RET rearrangements (RETr) are uncommon yet emerging oncogenic targets found in RAS/BRAF wild-type colorectal cancers (CRCs), particularly right-sided, MSI-high tumors. We describe the molecular landscape of metastatic CRCs harboring a somatic RETr detected by next generation sequencing (NGS) of cell-free DNA (cfDNA). cfDNA data complement previous descriptions of RETr in tissue, which are limited by small series of patients (pts) and cfDNA also provides a summary of genomic alterations (alts) across multiple metastatic sites in pts typically exposed to one or more lines of therapy.
Between 2/2015-3/2018, somatic RETr were identified among 4,234 consecutive metastatic CRC pts with tumor DNA detected on a 68-73 gene cfDNA assay (Guardant360®, Redwood City, CA). This validated NGS assay evaluates single nucleotide variants, and select indels, fusions, and copy number gains with high sensitivity and analytic specificity. Relevant clinicopathologic correlates were obtained from clinicians.
Seventeen RETr were detected in 16 pts (0.4%). Functionally significant alts in other cancer genes were found in 88% of samples with a RETr (median 9.5 additional alts, max 23). There was a high co-occurrence of canonical KRAS alts (14 alts in 7/16 pts), 5 of whom also had alts in NRAS (n = 4pts), the EGFR extracellular domain (ECD, n = 4), and/or BRAF V600E (n = 3). For 4 pts with available comprehensive tissue NGS results, the RETr was detected in cfDNA only. Two also had KRAS, NRAS, and EGFR ECD alts, one had an EGFR activating alt, and the fourth had a FGFR3 fusion, all detected only in cfDNA. Prior to cfDNA collection, all 4 had progressed on anti-EGFR therapy after a median of 12mo (range 8-16mo) of treatment. Four additional RETr/KRAS+ pts had either a KRAS alt that was not detected in tissue (n = 2) or co-occurred with an ALK fusion and/or BRAF V600E in pts who had prior anti-EGFR therapy (n = 2).
RETr commonly co-occur with RAS/RAF alts in cfDNA, a novel observation. The alt pattern and clinicopatholgoic history suggest RETr contribute to acquired resistance to anti-EGFR therapy in metastatic CRC. Our data also raise the question of whether driver RETr may be associated with primary resistance to anti-EGFR therapy.
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T.A. Rich, V.M. Raymond, Y. Shiotsu, R.B. Lanman: Employee, Stock owner: Guardant Health. Y. Kagawa, Y. Nakamura: Research support: Guardant Health. W. Okamoto: Research support: Guardant Health; Grant funding: MSD. T. Yoshino: Research support: Guardant Health; Grants: MSD KK, Sanofi KK, Sumitomo Dainippon Pharma Co Ltd, Chugai Pharmaceutical Co Ltd, GlaxoSmithKline KK, Nippon Boehringer Ingelheim Co Ltd; Consulting fees: Sanofi KK, Chugai Pharmaceuticals Co Ltd, Eli Lilly Japan, Merck Serono Co Ltd. All other authors have declared no conflicts of interest.