A RET fusion is a genetic alteration within cancer cells, involving a rearrangement where parts of two different genes combine. This alteration is not inherited but arises spontaneously within tumor cells during a person’s lifetime. Identifying a RET fusion provides significant information for understanding the cancer’s behavior.
The Science Behind RET Fusions
The RET gene normally provides instructions for making a protein that plays a role in cell growth, survival, and development, particularly in nerve cells and certain glandular tissues. This protein acts like a switch, turning on and off to regulate cellular processes. It is part of a complex signaling pathway that ensures cells divide and function appropriately.
A gene fusion occurs when a piece of one gene breaks off and mistakenly joins with a piece of a completely different gene. In the case of a RET fusion, a segment of the RET gene becomes fused to a portion of another gene. This genetic rearrangement results in the creation of a new, abnormal fusion gene that produces a dysfunctional protein.
This newly formed RET fusion protein behaves differently from the normal RET protein. Instead of being regulated, it remains constantly “on,” sending growth signals to the cell. This unregulated signaling drives uncontrolled cell proliferation and survival, promoting cancer development and progression. Understanding this constant “on” switch is central to developing specific therapies.
Associated Cancer Types
RET fusions are found in several types of cancer. They are most commonly observed in certain thyroid cancers, including papillary and medullary thyroid cancers. These fusions are distinct from inherited RET mutations that cause familial medullary thyroid carcinoma.
In non-small cell lung cancer (NSCLC), RET fusions occur in a small percentage of adenocarcinomas, making them a significant driver mutation. The presence of a RET fusion defines a distinct molecular subtype of NSCLC.
Beyond these, RET fusions have also been identified in other malignancies, including colorectal, pancreatic, and salivary gland cancers. This broader presence across different tumor types means that RET fusions are considered “tumor-agnostic,” indicating that their presence, rather than the cancer’s origin site, can guide treatment decisions.
Detection and Diagnosis
Identifying a RET fusion requires specialized laboratory testing, usually performed on a sample of tumor tissue obtained through a biopsy or surgery. In some instances, a blood sample, known as a liquid biopsy, can also be used to detect circulating tumor DNA. Comprehensive biomarker testing is recommended upon cancer diagnosis to uncover such targetable alterations.
One common method for detection is Next-Generation Sequencing (NGS), which can analyze large sections of DNA or RNA from a tumor. NGS can precisely identify various genetic alterations, including gene fusions, by reading the sequence of nucleotides. This approach provides a detailed molecular profile of the tumor.
Another technique is Fluorescence In Situ Hybridization (FISH), a visual test that uses fluorescent probes designed to bind to specific gene sequences. If a RET gene rearrangement or fusion is present, the probes will light up in a distinct pattern, allowing pathologists to visualize the genetic event. Immunohistochemistry (IHC) can also be utilized to detect the abnormal RET fusion protein in tumor cells, indicating the genetic fusion.
Targeted Therapeutic Approaches
The discovery of RET fusions has led to the development of targeted therapies. Unlike traditional chemotherapy, which broadly attacks rapidly dividing cells, targeted therapies interfere with the molecular pathways that drive cancer growth, such as the abnormal RET fusion protein. These medicines block the specific “on” signal that the fusion protein continuously sends.
FDA-approved medications, selpercatinib (Retevmo) and pralsetinib (Gavreto), are RET inhibitors. These small-molecule drugs bind to the active site of the RET fusion protein. By occupying this site, they prevent the protein from sending its unregulated growth signals, effectively turning the “on” switch back “off.” This action halts the uncontrolled proliferation of cancer cells.
Selpercatinib and pralsetinib are highly selective, primarily target the RET fusion protein with minimal impact on other cellular processes. This selectivity contributes to their effectiveness and results in fewer off-target side effects compared to conventional chemotherapy. These therapies represent an advancement in precision oncology, offering a tailored approach for patients whose tumors harbor a RET fusion.
Managing Treatment and Outcomes
For individuals with RET fusion-positive cancers, treatment with targeted RET inhibitors often leads to favorable outcomes, including tumor shrinkage and disease control. While these therapies are highly effective in managing the disease, they are not considered a cure. Treatment continues as long as the medication remains effective and side effects are manageable.
Patients undergoing treatment with RET inhibitors may experience various side effects, which are usually manageable and differ from those associated with chemotherapy. Common side effects include fatigue, high blood pressure, changes in liver enzyme levels, and diarrhea. Regular monitoring by the healthcare team helps address these issues promptly and adjust treatment as needed.
The development of specific RET inhibitors has improved the prognosis for patients with RET fusion-driven cancers compared to historical treatments. These advancements have transformed the treatment landscape, improving patient outcomes. Ongoing research explores ways to optimize these therapies and address potential drug resistance that may develop, ensuring long-term disease management.