Endometrial cancer arises in the lining of the uterus. This type of cancer is the most common gynecologic cancer. Within this disease, a subset of tumors are characterized by alterations in a specific protein called HER2. HER2, or Human Epidermal Growth Factor Receptor 2, is a protein found on the surface of some cancer cells that influences their growth and division. When HER2 is overexpressed or amplified, it contributes to uncontrolled cell proliferation, classifying these tumors as “HER2-positive.”
The Role of HER2 in Endometrial Cancer
HER2, also known as ERBB2, is a gene that produces a receptor protein on the cell surface. This protein relays signals for normal cell functions like growth and division.
In some endometrial cancers, changes occur in the HER2 gene. Gene amplification, where the cell makes too many copies of the HER2 gene, leads to excessive HER2 protein production on the cell surface, known as overexpression. This overexpression causes continuous signaling, triggering uncontrolled cell division and growth.
This uncontrolled cell growth can result in more aggressive tumor behavior and a poorer prognosis compared to tumors without HER2 alterations. Women with HER2-positive endometrial tumors, particularly those with gene amplification, may experience shorter overall survival rates. HER2 overexpression and amplification are more commonly observed in high-grade and advanced-stage endometrial cancers, such as uterine serous carcinoma and carcinosarcoma, which are more aggressive forms of the disease.
Identifying the HER2 status of an endometrial tumor is important for understanding its biological characteristics and guiding treatment decisions. This helps oncologists select therapies that specifically target the HER2 protein, potentially leading to more effective strategies. HER2 gene amplification in high-grade endometrial cancer, specifically uterine serous carcinoma, is approximately 17% to 30%, with protein overexpression observed in up to 80% of these tumors.
Identifying HER2 Positive Endometrial Cancer
After an initial diagnosis of endometrial cancer, typically confirmed through a biopsy, further tests are performed on the tumor tissue to determine its HER2 status. This identifies if the cancer cells have an abnormal amount of HER2 protein or too many copies of the HER2 gene, helping doctors understand the tumor’s characteristics.
One of the primary methods used is Immunohistochemistry (IHC), which detects the amount of HER2 protein present on the surface of cancer cells. A pathologist examines the stained tissue under a microscope and assigns a score based on the intensity and completeness of the HER2 protein staining on the cell membrane. Scores range from 0 to 3+, with 0 indicating no staining and 3+ indicating strong, complete membrane staining in a significant percentage of tumor cells. A score of 3+ by IHC classifies a tumor as HER2-positive.
If the IHC result is 2+, it is considered “equivocal,” meaning the HER2 status cannot be definitively determined by IHC alone. In such cases, another test called Fluorescence In Situ Hybridization (FISH) is performed. FISH directly measures the number of HER2 gene copies within the tumor cells. This test involves using fluorescent probes that bind to the HER2 gene and a control gene on chromosome 17. The ratio of HER2 gene copies to chromosome 17 copies is then calculated.
A HER2/CEP17 ratio of 2.0 or higher, or an average HER2 copy number of 6 or higher per nucleus, indicates HER2 gene amplification, classifying the tumor as HER2-positive. If the IHC score is 0 or 1+, the tumor is considered HER2-negative, and FISH testing is not required. These tests provide a comprehensive assessment of HER2 status, guiding treatment decisions.
Targeted Therapies for HER2 Positive Endometrial Cancer
Identifying HER2-positive status in endometrial cancer allows for the use of specific treatments known as targeted therapies. These drugs interfere with the HER2 protein’s activity, hindering cancer cell growth and survival. Targeted therapies work differently from traditional chemotherapy and often have distinct side effects.
One type of HER2-targeted drug is monoclonal antibodies, such as trastuzumab (Herceptin) and pertuzumab (Perjeta). Trastuzumab is a man-made immune system protein that attaches to the HER2 protein on the surface of cancer cells, blocking its growth-promoting signals. It is often used in combination with chemotherapy, typically carboplatin and paclitaxel, for advanced or recurrent HER2-positive endometrial cancer, particularly uterine serous carcinoma and carcinosarcoma. Pertuzumab binds to a different part of the HER2 protein, inhibiting its ability to pair with other HER family receptors, which can contribute to drug resistance. While the combination of trastuzumab and pertuzumab has shown activity in uterine cancer with HER2 amplification or specific mutations, further studies are needed to confirm efficacy and identify patients most likely to respond.
Another class of targeted therapies includes antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan (Enhertu). This drug combines a HER2 antibody with a chemotherapy drug, deruxtecan. The antibody acts as a “homing device,” delivering chemotherapy directly to HER2-positive cancer cells. This allows for a more focused delivery of the cytotoxic agent, potentially reducing damage to healthy cells. Trastuzumab deruxtecan is an option for advanced or recurrent HER2-positive endometrial cancer after other treatments have been tried, and studies have shown it can lead to a significant objective response rate in patients with HER2-expressing endometrial cancer.