How can one gene error drive so many different cancers?
The old model assumed each organ's cancer was a distinct disease, but RET fusions show that a single genetic mistake can fuel cancer in the lung, thyroid, pancreas, colon, and elsewhere. RET fusions are found in 1–2% of non-small-cell lung cancers, 10–20% of thyroid cancers, and less than 1% across a wide range of other tumor types [9]. A 2023 survey of over 1,500 thyroid samples found RET fusions in 11.4% of papillary thyroid cancers, and they were three times more common in children and adolescents (29.8%) than in adults (8.7%) [6]. This means the same molecular switch is flipped in very different tissues, which is why a drug that targets that switch can work across all of them.
The evidence goes beyond just finding the fusions—it shows they behave similarly across organs. In a 2022 pan-cancer analysis, RET fusions were identified in 15 different tumor types, including colorectal and breast cancers, with the same fusion partners recurring across them [7]. The most common partners—KIF5B, CCDC6, and NCOA4—appear in lung, thyroid, and colorectal cancers alike [7]. So the fusion isn't just a random passenger; it's a shared driver that unites cancers that were once thought to be completely separate diseases.
Do targeted drugs really work in all these different cancers?
Yes, and that's the core challenge to the organ-by-organ model: the same drug shrinks tumors in many different organs. In the phase 1/2 ARROW trial, pralsetinib produced responses in 57% of patients with 12 different RET fusion-positive tumor types (excluding lung and thyroid), including pancreatic and cholangiocarcinoma [2]. In a separate analysis, all three patients with pancreatic cancer and both with cholangiocarcinoma responded to pralsetinib [3]. These responses were durable, lasting a median of 12 months [2]. This is not a one-off—it's a pattern that holds across multiple tumor types.
The strongest evidence comes from a randomized phase 3 trial in lung cancer, which compared the targeted drug selpercatinib to standard chemotherapy with or without immunotherapy. Selpercatinib doubled progression-free survival (24.8 vs 11.2 months) and shrank tumors in 84% of patients, compared to 65% with standard care [1]. While this trial was in lung cancer, the pan-cancer data from ARROW shows that the same principle applies elsewhere [2][3]. The FDA has even approved these drugs for any solid tumor with a RET fusion, based on this tissue-agnostic evidence [9].
If the model is changing, how do we find these fusions?
Finding RET fusions is trickier than it sounds, and the method matters. A 2021 study found that fluorescence in situ hybridization (FISH), a common test, is sensitive but not specific—it flagged many rearrangements that weren't actually functional fusions [5]. In that study, only 9 of 30 FISH-positive cases were confirmed by RNA sequencing [5]. Another study found that FISH had a sensitivity of 86% and specificity of 99% when using a 19% cutoff, but could be optimized to 100% sensitivity with a three-tier scoring system [8]. The takeaway: a positive FISH result needs confirmation by a more precise method like RNA sequencing.
Liquid biopsies (blood tests) are also emerging, but they don't always match tissue results. A 2025 study across 23 tumor types found significant discrepancies in fusion detection rates between blood and tissue for several genes, including ALK and FGFR2 [4]. For RET specifically, tissue detection was higher in thyroid cancer (3.1%) than blood, but the study didn't find a significant difference for RET in most cancers [4]. This means that while blood tests are promising, they're not yet a substitute for tissue testing when it comes to RET fusions.
About These Sources
This answer is built on 9 peer-reviewed studies — published from 2021 to 2025, 1 from 2024 or later, 4 in Q1 journals, collectively cited 548 times — selected as the most relevant from 15 studies that passed quality screening, drawn from 81 papers retrieved from a database of over 500 million.
Sources used in this answer
First-Line Selpercatinib or Chemotherapy and Pembrolizumab in <i>RET</i> Fusion–Positive NSCLC
In a randomized phase 3 trial, selpercatinib doubled progression-free survival (24.8 vs 11.2 months) and improved response rate (84% vs 65%) compared to chemo-immunotherapy in first-line RET fusion-positive NSCLC.
Pan-cancer efficacy of pralsetinib in patients with RET fusion–positive solid tumors from the phase 1/2 ARROW trial
In the phase 1/2 ARROW trial, pralsetinib produced a 57% response rate across 12 different RET fusion-positive tumor types (excluding lung and thyroid), with responses independent of tumor type or fusion partner.
Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with <i>RET</i> fusion–positive solid tumors.
In an earlier ARROW analysis, pralsetinib achieved a 50% response rate in RET fusion-positive solid tumors other than lung and thyroid, including responses in all pancreatic and cholangiocarcinoma patients.
Abstract 2108: Comparative analysis of fusion gene detection rates in tissue versus blood samples from Chinese diverse solid tumors
A 2025 study across 23 tumor types found significant discrepancies in fusion detection rates between tissue and blood samples for several genes, but not for RET in most cancers.
RET Fluorescence In Situ Hybridization Analysis Is a Sensitive but Highly Unspecific Screening Method for RET Fusions in Lung Cancer
A study of 4,873 NSCLC patients found FISH is sensitive but unspecific for RET fusions, with only 9 of 30 FISH-positive cases confirmed by RNA sequencing.
RET fusion genes in pediatric and adult thyroid carcinomas: cohort characteristics and prognosis
In a cohort of 1,564 thyroid samples, RET fusions were found in 11.4% of papillary thyroid cancers, three times more often in pediatric/adolescent patients, and were associated with aggressive features.
Pan-tumor survey of RET fusions as detected by next-generation RNA sequencing identified RET fusion positive colorectal carcinoma as a unique molecular subset
A pan-tumor RNA sequencing survey identified RET fusions in 15 tumor types, with colorectal cancer as a unique molecular subset (high TMB, often MSI-H).
Analytical Accuracy of RET Fusion Detection by Break-Apart Fluorescence In Situ Hybridization
A validation study of RET break-apart FISH found a 19% cutoff gave 86% sensitivity and 99% specificity, but a three-tier scoring system improved sensitivity to 100%.
Precision oncology with selective RET inhibitor selpercatinib in <i>RET</i>-rearranged cancers
A review of selpercatinib in RET-rearranged cancers summarizes the tissue-agnostic activity that led to FDA approval, with RET fusions present in ~2% of NSCLC and 10-20% of thyroid cancers.