If you have been told your lung cancer is “RET-positive,” you may have heard the terms RET fusion and RET mutation and wondered what they mean. Here we help you to understand them.
If you or someone you love was recently diagnosed with RET-positive lung cancer, you may have come across two terms that sound almost identical: RET fusion and RET mutation. Although both terms involve RET alterations, they are not exactly the same thing.
First, a Quick Refresher: What Is the RET Gene?
Your body’s cells contain genes, essentially instruction manuals that tell cells how to grow, divide, and behave. One of those genes is called RET, which stands for “rearranged during transfection.” Under normal conditions, the RET gene helps regulate cell growth and plays a role in the development of nerve cells.
Think of it like a light switch. The RET gene is designed to turn on and off at the right times. When something goes wrong with the RET gene and it gets altered, that switch can get stuck in the “on” position — and cells start growing in a way they shouldn’t. That uncontrolled growth is what leads to cancer.
→ For more background, visit our full guide to RET-positive lung cancer.
What Is a RET Mutation?
A RET mutation (also called a point mutation) is essentially a typo in the genetic code. One small section of the RET gene gets misspelled (a single letter in the DNA sequence is changed, deleted, or duplicated) This “typo” changes how the RET protein works, which can cause it to become overactive.
Where is it most commonly found?
RET point mutations are most commonly associated with medullary thyroid cancer, both inherited (familial) and non-inherited (sporadic) forms. They can also occur in other cancer types.
Does this happen in lung cancer?
RET point mutations are not very common in lung cancer. RET fusions are the most commonly found alterations in lung cancer.
What Is a RET Fusion?
A RET fusion (also called RET gene rearrangements) is a different kind of genetic change. Instead of a “typo”, a fusion is more like a cut-and-paste error. A piece of the RET gene accidentally gets stitched together with a completely different gene. The result is an abnormal hybrid protein and it is almost always switched “on”, driving uncontrolled cell growth.
Where is it most commonly found?
RET fusions are the primary driver in RET-positive non-small cell lung cancer (NSCLC). They occur in approximately 1–2% of all NSCLC cases. They can also occur in papillary thyroid cancers.
Who tends to get RET fusion-positive lung cancer?
Research suggests that RET fusions are more commonly found in younger patients (<60), women, and people who have never smoked or smoked very little.
→ Learn more about why RET-positive lung cancer often affects non-smokers.
What genes does RET fuse with?
There are several known fusion partners, the gene that RET accidentally “merges” with. The most common ones in lung cancer are:
- KIF5B–RET — the most frequently identified fusion partner
- CCDC6–RET — the second most common
Does the type of RET fusion matter?
New research has found that RET fusion partners significantly influenced prognosis and therapeutic benefit. Patients with KIF5B-RET fusions experienced shorter progression-free survival (PFS) and overall survival (OS) compared to CCDC6-RET patients, whereas those with CCDC6-RET fusions demonstrated a more indolent disease and greater relative benefit from selective RET inhibitors. Read more about this study here.
In the ARROW pralsetinib study the treatment was effective across different RET fusion subtypes, with longer duration of response (median duration of response (DOR)) in CCDC6 fusions (47.9 months) compared to KIF5B (13.1 months). Read more about this study here.
In the LIBRETTO-431 selpercatinib study, in patients with KIF5B-RET fusion, the median progression-free survival (PFS) was 19.4 months, while mPFS was not reached in patients with CCDC6-RET fusion. The overall response rate (ORR) in patients with KIF5B-RET and CCDC6-RET was 65.3% and 83.0% respectively. Read more about this study here.
In addition to this, research funded by The Happy Lungs Project and led by Dr. John Heymach, is actively studying how different fusion partners affect how tumors respond to targeted therapy and particularly resistance to treatment. Learn more about this study here.
What Are the Treatment Options for RET Mutations or Fusions?
Currently FDA approved RET inhibitors are the primary treatment options for RET-driven cancers including fusions and mutations.
- Selpercatinib (Retevmo) is approved for adults with RET fusion-positive NSCLC and in patients 2 years of age and older with RET-mutant medullary thyroid cancer (MTC), RET fusion-positive thyroid cancer and RET fusion-positive solid tumors.
- Pralsetinib (Gavreto) is approved for adult patients with metastatic RET fusion-positive NSCLC (all type of fusions) and adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)*
→ Get more detail on targeted treatment options for RET fusion-positive NSCLC
How Do You Know Which Alteration You Have?
The way to know which type of alteration you have is through comprehensive biomarker testing, also called molecular testing or genomic testing. This is typically done on a tissue sample from a biopsy or, in some cases, a liquid biopsy (blood test).
If you have been diagnosed with metastatic NSCLC, current guidelines recommend that all patients have comprehensive biomarker testing to check for RET fusions/mutations along with other actionable drivers like EGFR, ALK, KRAS, and others. Knowing your specific tumor driver is the foundation of personalized treatment. Also the recent results of the LIBRETTO-432 trial presented at ASCO 2026 and published here, underscore the importance of comprehensive biomarker testing across all stages of disease including early-stage NSCLC.
If you have not had comprehensive biomarker testing, or if you are unsure what your results mean, it is worth asking your healthcare provider or oncologist specifically: “Was my tumor tested for actionable alterations including RET?”
→ Read more about when and how to ask about biomarker testing.
What Happens at Progression?
If an acquired RET mutation develops during treatment (as an acquired resistance mechanism), your oncologist may discuss adjusted treatment strategies or clinical trial options. This is an active area of research and exactly the kind of science that The Happy Lungs Project is working to advance.
If progression happens your oncologist may recommend to repeat a biopsy and tumor sequencing at the time of progression. Understanding what’s driving resistance through tumor sequencing helps guide next-step treatment decisions, whether that means a different therapy, a clinical trial, or a combination approach.
→ For more on what your RET alterations means at diagnosis and progression, see our resources and post: Resistance to RET treatment and Cracking the Code — What a RET Gene Alteration Means for Your Lung Cancer.
The Bottom Line
- A RET mutation is a spelling error inside the RET gene. It’s most commonly associated with thyroid cancer, not lung cancer though it can appear later as a resistance mechanism during cancer treatment.
- A RET fusion is when the RET gene fuses with a different gene entirely, creating an abnormal hybrid protein. Mainly found in NSCLC and papillary thyroid cancers. There are different types of RET fusions and the most common ones are RET-KIF5B and RET-CCDC6. Patients with KIF5B-RET fusions experienced shorter survival rates compared to CCDC6-RET patients, whereas those with CCDC6-RET fusions demonstrated a more indolent disease and greater relative benefit from selective RET inhibitors.
- FDA approved RET inhibitors are the primary treatment options for RET-driven cancers including fusions and mutations.
References
- American Lung Association. RET and Lung Cancer. Updated January 2026.
- Hoe et al. “Treatment of non–small cell lung cancer with RET rearrangements.” Cancer. 2025. doi:10.1002/cncr.35779
- Gautschi O, et al. “Selpercatinib in RET Fusion–Positive Non–Small Cell Lung Cancer: Final Safety and Efficacy.” J Clin Oncol. 2025.
- National Cancer Institute. Selpercatinib for RET-Positive Lung, Medullary Thyroid Cancers.
