Amplification of Wild-Type RET Represents a Novel Molecular Subtype of Several Cancer Types With Clinical Response to Selpercatinib

Abstract

Purpose: RET rearrangements and RET activating point mutations represent targetable genomic alterations in advanced solid tumors. However, the frequency and clinicopathologic characteristics of wild-type RET amplification in cancer and its potential role as a targetable oncogenic driver are not well-characterized.

Methods: In two institutional cohorts of patients with solid cancers from the Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC) whose tumors underwent next-generation sequencing (NGS), the frequency and clinicopathologic features of wild-type RET amplification in the absence of RET rearrangements or activating mutations was assessed. The findings were validated using merged data from The Cancer Genome Atlas (TCGA), Genomics Evidence Neoplasia Information Exchange (GENIE), and China Pan-Cancer data sets.

Results: The frequency of wild-type RET amplification across all solid cancers was 0.08% (26 of 32,505) in the DFCI cohort, 0.05% (26 of 53,152) in the MSKCC cohort, and 0.25% (71 of 28,623) in the cohort from TCGA, GENIE, and China Pan-Cancer. Cancer types with RET amplification included non-small-cell lung cancer (NSCLC), hepatobiliary cancer, prostate cancer, breast cancer, and others. The median RET copy number in RET-amplified cases was 7.5 (range, 6-36) in the DFCI cohort and 5.7 (range, 4-27.7) in the MSKCC cohort. Among 11 RET-amplified NSCLCs, eight had no other concurrent driver mutations. Finally, we report on a 69-year-old man with recurrent NSCLC harboring high-level wild-type RET amplification (22-28 copies) as the only identified putative genomic driver who experienced both a systemic and intracranial confirmed response to the RET inhibitor selpercatinib.

Conclusion: Amplification of wild-type RET represents a novel, targetable molecular subset of cancer.

FIG 1.

(A) Frequency of wild-type RET amplification overall and by individual cancer type in a pan-cancer cohort of 32,505 sequenced solid tumor cases from DFCI. (B) Frequency of wild-type RET amplification overall and by individual cancer type in a pan-cancer cohort of 53,152 solid tumor cases from MSKCC. (C) Frequency of wild-type RET amplification overall and by individual cancer type in 28,623 solid tumor cases from the TCGA Pan-Cancer Atlas, GENIE (excluding cases from DFCI and MSKCC), and the China Pan-Cancer data sets. For all three bar graphs (A-C), cancer types displayed are those with a frequency of >1% of the cohort and those in which >1 RET-amplified case was identified. Data Supplement (Table A2) summarizes frequencies across all observed cancer types. DFCI, Dana-Farber Cancer Institute; GENIE, Genomics Evidence Neoplasia Information Exchange; MSKCC, Memorial Sloan Kettering Cancer Center; NSCLC, non–small-cell lung cancer; TCGA, The Cancer Genome Atlas.

FIG 2.

(A) Copy number plot from NGS of the right axillary lymph node recurrence showing high-level RET amplification. The red arrow denotes the position of the RET gene along chromosome 10. The vertical dashed line represents the centromere position. (B) FISH of formalin-fixed paraffin-embedded tissue from the right axillary lymph node recurrence. The red 5′ probe covers most of the RET gene and sequences upstream of RET while the green 3′ probe is outside and downstream to RET. (C) Quantification of total RET intragenic transcript count (ie, all splice variants) using a targeted RNA NGS fusion assay by anchored multiplexed PCR in the patient case at diagnosis and recurrence compared with the mean intragenic transcript count from a historical cohort of NSCLC controls between 2015 and 2022. (D) CT imaging demonstrates a response to selpercatinib in the right axillary lymph node. (E) Contrast-enhanced brain MRI shows a response to selpercatinib in a right inferior frontal lobe metastasis. CT, computed tomography; FISH, fluorescence in situ hybridization; MRI, magnetic resonance imaging; NGS, next-generation sequencing; NSCLC, non–small-cell lung cancer; PCR, polymerase chain reaction.