and NRAS mutations have hereditary implications?

In colorectal cancer, KRAS and NRAS mutations are almost always somatic — they arise in the tumour cells during a person’s lifetime and are not inherited. They do not increase cancer risk in family members and do not require genetic counselling or family testing. This is different from MMR gene mutations (which can indicate Lynch syndrome) and BRCA mutations, both of which can be inherited.

In very rare cases, a germline (inherited) KRAS mutation can occur as part of an extremely rare syndrome called Noonan syndrome or a related condition, but this is not a relevant consideration for the vast majority of colorectal cancer patients. If you have concerns about hereditary cancer risk in your family, those concerns should be discussed in the context of your MMR/MSI testing results, family history, and other clinical factors — not your somatic KRAS or NRAS result.

What happens next

If you have just received your KRAS or NRAS result, what happens next depends on your overall situation:

If your tumour is RAS wild-type (no KRAS or NRAS mutation), your oncologist will review this alongside your BRAF result, tumour location, and stage to determine whether anti-EGFR therapy is appropriate for you. For metastatic disease, this result may mean cetuximab or panitumumab can be added to your chemotherapy regimen.
If your tumour has a KRAS or NRAS mutation other than G12C, anti-EGFR therapy will not be part of your plan. Your oncologist will discuss chemotherapy combined with bevacizumab or other approved regimens. Clinical trials targeting KRAS mutations beyond G12C may also be worth discussing.
If your tumour has a KRAS G12C mutation, your oncologist will discuss whether you are eligible for adagrasib plus cetuximab or sotorasib plus panitumumab, depending on your treatment history and overall health. If you have not yet received prior chemotherapy, these drugs are not yet approved in the first-line setting, but clinical trials may be available.

It is worth knowing that RAS mutations can occasionally evolve over time — particularly after treatment. If your cancer progresses or is re-biopsied, re-testing of KRAS and NRAS status may be relevant, especially if considering anti-EGFR therapy at a later point in treatment. Liquid biopsy (blood-based testing) may be used in some settings to monitor for emerging mutations without requiring a repeat tissue biopsy.

Questions to ask your doctor

Was my colorectal cancer tested for KRAS and NRAS mutations, and which specific mutations were found — or were none found?
Does my result make me eligible or ineligible for anti-EGFR therapy (cetuximab or panitumumab)?
If I have a KRAS G12C mutation, am I eligible for adagrasib plus cetuximab or sotorasib plus panitumumab? If not now, at what point in treatment might these become relevant?
Was my BRAF mutation status also tested, and how does it interact with my KRAS/NRAS result?
Does the location of my tumour (left-sided vs. right-sided) affect whether anti-EGFR therapy is recommended?
Are there clinical trials available for my specific KRAS mutation that I should know about?
If my cancer progresses, should KRAS and NRAS testing be repeated?
Does my KRAS or NRAS result have any implications for my family members?