Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes Journal Article
| Authors: | Offin, M.; Chan, J. M.; Tenet, M.; Rizvi, H. A.; Shen, R.; Riely, G. J.; Rekhtman, N.; Daneshbod, Y.; Quintanal-Villalonga, A.; Penson, A.; Hellmann, M. D.; Arcila, M. E.; Ladanyi, M.; Pe'er, D.; Kris, M. G.; Rudin, C. M.; Yu, H. A. |
| Article Title: | Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes |
| Abstract: | Introduction: EGFR-mutant lung cancers are clinically and genomically heterogeneous with concurrent RB transcriptional corepressor 1 (RB1)/tumor protein p53 (TP53) alterations identifying a subset at increased risk for small cell transformation. The genomic alterations that induce lineage plasticity are unknown. Methods: Patients with EGFR/RB1/TP53-mutant lung cancers, identified by next-generation sequencing from 2014 to 2018, were compared to patients with untreated, metastatic EGFR-mutant lung cancers without both RB1 and TP53 alterations. Time to EGFR–tyrosine kinase inhibitor discontinuation, overall survival, SCLC transformation rate, and genomic alterations were evaluated. Results: Patients with EGFR/RB1/TP53-mutant lung cancers represented 5% (43 of 863) of EGFR-mutant lung cancers but were uniquely at risk for transformation (7 of 39, 18%), 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 time to discontinuation than EGFR/TP53- and EGFR-mutant –only cancers (9.5 versus 12.3 versus 36.6 months, respectively, p = 2 × 10-9). The triple-mutant population had a higher incidence of whole-genome doubling compared to NSCLC and SCLC at large (80% versus 34%, p < 5 × 10-9 versus 51%, p < 0.002, respectively) and further enrichment in triple-mutant cancers with eventual small cell histology (seven of seven pre-transformed plus four of four baseline SCLC versus 23 of 32 never transformed, respectively, p = 0.05). Activation-induced cytidine deaminase/apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like mutation signature was also enriched in triple-mutant lung cancers that transformed (false discovery rate = 0.03). Conclusions: 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 whole-genome doubling and Activation-induced cytidine deaminase/apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like hypermutation which may represent early genomic determinants of lineage plasticity. © 2019 |
| Keywords: | tp53; rb1; egfr-mutation; small cell histologic transformation; whole genome doubling |
| Journal Title: | Journal of Thoracic Oncology |
| Volume: | 14 |
| Issue: | 10 |
| ISSN: | 1556-0864 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2019-10-01 |
| Start Page: | 1784 |
| End Page: | 1793 |
| Language: | English |
| DOI: | 10.1016/j.jtho.2019.06.002 |
| PUBMED: | 31228622 |
| PROVIDER: | scopus |
| PMCID: | PMC6764905 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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