This guide is primarily for stage IV patients with KRAS-mutated MSS colorectal cancer. KRAS mutations may be already present in your tumor, or may be acquired as a result of treatment.
We hope this guide will help you understand how to navigate your treatment options. Don’t worry if you don’t really understand what KRAS or MSS means yet. We will cover that, along with information about the rapidly changing landscape of KRAS-targeted therapies!
Please note, this guide is not really meant for stage II or III patients with a KRAS mutation. We know that many people with earlier-stage cancer may want to know about their mutations and sometimes like to get a “head start” on treatment options in case of progression. However, unless you are currently dealing with stage IV CRC, your KRAS status likely won’t impact your treatment plan.
If your disease is stage I-III, it may make sense for you to be proactive and stay on top of surveillance, including additional tools like ctDNA MRD testing if available to you.
As you learn about KRAS you might land on information about KRAS mutations in OTHER types of cancer. Because cancer is such a complex disease, these mutations act very differently across different cancer types. So make sure you only focus on how it is relevant for KRAS-mutated CRC.
Now that we have those disclaimers out of the way, what does this mutation really mean for you? Read on to learn more.
The big picture
What do I really need to know?
- Everyone with stage IV colorectal cancer should know their KRAS status. There are multiple ways of getting tested. Read more here
- The KRAS mutation is just one facet of your cancer. It can impact treatment choices, but it’s best to look at it in context. For example, how much your cancer has spread when you’re diagnosed, where you have metastases, and your response to chemo seem to be way more important than your particular KRAS mutation.
- KRAS status does change your treatment path, but ONLY if you are stage IV. In general, patients with KRAS mutations can’t receive EGFR inhibitors. There’s some nuance to this, see more below.
- You might hear people call KRAS mutations “undruggable.” To be clear, that doesn’t mean that standard-of-care treatments don’t work! Some KRAS mutations have specific treatments targeting the mutation available now. Other KRAS mutations do not have targeted treatments yet, but research is ongoing. However, this does NOT mean that your disease is untreatable. Standard of care has been thoroughly tested for everyone.
What is a mutation, anyway?
Our bodies are made up of trillions of cells, each containing two copies of cellular DNA. DNA is like an instruction manual that tells cells how to grow, divide and function. When DNA gets damaged, or changes in certain ways, this leads to mutations. Some mutations don’t matter, but others lead to cancer by letting cells grow out of control.
In colorectal cancer, certain mutations are especially important. KRAS is a driver mutation — meaning it helps cancer start or causes it to grow. These mutations happen over time due to aging, inflammation or environmental exposures.
What is KRAS?
RAS is a family of 3 genes: KRAS, HRAS and NRAS. In colorectal cancer, KRAS is the most commonly mutated gene of these three RAS family members.
These genes help control cell growth by sending signals inside the cell. Kind of like flipping a switch, these genes tell the cell when to divide.
In a healthy cell, RAS genes turn on and off at the right times. But if there’s a mutation (especially in KRAS), the gene can get stuck in the “on” position, leading to uncontrolled cell growth and cancer.
There are many types of KRAS mutations (KRAS G12D, KRAS G13D, KRAS G12C, etc) that can be targeted for treatments. More on this below!
Why does it matter?
If you have a KRAS mutation, certain drugs used to treat stage IV cancer called EGFR inhibitors (like cetuximab or panitumumab) are usually not given.
There’s good news if you have a KRAS G12C mutation (a small subset of patients, around 3–4%), because new KRAS G12C inhibitors have recently become available and may be used in combination with other treatments.
A lot of exciting research is focused on targeting KRAS mutations, so we expect more treatment options to emerge soon for other types of KRAS mutations as well.
How do I get my mutations tested?
Doctors test for specific mutations to better understand your cancer and sometimes to guide treatment decisions.
Your oncologist may order KRAS testing when you’re diagnosed. All stage IV patients should have this test done at diagnosis. Your KRAS status may be tested using a tumor biopsy, resected tumor tissue or blood. Common testing methods use an NGS panel or a PCR test, and many of these tests will also provide information on other mutations you may have.
When it comes to CRC, biomarkers including MSS/MSI-H, KRAS and BRAF are all relevant to treatment decisions, so get panel tumor testing done early where many biomarkers including KRAS are tested.
Deep dive
How do I read my test report?
On test reports, KRAS mutations are usually written in a specific format. We’ll go over this below.
Note: If you see “KRAS Wild-Type” or “WT”, that means the test did not detect a KRAS mutation in your cancer.
Here's how test reports work
KRAS mutations are usually written in a specific format: First the gene name, then a letter, a number, and another letter. Each part tells you something specific about the change.
