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Lung cancers with mutations in all three of the same genes make up only a twentieth of the targetable group, but they are the ones that turn into a different cancer, and they stop responding to treatment three times sooner than the rest.
Patients with EGFR, RB1 and TP53-mutant lung cancers identified by next-generation sequencing between 2014 and 2018 were compared with patients with untreated metastatic EGFR-mutant lung cancers lacking both RB1 and TP53 alterations. The triple-mutant group represented 43 of 863 EGFR-mutant lung cancers, 5%, but was uniquely at risk of transformation, 7 of 39, 18%, with no transformations among EGFR-mutant cancers without baseline TP53 and RB1 alterations. Irrespective of transformation, triple-mutant patients had a shorter time to EGFR inhibitor discontinuation than EGFR and TP53-mutant or EGFR-only cancers, 9.5 against 12.3 against 36.6 months. The triple-mutant population had a higher incidence of whole-genome doubling than non-small-cell lung cancer at large, 80% against 34%, further enriched in those that eventually became small-cell, and an APOBEC mutation signature was enriched in the cancers that transformed.
It gives the sequencing report a prognostic reading that does not depend on a repeat biopsy: an EGFR-mutant cancer that also carries RB1 and TP53 alterations will stop responding sooner and should be watched for a change of histology.
Shares Histologic transformation, RB1, Mutagenesis & mutational signatures, Mutational signature.
Shares Histologic transformation, RB1, Lineage plasticity & neuroendocrine transformation, Resistance routes: how a blocked pathway comes back.
Shares Histologic transformation, RB1, Lineage plasticity & neuroendocrine transformation, Resistance routes: how a blocked pathway comes back.
Shares Histologic transformation, Lineage plasticity & neuroendocrine transformation, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired).
Shares Charles M. Rudin, Journal of Thoracic Oncology, Lineage plasticity & neuroendocrine transformation, Memorial Sloan Kettering Cancer Center.
Shares Resistance routes: how a blocked pathway comes back, Clonal evolution & minimal residual disease, Drug resistance (primary and acquired), Memorial Sloan Kettering Cancer Center.
Shares Mutagenesis & mutational signatures, Mutational signature, TP53, Small-cell lung cancer.
Shares Mutagenesis & mutational signatures, Mutational signature, Clonal evolution & minimal residual disease, TP53.