RET Biomarker

Rearranged during transfection (RET) is anoncogene responsible for producing the RET protein. Oncogenes are genes that are a part of the host’s DNA that are abnormally altered as cells divide and that can lead to the development of cancer. DNA is the material that allows the body to make proteins that are the building blocks of living things.  

A wild-type RET (or RET-negative) protein acts as an “on-and-off” switch that binds other proteins to activate pathways associated with cell growth, migration, and survival.

RET alterations (or RET-positive) include both RET mutations (genomic changes) and RET fusions. RET gene fusions occur as the result of RET becoming fused (or stuck) to another unrelated gene, leading to the production of a RET fusion protein. In both cases, abnormal proteins are produced and these proteins often can only function as “on” switch, which results in uncontrollable cell growth, which may lead to cancer. Often this change is likened to a car with a stuck accelerator pedal that causes the driver to lose control of a car.

RET can function as a predictive biomarker, as it helps medical providers to understand how a patient’s tumor may respond to a treatment. 

RET alterations are rare in colorectal cancer, with less than 3% of colorectal cancer patients having alterations in RET. RET gene fusions, one type of RET alteration, are present in less than 1% of metastatic colorectal cancers.

There are currently no guidelines for RET biomarker testing in colorectal cancer. However, patients with locally advanced or metastatic CRC that has progressed despite systemic therapies may be recommended to have their tumor tested for cancer- causing genetic changes including the RET biomarker.

The most common method for RET biomarker testing is using next generation sequencing to identify RET mutations or fusions using tumor tissue samples.

The best way to determine whether RET biomarker testing is right for you is to ask your medical care provider.

A report for your RET biomarker may be reported as “RET wild-type,” “RET WT,” or “RET-negative” if there are no alterations in RET present. If there is a RET alteration, it may be listed as “RET-positive or RET mutated or RET-mt.” Depending upon your RET alteration, the report will often specify whether you have a RET fusion or a RET mutation.  

While rare in colorectal cancer, alterations in RET can help guide treatment decisions.

If your tumor is  RET-negative, it does not have a RET alteration. 

• Treatment options may be tailored based on the status of other biomarkers.

If your tumor is RET-positive, it does have a RET alteration. This alteration may be a mutation or a gene fusion. 

• Your treatment options depend on your tumor’s specific RET alteration.
• There is an FDA-approved targeted therapy to treat colorectal cancer with a RET gene fusion, selpercatinib.
  • Selpercatinib is a RET inhibitor therapy that selectively inhibits the RET protein. RET alterations lead to an abnormal protein that is always “on” leading to cancer cell growth. RET inhibitors, such as selpercatinib, function by turning “off” production of this abnormal protein to slow or stop the growth of cancer cells. 
  • The use of selpercatinib is FDA-approved for all locally advanced or metastatic solid tumors with RET gene fusions, including colorectal cancer, that have progressed despite other treatment approaches.