Here’s how it works:
- The name tells you what gene family we’re looking at
- The first letter is the normal (original) amino acid. Amino acids are the building blocks of proteins
- The number is the position where the change happens in the KRAS protein sequence
- The second letter is the mutated amino acid that replaced the original one and results in the changed protein
For example:
KRAS G12D means glycine (G) at position 12 in the KRAS protein is replaced by aspartic acid (D)
Key note: These mutations are NOT interchangable. G12C and G12D are just one letter apart in the alphabet, so you might think that the mutations are similar. You can think of a mutation as a lock, and a targeted treatment as a key. Each key only works on its specific lock.
Why does this matter? These small changes affect how the KRAS protein works and how your cancer responds to certain treatments.
One more note on reading your KRAS mutation status – your report might say G12x or G13x, for example. All this means is that the test used wasn’t designed to specify the mutation, but just shows that the particular position that has been mutated. For all practical purposes, mutations in RAS hotspots (places where the gene is commonly mutated) makes people with those tumors ineligible to get EGFR inhibitors. It doesn’t matter what it is mutated to for you to be ineligible.
So when is it important to know the specific mutation? When there are targeted therapies for a specific mutation, such as KRAS G12C, this is important. Right now we have targeted therapies for KRAS G12C, so if your report says G12x and you have metastatic CRC, ask for an additional test that will provide your specific mutational information.
Are KRAS mutations inherited?
No, KRAS mutations usually don’t come from your family, and you can’t pass KRAS mutations on to your children. KRAS mutations are part of your tumor’s DNA, not your normal cellular DNA! They arise over time, probably due to environmental factors, aging or inflammation.
How common are KRAS mutations?
KRAS mutations are one of the most common mutations in colorectal cancer – found in about 45% of metastatic CRC cases. It is most often associated with “right-sided” colorectal cancer.
And they are super common in a lot of other cancers, too. Here’s a graphic that shows the breakdown of specific KRAS mutations in CRC (with more specifics for G12 since those are most common):
It is important to note that KRAS mutations act differently in different types of cancer, so a treatment that targets a KRAS mutation in, say, lung cancer, may not work the same in CRC. Cancer just isn’t a simple disease!
How does my KRAS mutation affect my prognosis?
Prognosis is one of the trickiest issues in cancer treatment. It is really easy to get caught up on the statistics (believe us, we know!) The bottom line on prognosis is that none of us are a number – we are all individuals with many factors that impact our health.
Some studies say patients with KRAS mutations have worse outcomes, and other studies say they don’t. In general, KRAS mutations in metastatic colorectal cancer do have a modest negative impact on prognosis. The important thing to remember is to pay attention to the specific KRAS mutation studied, as not all KRAS mutations are the same when it comes to prognosis.
The impact of KRAS mutations are not as strong as BRAF mutations, significant tumor burden, or poor ECOG score.
So KRAS is an important biomarker for treatment planning in stage IV CRC, but it’s not a standalone predictor of outcome.
Retesting KRAS mutations
Because your KRAS status affects treatment options (whether or not you might get EGFR inhibitors, for example), it’s a good idea to re-check your KRAS status multiple times throughout your treatment, particularly at disease progression or before changing therapies. Liquid biopsies can be an efficient way to check your KRAS status using blood. For multiple reasons, there may be variations in your KRAS results during treatment. This will help ensure your treatment decisions reflect the current biology of your tumor, not just what was true at diagnosis.
If there is a change in your KRAS status, discuss with your doctor how this may impact your treatment options.
Established treatments
At this time, there’s one important thing to understand in the treatment landscape regarding KRAS mutations. Unless you have KRAS G12C or are entering a clinical trial for another KRAS mutation, your treatment plan is “standard of care.” Read on for a quick overview:
| | KRAS G12C | Other KRAS mutations |
|---|---|---|
|
Stage I-III |
Standard of care (SOC)* |
Standard of care (SOC)* |
|
Stage IV |
First-line — Chemotherapy +/- VEGFi targeted therapy (bevacizumab) |
First line — Chemotherapy +/- VEGFi targeted therapy (bevacizumab) |
* Per NCCN guidelines
You might be asking, wait ― why add an EGFR inhibitor for stage IV patients when KRAS-mutated tumors don’t usually respond? It’s true that so far, patients with KRAS mutations were told that EGFR inhibitors (like cetuximab or panitumumab) don’t work. That’s still true when EGFR inhibitors are used alone or with standard chemotherapy.
But here’s the twist based on new research!
