Ovarian cancer represents a complex disease with varied biological drivers, making personalized treatment approaches increasingly important. For a subset of patients, the presence of a specific molecular feature, the Human Epidermal growth factor Receptor 2 (HER2) protein, dictates the course of the disease and opens the door to specialized therapies. The HER2 protein acts as a biomarker, identifying tumors that may respond uniquely to treatments designed to block its signaling pathways. Understanding this protein’s role and how to precisely detect its presence is fundamental to managing this particular subtype of ovarian malignancy.
Understanding the HER2 Protein
The HER2 protein, also known as ErbB2, is a receptor found on the surface of many human cells and is part of a larger family of epidermal growth factor receptors. This protein is encoded by the \(ERBB2\) gene located on chromosome 17. In healthy cells, HER2 plays a role in regulating cell growth, division, and repair by receiving external signals and transmitting them into the cell interior.
HER2 is unique among its family members because it does not bind directly to a growth factor ligand. Instead, it functions primarily as a partner, readily forming pairs, or dimers, with other activated HER family receptors, such as HER1 or HER3. This dimerization activates a cascade of signals inside the cell, ultimately promoting cell survival and proliferation.
In a cancer setting, the \(ERBB2\) gene can undergo a process called gene amplification, where many extra copies of the gene are created. This increase in gene copies results in a significant “overexpression” of the HER2 protein, meaning the cancer cell surface is covered with an abnormally high number of these receptors. With an abundance of receptors, the cell’s internal signaling pathways become hyperactive and unregulated. The excess HER2 receptors constantly send growth signals, activating pathways like the PI3K/AKT and MAPK pathways, which drive uncontrolled cell division and tumor growth.
Identifying HER2 Status in Ovarian Cancer
HER2 positivity is most frequently observed in certain subtypes of ovarian cancer, notably mucinous and serous carcinomas. The primary method for assessing HER2 status is Immunohistochemistry (IHC), a technique that uses specific antibodies to stain the HER2 protein on the surface of tumor cells. IHC results are reported on a scale from 0 to 3+. A score of 0 or 1+ is considered HER2-negative, indicating a low level of protein expression.
A score of 3+ signifies strong, complete staining of the cell membrane, which is classified as HER2-positive. The intermediate score of 2+ is classified as “equivocal” because it does not definitively confirm protein overexpression driven by gene amplification.
When an IHC result is equivocal (2+), a second test is required to confirm the tumor’s status. This confirmation is typically done using Fluorescence In Situ Hybridization (FISH), which is a molecular test that counts the number of \(ERBB2\) gene copies within the cell nucleus. Only tumors confirmed as HER2-positive (IHC 3+ or IHC 2+ with confirmed gene amplification by FISH) are generally eligible for HER2-targeted treatments.
Targeted Treatment Strategies
The identification of HER2 overexpression transforms the treatment approach, allowing for the use of targeted agents that directly interfere with the protein’s function. The earliest and most recognized therapy is Trastuzumab, a monoclonal antibody designed to bind to the extracellular domain of the HER2 receptor. By binding, Trastuzumab blocks the receptor from engaging in dimerization, thereby halting the hyperactive growth signaling pathways.
Trastuzumab also recruits the body’s immune system to attack the cancer cells, a process known as Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). While Trastuzumab monotherapy has shown limited success in initial ovarian cancer trials, it is often utilized in combination with traditional chemotherapy to enhance its effect.
More recently, a newer class of drugs called Antibody-Drug Conjugates (ADCs) has shown promise for HER2-positive solid tumors, including ovarian cancer. These agents, such as Trastuzumab Deruxtecan (T-DXd), represent a sophisticated delivery system. The ADC consists of a HER2-targeting antibody linked to a potent chemotherapy payload.
The antibody component acts as a “homing device,” binding specifically to the HER2 protein on the cancer cell surface. Once bound, the ADC is internalized by the cell, where the linker is cleaved to release the chemotherapy agent, delivering a high concentration of the cytotoxic drug directly to the tumor while minimizing exposure to healthy tissues.
Another strategy involves dual HER2 blockade, which uses two different anti-HER2 agents to target the receptor from multiple angles. Agents like Pertuzumab, another monoclonal antibody, or Lapatinib, a small-molecule inhibitor that blocks the HER2 receptor’s internal signaling domain, have been explored. This dual approach aims to overcome mechanisms of resistance that can develop when only a single pathway is blocked.