Analysis of Cell-Free DNA from 32,989 Advanced Cancers Reveals Novel Co-occurring Activating <i>RET</i> Alterations and Oncogenic Signaling Pathway Aberrations.

Abstract

<i>RET</i> is an emerging oncogenic target showing promise in phase I/II clinical trials. An understudied aspect of <i>RET</i>-driven cancers is the extent to which co-occurring genomic alterations exist and how they may impact prognosis or therapeutic response. Somatic activating <i>RET</i> alterations were identified among 32,989 consecutive patients with metastatic solid tumors tested with a clinical cell-free circulating tumor DNA (cfDNA) assay. This comprehensive next-generation sequencing (NGS) assay evaluates single-nucleotide variants, and select indels, fusions, and copy number gains in 68-73 clinically relevant cancer genes. A total of 176 somatic activating <i>RET</i> alterations were detected in 170 patients (143 fusions and 33 missense mutations). Patients had non-small cell lung (NSCLC, <i>n</i> = 125), colorectal (<i>n</i> = 15), breast (<i>n</i> = 8), thyroid (<i>n</i> = 8), or other (<i>n</i> = 14) cancers. Alterations in other oncogenic signaling pathway genes were frequently identified in <i>RET</i>-positive samples and varied by specific <i>RET</i> fusion gene partner. <i>RET</i> fusions involving partners other than <i>KIF5B</i> were enriched for alterations in MAPK pathway genes and other bona fide oncogenic drivers of NSCLC, particularly <i>EGFR</i>. Molecular and clinical data revealed that these variants emerged later in the genomic evolution of the tumor as mechanisms of resistance to EGFR tyrosine kinase inhibitors. In the largest cancer cohort with somatic activating <i>RET</i> alterations, we describe novel co-occurrences of oncogenic signaling pathway aberrations. We find that <i>KIF5B</i>-<i>RET</i> fusions are highly specific for NSCLC. In our study, only non-<i>KIF5B</i>-<i>RET</i> fusions contributed to anti-<i>EGFR</i> therapy resistance. Knowledge of specific <i>RET</i> fusion gene partner may have clinical significance.