Data from 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

<div>AbstractPurpose:<p><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.</p>Experimental Design:<p>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.</p>Results:<p>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.</p>Conclusions:<p>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.</p></div>