RET fusions as primary oncogenic drivers and secondary acquired resistance to EGFR tyrosine kinase inhibitors in patients with non-small-cell lung cancer
Abstract Background RET fusions are rare oncogenic drivers in non-small cell lung cancer (NSCLC). While activating RET rearrangements are found in NSCLC patients harboring epidermal growth factor receptor ( EGFR ) genetic alterations at resistance to EGFR inhibitors, the extent to which co-occurring...
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Published in | Journal of translational medicine Vol. 20; no. 1; pp. 1 - 390 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
BioMed Central Ltd
04.09.2022
BioMed Central BMC |
Subjects | |
Online Access | Get full text |
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Summary: | Abstract
Background
RET
fusions are rare oncogenic drivers in non-small cell lung cancer (NSCLC). While activating
RET
rearrangements are found in NSCLC patients harboring epidermal growth factor receptor (
EGFR
) genetic alterations at resistance to EGFR inhibitors, the extent to which co-occurring genomic alterations exist and how they might affect prognosis or therapy response is poorly understood.
Methods
Targeted next-generation sequencing (NGS) was used to assess 380 baseline patients with primary
RET
fusions and 71
EGFR
-mutated NSCLC patients who acquired
RET
fusions after developing resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs).
Results
Primary
RET
fusions were more likely associated with females and younger age, with
KIF5B
being the predominant fusion partner. In baseline patients, both
SMAD4
(5.3% vs. 0.0%,
P
= 0.044) and
MYC
copy-number gain variants (6.9% vs. 0.0%,
P
= 0.009) were more frequently co-mutated with
KIF5B-RET
than
CCDC6-RET
. By contrast,
CDKN2A
(11.3% vs. 2.4%,
P
= 0.003) mutations were significantly enriched in
CCDC6-RET
-rearranged baseline patients. A significant increase in the proportion of
CCDC6-RET
was observed in acquired
RET
-rearranged patients (47.3% vs. 22.5%,
P
< 0.001). The median progression-free survival (PFS) of patients harboring
RB1
and
TP53
double-mutations (5.5 vs. 10.0 months,
P
= 0.020) or
ERBB2
amplification (5.6 vs. 10.0 months,
P
= 0.041) was significantly shorter than the wild-type counterparts. Moreover, we identified that
RET
fusions were more likely associated with acquired resistance (AR) to third-generation EGFR-TKIs than previous generations of EGFR-TKIs.
Conclusions
In conclusion, we depicted the mutational profiles of NSCLC patients who harbor
RET
fusions at baseline or after resistance to EGFR-TKIs. Furthermore, our results suggest that
RET
fusions mediate secondary resistance to third-generation EGFR-TKIs and might be associated with poor prognosis in patients with NSCLC. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1479-5876 1479-5876 |
DOI: | 10.1186/s12967-022-03593-3 |