Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes

Abstract

EGFR -mutant lung cancers are clinically and genomically heterogeneous with concurrent RB1/TP53 alterations identifying a subset at increased risk for small cell transformation. The genomic alterations that induce lineage plasticity are unknown. Patients with EGFR/RB1/TP53 -mutant lung cancers, identified by NGS from 2014–2018, were compared to patients with untreated, metastatic EGFR -mutant lung cancers without both RB1 - and TP53 -alterations. Time to EGFR-tyrosine kinase inhibitor (EGFR-TKI) discontinuation (TTD), overall survival, SCLC transformation rate, and genomic alterations were evaluated. Patients with EGFR/RB1/TP53 -mutant lung cancers represented 5% (43/863) of EGFR -mutant lung cancers but were uniquely at risk for transformation (18%, 7/39), with no transformations in EGFR -mutant lung cancers without baseline TP53 and RB1 alterations. Irrespective of transformation, patients with EGFR/TP53/RB1 -mutant lung cancers had a shorter TTD than EGFR / TP53 and EGFR -mutant only cancers (9.5 vs 12.3 vs 36.6 months respectively, p = 2×10 −9 ). The triple-mutant population had a higher incidence of whole genome doubling (WGD) compared to NSCLC and SCLC at large (80% vs 34%, p < 5×10 −9 ; vs 51%, p < 0.002 respectively) and further enrichment in triple-mutant cancers with eventual small cell histology (7/7 pre-transformed plus 4/4 baseline SCLC vs 23/32 never transformed respectively, p = 0.05). AID/APOBEC mutation signature was also enriched in triple-mutant lung cancers that transformed (FDR = 0.03). EGFR/TP53/RB1 -mutant lung cancers are at unique risk of histologic transformation, with 25% presenting with de novo SCLC or eventual small cell transformation. Triple-mutant lung cancers are enriched in WGD and AID/APOBEC hypermutation which may represent early genomic determinants of lineage plasticity.