The term “RET-positive” cancer does not describe a type of cancer, like lung or thyroid, but a specific genetic characteristic within the cancer cells. The RET gene provides instructions for making a protein involved in cell signaling and growth. In a RET-positive cancer, this gene has undergone an alteration that disrupts its normal function.
The RET protein acts as an accelerator pedal for cell growth; it’s meant to be pressed and released as needed. A RET alteration causes this pedal to become stuck in the “on” position. This leads to constant, uncontrolled signals telling the cells to divide and multiply, which drives the formation and spread of a tumor.
Understanding RET Gene Alterations
Changes to the RET gene that drive cancer happen in two ways. The first is through inherited, or germline, mutations. These mutations are present in every cell of a person’s body from birth, are passed down through families, and create a higher risk of developing certain cancers.
These inherited mutations are associated with a condition called Multiple Endocrine Neoplasia type 2 (MEN2). MEN2 is a hereditary cancer syndrome that creates a high likelihood of developing certain cancers. The specific mutation can help predict the disease’s aggressiveness and guide decisions about preventive measures, such as surgery.
A more common scenario involves somatic alterations, which are acquired during a person’s lifetime and are not inherited. These changes, which can be mutations or a rearrangement called a fusion, occur only within the tumor cells. This means they are not present in the healthy cells of the body and cannot be passed on to children.
Cancers Driven by RET Alterations
RET alterations are most strongly linked with specific types of thyroid and lung cancer. In thyroid malignancies, the connection is particularly strong with medullary thyroid cancer (MTC). A substantial majority of MTC cases, whether sporadic or part of a hereditary syndrome like MEN2, are driven by RET mutations. Patients with MTC often present with a painless lump or nodule in the neck area.
RET alterations, typically fusions rather than mutations, are also found in about 10-20% of papillary thyroid cancers, the most common form of thyroid cancer.
In non-small cell lung cancer (NSCLC), RET alterations represent a distinct subgroup of the disease. Approximately 1-2% of all NSCLC cases are driven by a RET fusion. These cancers are often found in people who are younger than the average lung cancer patient and in individuals who have never smoked or have a light smoking history.
Beyond the thyroid and lungs, RET alterations are rare drivers in other malignancies, accounting for a small percentage of these diseases. When a RET alteration occurs in these cancers, it offers a specific target for therapy. These include:
- Colorectal cancer
- Breast cancer
- Salivary cancer
- Pancreatic cancer
Testing for RET Alterations
To determine if a cancer is RET-positive, doctors perform biomarker or genomic testing. This process analyzes cancer cells for specific genetic markers, including RET alterations, that could be driving the tumor’s growth. The results guide treatment decisions by identifying patients who may benefit from therapies designed to target the RET pathway.
The standard method for this analysis is a tissue biopsy, where a small sample of the tumor is surgically removed and sent to a laboratory. Pathologists then use a technique called Next-Generation Sequencing (NGS). NGS allows for the simultaneous analysis of hundreds of genes, providing a comprehensive profile of the tumor and detecting any RET fusions or mutations.
An alternative method is the liquid biopsy, a simple blood test that detects tiny pieces of DNA tumors shed into the bloodstream, known as circulating tumor DNA (ctDNA). A liquid biopsy can be useful when a traditional tissue biopsy is not feasible due to the tumor’s location or the patient’s health. It can also be used to monitor the cancer’s response to treatment over time.
Targeted Therapies for RET-Positive Cancers
The identification of a RET alteration allows for an approach called targeted therapy. Unlike traditional chemotherapy, which affects all rapidly dividing cells, targeted therapies are designed with greater precision. These drugs block specific molecules involved in cancer growth, leading to fewer side effects. For RET-positive cancers, this means using drugs known as RET inhibitors.
RET inhibitors function by recognizing and binding to the altered RET protein. This action blocks the protein’s signaling activity, effectively turning off the “stuck accelerator” that was promoting uncontrolled cell growth. By halting these growth signals, RET inhibitors can cause tumors to shrink or stop growing.
The U.S. Food and Drug Administration (FDA) has approved specific RET inhibitors for treating patients with RET-positive cancers. Medications such as selpercatinib and pralsetinib have shown effectiveness in treating both RET-fusion positive non-small cell lung cancer and RET-mutated thyroid cancers. These oral medications offer a tailored treatment option for patients whose cancers are defined by this genetic marker.