Background
The receptor tyrosine kinase (RTK), RET, is an emerging oncogenic target. Inhibitors targeting activating RET alterations (alts), including on-target resistance alts, are being studied in solid tumors. We present a large cohort of patients (pts) with metastatic solid tumors and somatic RET alts detected by next generation sequencing (NGS) of cell-free DNA (cfDNA). cfDNA provides a global description of RET and other genomic alts in advanced disease, typically exposed to one or more lines of systemic therapy, complementing previous descriptions of RET alts in tissue which is often obtained from early stage/untreated tumors (e.g. TCGA).
Methods
Somatic activating RET alts (fusions/missense alts predicted to be oncogenic) were identified from 32,991 consecutive pts tested with a 68-73 gene cfDNA assay (Guardant Health, CA) between 02/2015-07/2017. This comprehensive NGS assay evaluates single nucleotide variants, and select indels, fusions, and copy number gains. Variants of uncertain significance and synonymous alts were excluded.
Results
175 somatic activating RET alts were detected in 170 pts with non-small cell lung (NSCLC, n=123), colorectal (n=15), breast (n=8), thyroid (n=8), or other cancers (n=13). 141 pts had 142 RET fusions involving 7 different partners, most commonly KIF5B (n=77). Nineteen unique activating RET missense alts were detected in 29 pts, the most common being M918T (n=8). Two pts had multiple activating RET missense alts.
Advanced cancers with activating RET alts commonly harbored additional alts in oncogenic signaling pathway genes: other RTKs (n=57 pts), cell cycle (n=48), MAPK (n=46), PI3K (n=27). The frequency and distribution of alts in these co-occurring pathway genes varied by specific RET alt. Missense RET alts had a lower proportion of co-occurring TP53 alts and a higher proportion of PIK3CA alts compared to RET fusions. Non-KIF5B-RET fusions were enriched for co-occurring alts in MAPK and other RTK genes relative to tumors with KIF5B-RET fusions. In pts with NSCLC, KIF5B-RET fusions were rarely observed with other bona fide oncogenic drivers whereas known EGFR driver alts were identified in pts with CCDC6-RET (10/31), NCOA4-RET (4/14), and TRIM24-RET (1/2) fusions. 12/15 had EGFR T790M and 3/12 had C797S mutations. Prior treatment with anti-EGFR therapy was confirmed in 5 pts. The RET fusion arose without (n=1), concurrent with (n=2), and subsequent to (n=2) emergence of T790M.
Conclusions
In the largest cohort of pts with advanced cancers harboring RET activating alts, we describe novel co-occurrences of oncogenic signaling pathway aberrations. Additionally, our findings suggest that CCDC6- and NCOA4-RET fusions may contribute to anti-EGFR therapy resistance in NSCLC. Understanding the clinical significance of co-occurring alts is essential to evaluating the efficacy of RET-directed therapies.
Citation Format: Karen L. Reckamp, Thereasa A. Rich, Young Kwang Chae, Robert C. Doebele, Wade T. Iams, Michael Oh, Victoria M. Raymond, Richard B. Lanman, Thomas E. Stinchcombe, Vivek Subbiah, David R. Trevarthen, Oliver P. Gautschi. Analysis of cell-free DNA from 32,991 advanced cancers reveals novel co-occurring activating RET alterations and oncogenic signaling pathway aberrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 936.