In patients with KRAS G12C mutations, when paired with a KRAS G12C inhibitor like adagrasib or sotorasib, an EGFR inhibitor helps shut down a backup pathway the tumor uses to stay alive. By combining the two treatments, the KRAS G12C inhibitor targets the main tumor growth driver and the EGFR inhibitor blocks the tumor’s escape route.
This dual attack has shown better results in clinical trials than either drug alone, and that’s why this combination is now part of treatment guidelines.
No mutation left behind
Some people are concerned when they hear there aren’t targeted therapies available for their specific mutation, and that they are “just” receiving chemotherapy like FOLFOX or FOLFIRI. Chemo is the most effective treatment for MSS colorectal cancer, whether you have a KRAS mutation or not.
If treatment is a meal, the entree is chemotherapy! You can have different side dishes based on your specific mutation(s). This means whether you have a KRAS mutation or not, chemo is doing the main work for you.
For example, people with KRAS mutations can have a side of bevacizumab. If you have KRAS G12C, your side dishes are tailored to your specific circumstances.
Know that regardless of your mutation, you’ll still have a treatment designed for you.
Emerging treatments
There’s a lot going on in the RAS world these days. With so many new trials launching, this guide could be out of date the moment it’s published. So rather than listing every study, we’ll highlight a few key areas of active research — with the understanding that new strategies may be right around the corner. If you’re interested in learning about specific trials, join COLONTOWN to become part of our RAS CLINIC group.
The NCI RAS Initiative is a major research program led by the National Cancer Institute to find better ways to treat cancers driven by RAS mutations, including KRAS. Once thought “undruggable,” RAS proteins are now the focus of breakthrough science. The initiative brings together experts from government, academia, and industry to develop new drugs, tools, and strategies — all aimed at targeting RAS-driven cancers more effectively.
Researchers are working hard to:
- Bring targeted therapy to first-line and combine with chemotherapy for KRAS G12C
- Develop drugs that target more KRAS mutations, like G12D and G12V
- Improve combinations of KRAS inhibitors and EGFR inhibitors
- Use liquid biopsies to monitor resistance mutations and guide rechallenge therapy
- Develop pan-RAS inhibitors (which target KRAS, NRAS and HRAS mutations) and pan-KRAS inhibitors (these target multiple types of KRAS mutation so patients with different KRAS mutations can be on the same drug)
- Look at new drug combinations that block upstream regulators like SHP2 and SOS1, which help activate KRAS
- Develop drugs for downstream pathway targets like MEK
- Investigate KRAS-targeted vaccines and immunotherapies
The goal of all of these research angles is to shut down the KRAS pathway more completely. Ultimately, the ongoing research and clinical trials will continue to reveal potential treatment strategies, and with them, improved patient outcomes.
Why are some KRAS mutations hard to target?
KRAS is like a master switch inside your cells — when it’s mutated, it can stay permanently “on,” constantly telling the cell to grow and divide. That alone makes it dangerous.
But here’s the real challenge: A KRAS mutation can also activate multiple downstream pathways that fuel cancer growth.
Even if you block one pathway (like EGFR upstream), the KRAS protein can still:
- Trigger the MAPK pathway (which promotes cell division)
- Activate the PI3K pathway (which helps cells survive and resist stress)
- Interact with other signaling networks, allowing the tumor to adapt
Because of this redundancy and flexibility, KRAS-driven cancers are good at finding workarounds — which is what made shutting down KRAS mediated signaling pathways very difficult. In addition, researchers had a very hard time finding effective compounds which could block KRAS mutants from staying on, despite trying very hard for many decades.
Only recently, with breakthroughs like KRAS G12C inhibitors, have researchers found new ways to trap KRAS in its inactive form.
Researchers selected the G12C mutation as the initial study target because the cysteine represented by C is an amino acid with a reactive sulfur group. This allowed researchers to design a molecule to permanently bind to this cysteine, sort of “supergluing” the KRAS protein in its inactive state.
There are dozens of enrolling clinical trials underway testing new ways to stop KRAS mutations in their tracks.
Other mutations such as G12D, G12V, and G13D do not have a reactive cysteine in place of glycine, so G12C inhibitors do not work in these cases. But a lot of research is ongoing, and remember, ALL KRAS mutations used to be considered undruggable!
Want to learn more about RAS mutations?
Want to learn from patients with RAS mutations? Ask to join TOM’S RAS CLINIC for KRAS/NRAS/HRAS+ clinical trials group.
We also recommend you join either TOM’S MSS CLINIC or TOM’S MSI-HIGH CLINIC group (whichever is applicable to you) as you are not limited to enrolling in targeted KRAS trials only.
Want to join COLONTOWN? Fill out the registration form here.
