HER2 in Colorectal Cancer

by Jason Wasserman MD PhD FRCPC
March 25, 2026

HER2 — also known as ERBB2 — is a gene that drives the growth of cancer cells when it is overactive. Although HER2 amplification is best known in breast and gastric cancers, it also occurs in colorectal cancer and, until recently, was a finding without a dedicated treatment. That has changed substantially. Two HER2-targeted therapies are now approved for HER2-positive metastatic colorectal cancer, and the field is advancing quickly. Finding a HER2 alteration in a colorectal cancer is now an actionable result — it opens the door to specific treatments. Also, it explains why a tumour may have stopped responding to anti-EGFR therapy. Understanding what HER2 testing means for colorectal cancer is therefore increasingly important for patients navigating their treatment options.

What HER2 is and what it does

HER2 is a gene that provides instructions for making a protein — the HER2 receptor — that sits on the surface of cells and helps receive signals telling the cell to grow and divide. In a healthy cell, a normal amount of HER2 protein is present and helps regulate cell growth in a controlled way. When the HER2 gene is amplified — meaning extra copies of the gene are present — the cell produces far too much HER2 protein. This floods the cell surface with receptors that continuously send growth signals, even when the cell should stop dividing. The result is uncontrolled cell proliferation that drives tumour growth.

In most colorectal cancers, HER2 amplification and overexpression are caused by a somatic alteration — a change that occurs in the cancer cells during a person’s lifetime, not one inherited from a parent. Less commonly, HER2 can also carry activating point mutations (changes in a single location in the gene) that permanently activate the HER2 receptor. Both amplification and activating mutations make HER2 a potential target for treatment.

How common is HER2 alteration in colorectal cancer?

HER2 amplification or overexpression is present in approximately 3-5% of colorectal cancers overall. However, this frequency is considerably higher in specific subgroups. Among patients with RAS wild-type, BRAF wild-type colorectal cancer — the group most likely to be considered for anti-EGFR therapy — HER2 amplification is found in approximately 6 to 8% of cases.

HER2-amplified colorectal cancers have a characteristic profile that distinguishes them from other colorectal cancer subtypes:

Left-sided tumour location. HER2 amplification is significantly more common in left-sided colorectal cancers (descending colon, sigmoid colon, and rectum) than in right-sided ones. This contrasts with BRAF V600E mutations, which are more common on the right side.
RAS and BRAF wild-type status. HER2 amplification and KRAS, NRAS, or BRAF mutations are largely mutually exclusive — they very rarely occur in the same tumour. This means that HER2 amplification is found almost exclusively in tumours that are RAS and BRAF wild-type.
Anti-EGFR resistance. HER2 amplification is one of the reasons why some RAS/BRAF wild-type tumours do not respond to anti-EGFR therapy (cetuximab or panitumumab) as expected. The HER2 pathway can drive tumour growth independently of EGFR, bypassing the drug’s effect. HER2 testing is therefore relevant both as a treatment target and as an explanation for resistance.

Why is the test done

To identify eligibility for HER2-targeted therapy

Two HER2-targeted treatment regimens are now FDA-approved for patients with HER2-positive metastatic colorectal cancer, and HER2 amplification or overexpression must be identified before these treatments are considered. Current guidelines recommend HER2 testing for all patients with metastatic colorectal cancer as part of standard molecular profiling.

To explain resistance to anti-EGFR therapy

In patients with RAS/BRAF wild-type colorectal cancer who do not respond to anti-EGFR therapy, or whose tumours progress after an initial response, HER2 amplification is one of the mechanisms that can explain this resistance. Identifying HER2 amplification in this context is clinically useful because it points to a treatment strategy — HER2-targeted therapy — that may remain effective even when anti-EGFR drugs are not.

To provide prognostic context

HER2 amplification may be associated with a modestly less favourable prognosis in some studies, though this finding is not consistent across all datasets. The treatment implications of a HER2-positive result are currently more important than its prognostic significance.

How the test is performed

HER2 testing in colorectal cancer is performed on tumour tissue from a biopsy or surgically removed specimen. The testing approach differs somewhat from HER2 testing in breast cancer, because colorectal cancer cells display different staining patterns, and the criteria for calling a result “positive” have been adapted specifically for colorectal cancer.

