Andreev-Drakhlin, Alexander

AbstractActivating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions are potent drivers of oncogenesis. The recent FDA approvals of highly potent and selective RET inhibitors, selpercatinib and pralsetinib, has altered the therapeutic management of RET aberrant tumors. There is ample evidence of the role of RET signaling in certain cancers. RET aberrations as fusions or mutations occur in multiple cancers, however, there is considerable phenotypic diversity. There is emerging data on the lack of responsiveness of immunotherapy in RET-altered cancers. Herein, we review the registrational data from the selective RET-inhibitor trials, and comprehensively explore RET alterations in pan-cancer adult malignancies and their co-alterations. These co-occuring alterations may define the future of RET inhibition from specific selective targeting to customized combination therapies as data are rapidly emerging on both on-target and off-target acquired resistance mechanisms. Fascinatingly, oncogenic RET fusions have been reported to mediate resistance to EGFR inhibition and KRASG12C inhibition.

Abstract Background: Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions have been recognized as potent drivers of oncogenesis in multiple malignancies. Recently, highly potent and selective RET inhibitors, selpercatinib and pralsetinib have been FDA approved for RET fusion+ NSCLC and selpercatinib for RET+ thyroid cancers. Here we present a comprehensive analysis of RET alterations in pan-cancer adult malignancies. Patients and methods: 96,324 samples from 89,754 patients available from AACR Project Genie database version 8 were analyzed for the prevalence of RET fusions, mutations, and copy number alterations in diverse cancer types accessed July 21, 2020. The races of the samples within the cohort were 69,962 (72.6%) white, 5,388 (5.6%) Black, 4,909 (5.1%) Asian, 163 (0.17%) Native American, 48 (0.05%) Pacific Islander, and 15,854 (16.5%) were unknown. Results: There were 56,382 (58.5%) samples from primary tumors, 24,204 (25.1%) samples from unspecified metastasis sites, 4,798 (5.0%) from distant organ metastasis, 1,379 (1.4%) from lymph node metastasis, 1,279 (1.3%) from local recurrence, and 8,282 (8.6%) unknown. In 96,324 tumor samples there were 2,706 (2.81%) RET alterations. This included 223 (0.23%) fusions, 1,689 RET mutations found (1.75%) in 21 tumor histologies, and 794 (0.82%) RET amplifications identified; where the most abundant tissues harboring RET fusions were NSCLC (n = 121), papillary thyroid cancer (n = 53), breast cancer (n = 8) and colorectal cancer (n = 7) and the most abundant tissues harboring RET missense mutations were NSCLC (n = 355), colorectal cancer (n = 292), melanoma (n = 236), and thyroid cancer (n = 127). NSCLC samples with RET fusions had significantly co-altered KRAS, SETD2, PVRL4, EZH1, and RRAGC. Conclusions: RET fusions represent extremely rate events in multiple cancers. RET missense mutations occur in 2% of malignancies. Most RET missense variants are described as variants of unknown significance, limiting the impact of precision oncology for the majority of patients with RET alterations. Further functional characterization of RET variants is warranted because RET is highly targetable with therapeutics. Citation Format: Jacob J. Adashek, Alexander Andreev-Drakhlin, Jason Roszik, Aakash P. Desai, Vivek Subbiah. The landscape of 2,706 RET alterations from 89,754 adult patients with cancer: Clinical implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1221.