Colorectal cancer is a common malignancy that originates in the colon or rectum. While many cases are managed with standard treatments, a distinct subset of these cancers exhibits a particular molecular characteristic known as HER2 positivity. HER2, or Human Epidermal Growth Factor Receptor 2, refers to a protein located on the surface of cells. When this protein becomes overactive, it can stimulate cell growth and division. Understanding the HER2 status of a colorectal tumor is important because it can guide specific treatment approaches for patients.
Understanding HER2 in Colorectal Cancer
The HER2 protein normally functions as a receptor on the surface of healthy cells, helping to regulate processes like cell growth, division, and repair. It is a member of the epidermal growth factor receptor (EGFR) family, which plays a role in various cellular signaling pathways. When HER2 is activated, it can bind with other receptors in its family, initiating a cascade of events that promote normal cell proliferation.
In some cancer cells, however, the HER2 gene can undergo amplification, leading to an overproduction or overexpression of the HER2 protein on the cell surface. This excess of HER2 receptors can result in uncontrolled cell growth and tumor formation. While most colorectal cancers do not have this alteration, HER2 amplification or overexpression is found in approximately 3% to 5% of colorectal tumors. This makes HER2-positive colorectal cancer a distinct subtype.
Identifying HER2-Positive Colorectal Cancer
Detecting HER2 positivity in colorectal cancer patients is important, as it directly influences treatment decisions. Several laboratory methods are used to assess HER2 status. These tests are performed on tumor tissue obtained from biopsy samples or surgical specimens.
One common testing technique is Immunohistochemistry (IHC), which measures the amount of HER2 protein present on the surface of cancer cells. IHC results are scored from 0 to 3+, with a score of 3+ indicating HER2 overexpression. If an IHC test yields a borderline score, 2+, further testing is often performed to confirm HER2 gene amplification.
Fluorescence In Situ Hybridization (FISH) is another method used to detect HER2 gene amplification. This technique looks for extra copies of the HER2 gene within the cancer cells. Next-Generation Sequencing (NGS) can also identify HER2 gene amplification and even activating HER2 mutations. These comprehensive genomic tests are increasingly used, as they can detect a range of actionable alterations in one analysis.
Targeted Therapies for HER2 Colorectal Cancer
Targeted therapies for HER2-positive colorectal cancer represent a modern approach to treatment, differing from traditional chemotherapy by specifically blocking the overactive HER2 pathway. The Food and Drug Administration (FDA) has granted accelerated approval to the combination of tucatinib and trastuzumab for HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer that has progressed after prior chemotherapy. This combination is considered a preferred option for this patient population.
Monoclonal antibodies are a type of targeted therapy that binds to the HER2 protein on the cell surface, blocking its ability to signal cancer cells to grow. Trastuzumab is a well-established anti-HER2 monoclonal antibody that binds to a specific domain of the HER2 receptor, inhibiting its signaling. Pertuzumab is another monoclonal antibody that targets a different part of the HER2 protein, specifically preventing HER2 from pairing with other HER receptors. When used in combination, like trastuzumab and pertuzumab, these antibodies can provide more comprehensive HER2 inhibition.
Tyrosine kinase inhibitors (TKIs) are small molecule drugs that work by blocking the activity of the HER2 protein from inside the cell. Tucatinib is an example of a TKI that has shown significant activity in combination with trastuzumab for HER2-positive metastatic colorectal cancer. This dual HER2-targeted therapy has resulted in substantial antitumor activity in clinical trials.
Another type of targeted therapy is antibody-drug conjugates (ADCs), which combine a monoclonal antibody with a chemotherapy drug. Fam-trastuzumab deruxtecan-nxki (T-DXd) is an ADC that delivers a potent chemotherapy payload directly to HER2-expressing cancer cells. The antibody portion of T-DXd binds to HER2, and once internalized by the cancer cell, the chemotherapy drug is released, causing DNA damage and cell death, including in neighboring cells. T-DXd has demonstrated activity in previously treated HER2-expressing metastatic colorectal cancers, even in cases where other HER2-targeted regimens have been used. These targeted therapies are often utilized in later lines of treatment for patients whose cancer has progressed on standard chemotherapy regimens.