Immunohistochemistry (IHC)

Immunohistochemistry (IHC) is typically the first step. This test uses antibodies to stain tissue sections for the HER2 protein, and a pathologist evaluates the staining pattern and intensity under the microscope. Results are reported on a scale of 0 to 3+:

0 (negative). No staining or minimal staining in fewer than 10% of tumour cells. The tumour is HER2-negative.
1+ (negative). Faint or barely perceptible incomplete membrane staining in 10% or more of tumour cells. The tumour is HER2-negative.
2+ (equivocal). Moderate to complete membrane staining in 10% or more of tumour cells, or strong complete membrane staining in fewer than 10% of cells. The result is uncertain and requires additional testing with FISH or NGS to determine whether the HER2 gene is truly amplified.
3+ (positive). Strong, complete membrane staining in 10% or more of tumour cells. The tumour is HER2-positive.

It is worth noting that IHC criteria for HER2 positivity in colorectal cancer use a higher threshold than breast cancer — a finding of strong staining needs to be present in at least 10% of cells (rather than just 1 cell, as in breast cancer), reflecting the different biology and higher degree of tumour heterogeneity seen in colorectal cancer.

Fluorescence in situ hybridization (FISH) and in situ hybridization (ISH)

FISH (or a related technique called ISH) directly counts the number of copies of the HER2 gene in tumour cells. If the gene is amplified — meaning there are significantly more copies than normal — the result is FISH-positive, confirming HER2 amplification. FISH is usually performed when the IHC result is 2+ (equivocal) to resolve whether true amplification is present.

Next-generation sequencing (NGS)

Next-generation sequencing (NGS) panels can simultaneously detect HER2 gene amplification and HER2 point mutations, as well as KRAS, NRAS, BRAF, MMR status, and many other cancer-related genes. As comprehensive molecular profiling becomes routine in metastatic colorectal cancer, NGS is increasingly used to detect HER2 alterations alongside all other relevant biomarkers in a single test.

How results are reported

HER2 results in colorectal cancer are reported in the molecular testing or biomarker section of your pathology report. Common ways results are described include:

HER2-negative (IHC 0 or 1+). The tumour does not show meaningful HER2 protein overexpression. HER2-targeted therapy is not indicated based on this result.
HER2 equivocal (IHC 2+). The result is uncertain. Additional testing with FISH or NGS is needed to determine whether HER2 gene amplification is present. Your report may note that reflex testing has been or will be ordered.
HER2-positive (IHC 3+, or IHC 2+ with FISH/ISH amplification confirmed). The tumour overexpresses the HER2 protein and/or shows HER2 gene amplification. This result may make a patient eligible for HER2-targeted therapy.
HER2 amplification by NGS. If tested by next-generation sequencing, the report may describe HER2 amplification as a gene copy number gain, with or without accompanying protein overexpression data. The clinical interpretation depends on the degree of amplification and the overall testing context.
HER2 mutation detected. Less commonly, NGS may identify an activating point mutation in HER2 rather than amplification. The treatment implications of HER2 mutations are still being defined, and your oncologist will explain what the specific mutation means for your situation.

What the result means

HER2-negative

A HER2-negative result means HER2-targeted therapy is not indicated based on this test. This is the most common result, as HER2 amplification is present in only a small proportion of colorectal cancers. HER2 negativity does not affect eligibility for other treatments — your care team will assess treatment options based on your RAS, BRAF, MMR, and other biomarker results.

HER2 equivocal (IHC 2+)

An equivocal result means the IHC staining falls within an intermediate range, which cannot conclusively determine whether meaningful HER2 overexpression is present. Additional testing — typically FISH or ISH — will be performed to check whether the HER2 gene itself is amplified. If FISH confirms amplification, the tumour is reclassified as HER2-positive. If amplification is not confirmed, it is reclassified as HER2-negative. If your result is currently 2+, your care team will explain whether reflex testing has been ordered and what to expect next.

