Amplification of Wild-Type <i>RET</i> Represents a Novel Molecular Subtype of Several Cancer Types With Clinical Response to Selpercatinib.

Abstract

<i>RET</i> rearrangements and <i>RET</i> activating point mutations represent targetable genomic alterations in advanced solid tumors. However, the frequency and clinicopathologic characteristics of wild-type <i>RET</i> amplification in cancer and its potential role as a targetable oncogenic driver are not well-characterized. 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 <i>RET</i> amplification in the absence of <i>RET</i> 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. The frequency of wild-type <i>RET</i> 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 <i>RET</i> amplification included non-small-cell lung cancer (NSCLC), hepatobiliary cancer, prostate cancer, breast cancer, and others. The median <i>RET</i> copy number in <i>RET</i>-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 <i>RET</i>-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 <i>RET</i> 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. Amplification of wild-type <i>RET</i> represents a novel, targetable molecular subset of cancer.