HER2-positive

A HER2-positive result — confirmed by IHC 3+ staining or by FISH-confirmed amplification in an IHC 2+ case — is an actionable finding in metastatic colorectal cancer. It means your tumour is driven partly by overactivation of the HER2 receptor, and HER2-targeted therapies may be effective. Two approved regimens are now available, and the treatment decision will depend on your prior treatment history, RAS mutation status, and other clinical factors (see the treatment section below).

If your tumour is HER2-positive, it is also very likely to be RAS and BRAF wild-type, since these alterations rarely co-exist with HER2 amplification. This means that anti-EGFR therapy (cetuximab or panitumumab) might otherwise have been considered for your cancer, but HER2 amplification is a known mechanism of resistance to anti-EGFR drugs, and HER2-targeted therapy is likely to be a better option for this molecular subgroup.

Treatment implications of HER2-positive colorectal cancer

HER2-positive colorectal cancer was, for many years, treated the same as HER2-negative disease, simply because no approved HER2-targeted options existed. The past two years have changed this. Two distinct HER2-targeted regimens are now FDA-approved for previously treated HER2-positive metastatic colorectal cancer, and first-line trials are ongoing.

Tucatinib plus trastuzumab (MOUNTAINEER)

Tucatinib (Tukysa) is a targeted therapy that selectively inhibits the HER2 protein’s internal signalling domain (it is called a tyrosine kinase inhibitor, or TKI). Trastuzumab (Herceptin) is a monoclonal antibody — a laboratory-made protein — that binds directly to the outside of the HER2 receptor, blocking its activity. Together, they attack HER2 from two different angles simultaneously.

In January 2023, the FDA granted accelerated approval to tucatinib plus trastuzumab for patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that had progressed after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This was the first-ever FDA-approved HER2-targeted treatment specifically for colorectal cancer. The approval was based on the MOUNTAINEER trial, in which 84 patients received the combination. The overall response rate was 38%, and the median duration of response was 12.4 months, with 81% of responders maintaining their response for at least 6 months. In a disease where standard third-line options have limited effectiveness, these results represented a meaningful advance.

An important eligibility requirement for tucatinib plus trastuzumab is that the tumour must be RAS wild-type (meaning no KRAS or NRAS mutations). This is not a coincidence — as described above, HER2 amplification and RAS mutations very rarely co-exist in the same tumour, so most HER2-positive colorectal cancers will automatically meet this criterion. If your tumour is HER2-positive, your oncologist will confirm your RAS status as part of treatment planning.

Trastuzumab deruxtecan (Enhertu; T-DXd)

Trastuzumab deruxtecan (T-DXd; brand name Enhertu) is a different type of drug called an antibody-drug conjugate. It works by combining trastuzumab — the same HER2-targeting antibody described above — with a chemotherapy payload called deruxtecan. Trastuzumab acts as a delivery vehicle, targeting cells that express the HER2 receptor on their surface. Once the drug binds to HER2 and is pulled into the cancer cell, it releases the chemotherapy agent directly inside, killing the cell from within. This design makes T-DXd more targeted than conventional chemotherapy while retaining potent cancer-killing activity.

In August 2024, the FDA granted accelerated approval to T-DXd for adult patients with any unresectable or metastatic HER2-positive (IHC 3+) solid tumour who have received prior systemic therapy and have no satisfactory alternative treatment options. This was a tumour-agnostic approval — meaning it covers multiple cancer types, including colorectal cancer — based in part on data from the DESTINY-CRC02 trial. In the colorectal cancer cohort of that trial, the overall response rate was approximately 38-47%, with notably stronger responses in patients whose tumours showed IHC 3+ staining (response rate approximately 61%) compared to IHC 2+/FISH-positive tumours. Unlike tucatinib plus trastuzumab, T-DXd does not carry a RAS wild-type restriction, meaning it may be considered even in RAS-mutated HER2-positive colorectal cancers in some circumstances.

T-DXd carries a specific safety concern called interstitial lung disease (ILD) — inflammation of the lung tissue — which has been observed across clinical trials of this drug in multiple cancer types. This is a potentially serious side effect that requires careful monitoring, and your oncologist will discuss the risk and monitoring plan with you if T-DXd is considered.

How your oncologist chooses between these options

The choice between tucatinib plus trastuzumab and T-DXd — and the sequencing of these with other treatments — will depend on factors including your RAS mutation status, prior treatment history, whether you have already received anti-HER2 therapy, your overall health, and the specific characteristics of your cancer. Both drugs are currently approved in the previously treated setting (after prior chemotherapy), and the use of HER2-targeted therapy earlier in the treatment sequence is being investigated in clinical trials. Your oncologist will discuss which option, if any, is appropriate for your situation.

The future of HER2-targeted treatment in colorectal cancer

Research into HER2-targeted therapy for colorectal cancer is very active. The phase III MOUNTAINEER-03 trial is evaluating tucatinib plus trastuzumab in combination with mFOLFOX6 chemotherapy as a first-line treatment for HER2-positive metastatic colorectal cancer, which could eventually move HER2-targeted therapy to the front of treatment rather than after multiple prior lines. Other combinations are also being explored. Patients with HER2-positive colorectal cancer may have access to relevant clinical trials, and asking your oncologist about these options is worthwhile.

HER2 as a resistance mechanism to anti-EGFR therapy

For patients who have RAS/BRAF wild-type colorectal cancer and are being considered for or have received anti-EGFR therapy, HER2 amplification is particularly relevant. When a tumour carries HER2 amplification, blocking the EGFR receptor with cetuximab or panitumumab often has limited effect, because the cancer is already receiving growth signals from the overabundant HER2 pathway — a separate route that anti-EGFR drugs do not block. This means HER2-positive tumours may appear to be good candidates for anti-EGFR therapy on paper (because they are RAS and BRAF wild-type), but in practice, do not respond as expected.

This is one reason why testing for HER2 — alongside RAS, BRAF, and tumour sidedness — provides a more complete picture of anti-EGFR eligibility than RAS/BRAF testing alone. Some oncologists now consider HER2 status when initially planning anti-EGFR therapy for metastatic colorectal cancer, particularly in settings where comprehensive molecular profiling is available upfront.

Does HER2 status have hereditary implications?

In colorectal cancer, HER2 amplification and HER2 mutations are almost always somatic — they arise in the cancer cells during a person’s lifetime and are not inherited. A HER2 result in a colorectal cancer does not mean your family members face an elevated cancer risk from this finding, and it does not prompt genetic counselling or family testing on its own. Hereditary colorectal cancer risk is evaluated through MMR/MSI testing (for Lynch syndrome) and other clinical assessments — not through HER2 status.

What happens next

If your HER2 result has recently come back, the next steps depend on your situation:

If your result is HER2-negative (IHC 0 or 1+), HER2-targeted therapy is not indicated. Your treatment plan will proceed based on your other biomarker results and the stage of your cancer.
If your result is HER2 equivocal (IHC 2+), additional testing — typically FISH or ISH — will be needed to determine whether the HER2 gene is amplified. Your care team will arrange this and explain the next steps once confirmation testing is complete.
If your result is HER2-positive, your oncologist will discuss whether you are eligible for tucatinib plus trastuzumab, T-DXd, or both, depending on your prior treatment history, RAS status, and overall health. If you are earlier in your treatment course, your oncologist may also mention relevant clinical trials studying HER2-targeted therapy in the first-line setting.

It is also worth noting that HER2 status can occasionally change over time or differ between the primary tumour and metastatic sites — a phenomenon known as tumour heterogeneity. If your cancer has progressed or has been re-biopsied, retesting of HER2 status may occasionally be warranted, particularly if the original result was borderline or if prior anti-HER2 therapy has been given. Your oncologist will advise on whether retesting is relevant in your case.

Questions to ask your doctor

Was my colorectal cancer tested for HER2 amplification or overexpression, and what was the result?
If my result was IHC 2+ (equivocal), has FISH or NGS been ordered to confirm or rule out HER2 amplification?
If my tumour is HER2-positive, am I eligible for tucatinib plus trastuzumab, or trastuzumab deruxtecan?
Does my RAS mutation status affect which HER2-targeted therapy I might be offered?
Could HER2 amplification explain why my tumour didn’t respond well to anti-EGFR therapy?
Are there clinical trials studying HER2-targeted therapy that I should know about?
Does my HER2 result have any implications for my family members?